Open Access Repository of Indian Theses

Madapa, Jaipal

Abstract 
i 
 
 
The thesis entitled “Synthesis of Structurally Diversified Spirooxindole and 3-
Alkylidene Oxindole Heterocycles via Aryne and Alkyne Insertion; Total 
Synthesis of Spindomycin-B” has been divided into four chapters. Chapter-I deals 
with the introduction to spirooxindoles, 3-alkylidene oxindoles and arynes. Chapter-
II deals with the synthesis of indanone fused and cyclopentannulated spirooxindoles. 
Chapter-III deals with the synthesis of 3-spirocyclohexanyl-2-oxindoles and total 
synthesis of spindomycin-B. Chapter-IV deals with the synthesis of 3-alkylidene 
oxindole heterocycles. 
Chapter-I: Introduction to spirooxindoles, 3-alkylidene oxindoles and arynes. 
Spirooxindoles: 
 
 
Figure 1: Spirooxidole motif 
Spirocyclic compounds have been prevalent in organic synthesis due to their unique 
three dimensional structures, as well as their broad range of biological activity 
profiles. In particular, during the past decade spirooxindoles have emerged as 
attractive synthetic targets because of their occurrence in numerous natural products 
and biologically active molecules. The key structural features of these spirooxindoles 
are characterized by the presence of wide-ranging spiro rings fused at the C3 
position of the oxindole core, in particular with diverse heterocyclic and carbocyclic 
motifs.  Few representative examples of numerous natural products (e.g., 1−5, Figure 
2) and pharmacologically relevant drugs (e.g., 6−10, Figure 2) representing 
structural diversity shown here. Spirooxindoles seems to be promising candidates for 
drug discovery, since they incorporate both oxindole and heterocyclic moieties 
simultaneously.  A number of spirooxindoles have shown different degrees of 
anticancer activities mainly based on the spiro rings fused at the C3 position of 
oxindole scaffold and substituents on the oxindole nucleus. Among these, many 
Abstract 
ii 
 
natural spirooxindoles like spirotryprostatins A (1) and B (2) also shown excellent 
anticancer activities. More importantly, some synthetic spirooxindoles such as MI-
888 (6) and NITD 609 (7, Fig. 2) have been in preclinical research for the treatment 
of human cancers and malaria respectively. 
 
 
Figure 2: Natural and Synthetic lead compounds with spirooxindole scaffold 
3-Alkylidene oxindoles: 
 
Figure 3: 3-Alkylidene oxindole core 
3-Alkylidene oxindoles represent a privileged scaffold in medicinal chemistry, as 
they are ubiquitous in wide range of pharmaceutical agents and biologically active 
molecules. In addition to their therapeutic value, they are also useful intermediates in 
total synthesis, frequently exploited in cycloaddition reactions to gain access to 
Abstract 
iii 
 
spirocyclic oxindole natural products. Many of which exhibit potent biological 
activities, such as anticancer, antibacterial, antifungal, antiviral and antiangiogenic 
properties. For instance, sunitinib (SU11248, 11) is a orally active receptor tyrosine 
kinase (RTK) inhibitor marketed by Pfizer as Sutent
®
 and was approved by the FDA 
in 2006 for the treatment of advanced renal cell carcinoma and gastrointestinal 
stromal tumours.  
 
Figure 4: Synthetic drug(Sutent
®
) with 3-alkylidene oxindole moiety 
Despite the large number of 3-alkylidene oxindoles isolated from natural sources 
display significant biological activities (Figure 5, 12–16), the synthetically 
developed  3-alkylidene oxindoles have also been found to display significant 
biological activities and many are drug candidates in the market (Figure 5, 17–20). 
 
 
 
Figure 5: Natural and synthetic compounds with 3-alkylidene oxindole core 
 
Abstract 
iv 
 
Arynes: 
In the preceding decade, aryne chemistry has re-emerged as a powerful synthetic tool 
for synthesizing biologically active complex natural products and diverse chemical 
entities. Benzyne or 1,2-dehydrobenzene is an extremely reactive species due to the 
nature of its strained triple bond formed by the overlap of two sp
2
 orbitals orthogonal 
to the aromatic π-system (see Figure 6). The weakness of the bond due to poor 
orbital overlap produces a highly unstable, electrophilic intermediate which has to be 
generated in situ. This intermediate cannot be isolated under most reaction 
conditions; thus, it must be trapped in situ.  
 
Figure 6: (a) Ortho-Benzyne; (b) Overlap of p-orbitals to form aromatic π-system; 
(c) Overlap of sp
2 
orbitals to form strained p-bond 
 
Generally, arynes are quite electrophilic. Thus, a broad range of nucleophiles are 
capable of reacting with an aryne, and this reactivity has been exploited to a great 
extent in organic synthesis.  
Kobayashi method for generation of benzyne: 
In 1983, Kobayashi first introduced a new mild method for generating benzyne by 
the fluoride-induced 1,2-elimination of o-(trimethylsilyl)aryl triflates (scheme 1). 
Synthetic chemists have been attracted to Kobayashi’s method for its convenience, 
efficiency, tolerance of functional groups, and mild reaction conditions. Thus, aryne 
chemistry has quickly emerged as an important synthetic tool  in the field of 
synthetic organic chemistry. 
 
 
Scheme 1: Kobayashi method for generation of aryne 
Aryne Reactions: 
The synthetic applications of arynes are remarkably diverse and a large number of 
aryne reactions found in the literature can be classified into several main categories 
Abstract 
v 
 
shown in (Figure 7). Mainly aryne reactions are categorised into arylation, insertion, 
annulation and transition- metal catalyzed and multicomponent reactions. 
 
 
Figure-7: Representative reactions of benzyne 
 
Chapter-II: Synthesis of indanone fused and cyclopentannulated 
spirooxindoles: 
In this chapter, we reported a transition-metal free, one-pot access to 3,3-five 
membered fused carbocylic spirooxindoles through the incorporation of arynes and 
activated alkynes (as alkynones) into 3-carboethoxy methyl oxindoles to furnish 
diverse range of spirooxindoles.  
 
Figure-1: Natural and Synthetic spirooxindoles containing five membered spiro-
fusion 
Abstract 
vi 
 
3,3'-five membered (carbocyclic or heterocyclic) ring fused spirooxindole motifs are 
found in numerous natural products and pharmaceutically lead compounds. These 
spirooxindoles exhibits wide spectrum of biological activities like anticancer, 
antiviral, antifungal, and antimigraine activities. Representative natural products 
citrinadin B 1 (anticancer), notoamide B 2 (anticancer), spirotryptostatin A 3 
(antimitotic), prosugatoxin 4 (anti-nicotinic), Horsifiline 8 (analgesic) and 
pharmaceutically lead compounds XEN 907 5 (sodium channel blocker), MI77301 6 
(anticancer), XEN402 7 (analegesic & chronic pain)  are showed in (Figure 1, 1-8). 
Owing to the importance of 5-membered spirocyclic oxindoles, for the first time we 
have developed an efficient method for the synthesis of pharmaceutically relevant 
indanone fused  and cyclopentannulated spirooxindoles in high yields by reacting 
various 3-carboethoxy methyl oxindoles with arynes  and ynenones. 
 Towards this initially we have studied the reaction of variously substituted 3-
carboethoxy methyl oxindoles with arynes in the presence of CsF as base in THF at 
100 
o
C to deliver the anticipated indanone fused spirooxindoles in decent yields 
(Table 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abstract 
vii 
 
Table 1: Synthesis of various substituted indanone fused spirooxindoles. 
 
 
 
 
Abstract 
viii 
 
 
It was predicted that the reaction occurs through the cyclopentenoid intermediate to 
deliver the spirooxindoles. 
 
Scheme 1: Plausible mechanism for the formation of indanone fused spirooxindoles 
Synthesis of cyclopentannulated spirooxindoles:  
After the successful demonstration of arynes with 3-carboethoxy methyl oxindoles, 
we have also studied the reaction of alkynes (as alkynones) with 3-carboethoxy 
methyl oxindoles to extend the scope and potentiality of the reaction. In this study, 
we have obtained cyclopentannulated spirooxindoles in good yields by reacting 3-
carboethoxy methyl oxindoles with alkynes in the presence of Cs2CO3 as a base in 
DMF at room temperature as shown in (Table 2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abstract 
ix 
 
Table 2: Synthesis of various substituted cyclopentannulated spirooxindoles 
 
 
 
 
 
 
Abstract 
x 
 
The possible mechanism for the formation of the cyclopentannulated spirooxindoles 
is depicted in Scheme 2. 
 
Scheme-2:  Plausible reaction mechanism for the formation of spirooxindoles 
In conclusion, we have developed a new efficient method for the synthesis of 
indanone fused and cyclopentannulated spirooxindoles via aryne and alkyne 
incorporation, in one-pot, transition-metal free operation and successfully 
synthesized various substituted indanone fused cyclopentannulated spirooxindoles in 
good yields. Synthesized compounds were characterized by 
1
H & 
13
C, IR, HRMS 
spectral studies, and also confirmed by analyzing one of scaffold with single crystal 
X-Ray analysis. Utilising this method we synthesized 31 new spirooxindole 
molecules and submitted these scaffolds for national mol bank for screening their 
biological properties. 
Chapter-III: Synthesis of 3-spirocyclohexanyl-2-oxindoles and total synthesis of 
spindomycin B: 
In this chapter a novel and one-pot approach for accessing 6-membered 
spirooxindoles and the synthesis of spindomycin B is discussed.  
 Spirooxindoles those embodying a 3,3’-fused six-membered rings are often 
found in many bioactive natural products and are considered as privileged scaffolds 
in medicinal chemistry.
 
The spirooxindole motif is essential for the biological 
activity of the molecule, and therefore play an important role in the synthesis of new 
pharmaceutical products. Representative natural products include spindomycin A 1 
and B 2 (tyrosine kinase inhibitor), gelsemine 3, gelseverine 4 (antidepressant), 
Abstract 
xi 
 
maremycin F 5 and synthetic compounds satavaptan 6 (hyponatremia), 7 (MDM2-
p53 inhibitor) and NITD609 8, a potent antimalarial lead in nanomolar scale which 
kills the blood strain of Plasmodium falciparum (Figure 1, 1-8). The synthesis of 
spirooxindoles has been an active research field because of their numerous 
applications. There is continuing interest in the development of improved methods 
for the synthesis of spirooxindoles. Owing to their importance as one of the most 
represented building block in natural bioactive products. The continuous 
development of different routes to spirooxindoles has been a growing field in 
medicinal chemistry. 
 
Figure-1: 3,3’-Fused six-membered spirooxindoles  
Our own interest in 3-spirocyclohexanyl-2-oxindoles, has led to the development of 
an efficient domino protocol (Michael addition followed by SNAr) for the synthesis 
of pharmaceutically relevant 3-spirocyclohexanyl fused  spirooxindoles in high 
yields. Accordilingly, various substituted oxindoles were treated with several ortho 
bromo ynenones at 100 
o
C using Cs2CO3 as the base,  to give the corresponding 
products. Shown in (Table 1). 
Abstract 
xii 
 
Table 1:  Reaction of various substituted oxindoles with o-bromoaryl ynones  
 
 
 
Abstract 
xiii 
 
 
Scheme -1: Plausible reaction mechanism for the spirooxindole formation 
  
After successful spiroannulation of oxindoles with o-bromoaryl ynones via Michael 
followed by SNAr reaction, we have also implemented similar protocol on β-
bromoalkenyl ynones to explore the scope of our domino reaction. 
 Accordingly, various substituted oxindoles  were engaged with readily 
obtainable diverse cylic β-bromoalkenyl ynones under our optimized conditions 
(Cs2CO3, DMF, 100 
o
C) to afford the corresponding tetracyclic spiroannulated 
compounds, in good yields, as shown Table 2. 
 
 
 
 
 
 
 
 
 
 
Abstract 
xiv 
 
Table 2: Reaction of various substituted oxindoles with β-bromoalkenyl ynones 
 
Abstract 
xv 
 
 
 
Scheme 2: Plausible mechanism Tandem Michael addition followed by addition-
elimination (AdNE) reactions (A→B→C→13a).  
Total synthesis of alkaloid spindomycin B: 
To further evaluate the scope and efficiency of our one-pot β-bromoalkenyl ynone 
mediated oxindole spiroannulation methodology, we extended it to β-bromoalkenyl 
enones as partners for oxindole and synthesized recently isolated natural product 
spindomycin B. 
 
Figure 3 
These tetracyclic alkaloids were isolated from rhizosphere strain Streptomyces sp. 
xzqh-9 in 2014 by X. Deng et. al., and their structures and absolute configuration 
have been determined through 2D NMR and electronic circular dichroism (ECD). 
Among the two sibling alkaloids spindomycin B displayed weak (30µM) inhibitory 
activity against tyrosine kinase Bcr-Abl implicated in chronic myeloid leukemia 
(CML).  
 
 
Abstract 
xvi 
 
Retrosynthetic analysis of spindomycin B: 
While looking at the molecule in retrosynthetic perspective, it can be cleaved at 
enolic hydroxy to get compound 16, which can be synthesized using Rubottom 
oxidation followed by DMP oxidation. Compound 16 inturn is disconnected at 
benzylic linkage to give two fragments 17 and 18. Both the fragments 17 and 18 can 
be coupled using our domino process (Michael addition followed by AdNE). The 
fragment 18 can be accessed from commercially available cylopentanone, whereas 
the fragment 17 can be prepared from known protocol starting from commercially 
available oxindole (Scheme 7). 
 
Scheme-3: Retrosynthetic analysis for spindomycin B 
Synthesis of fragment 18: 
 
Scheme-4: Synthesis of fragment 20 
We began our synthesis for fragment 18 from the commercially available 
cyclopentanone, which was converted to its corresponding 2-bromocyclopent-1-
enecarbaldehyde using known Vilsmeier–Haack reaction protocol to afford 
compound 19 in 60% yield. The compound 19 was treated with 
propenylmagnesiumbromide in THF (2.0 M in THF) at -78 
o
C to obtain vinylic 
alcohol 20 in 80% yield. The compound 20 was converted to the corresponding keto 
using IBX in DMSO at room temperature to give compound 18 in 81% yield 
(Scheme 4).  
Abstract 
xvii 
 
Coupling of  17 and 18: 
The reaction between N-methyl oxindole 17 and cross conjugated -
bromocyclopentenyl enone 18 probed under optimized conditions (Cs2CO3, DMF, 
100 
o
C) to afford the expected spiroannulated tetracyclic oxindole 16 as a mixture of 
inseparable diastereomers and was as such elaborated to diastereomeric α-
hydroxyketones 21 following Rubottom oxidation protocol. Thus, 16 with LiHMDS 
and TMSCl afforded silyl-enol ether, which upon further epoxidation with mCPBA 
and TBAF exposure led to α-hydroxyketone 21 as a mixture of diastereomers. DMP 
(Dess-Martin periodinane) oxidation of 21 and concomitant enolization afforded 
spindomycin B (15) in 53% overall yield. The spectral data of the synthetic 
spindomycin B was found to be identical with that reported natural product. We also 
determined the structure by investigating its single crystal   X-ray analysis Scheme 5. 
Scheme-5: Synthesis of spindomycin B 
In conclusion, we have developed a one-pot, metal free spiroannulation strategy to 
conveniently access 3-spirocyclohexanyl-2-oxindole motif from oxindoles and -
bromoaryl ynones and further extended this domino protocol to -bromoalkenyl 
ynones and -bromoalkenyl enones. As an application of this new method, the first 
total synthesis of tetracyclic alkaloid spindomycin B has been accomplished.  
Abstract 
xviii 
 
Chapter-IV : Synthesis of 3-alkylidene oxindole heterocycles: 
In this chapter we reported a simple and an efficient method for the synthesis of 3-
alkylidene oxindoles via a base promoted Michael addition followed by double bond 
migration reaction, endowed with an interesting 3-alkylidene oxindole moiety 
suitable for further elaboration (indole, quinoline, pyridine and  pyran derivatives) . 
 3-alkylidene oxindoles are found in various biologically active natural 
products, pharmaceutical lead compounds and important synthetic intermediates in 
accessing the complex natural products. This class of compounds always a valuable 
targets for both synthetic and medicinal chemists. Characteristic examples of natural 
and synthetic 3-alkylidene oxindoles 1-8 are shown in Figure 1. Representative 
synthetic drug candidates that structurally features 3-alkylidene oxindole is 
nintedanib 5 (idiopathic pulmonary fibrosis (IPF), non-small-cell lung cancer) 
approved by the FDA in 2014. Sunitinib 6 (renal cell carcinoma and gastrointestinal 
and stromal tumours) approved by FDA in 2006. Natural product soulieotine 4 
(inflammatory analgesic), that fall into the class of 3-alkylidene oxindoles. 3-
alkylidene oxindoles are benzofused γ-lactam holding exocylic olefins known for 
their vinylogus reactivity, and crucial for the spirocyclization reactions.  
 
Abstract 
xix 
 
 
Figure 1: Natural and synthetic compounds with 3-alkylidene oxindoles 
Preparation of 3-alkylidene oxindoles using ynones and oxindoles were so far not 
reported. We developed a novel method for the preparation of substituted 3-
alkylidene oxindoles in high yields by reaction of yneones with a N-alkyl oxindoles 
at room temperature using Cs2CO3 as a base shown in Table 1. 
 
 
 
 
 
 
 
Abstract 
xx 
 
Table 1: Reaction of various substituted oxindoles with aryl ynones 
 
 
 
Abstract 
xxi 
 
 
 
Scheme 1: Plausible reaction mechanism 
 
In conclusion, we have developed a novel and efficient strategy for accessing 3-
alkylidene oxindoles via Michael addition followed by double bond migration of 
oxindoles & alkynones. A series of N-arylated, α,β-unsaturated ynones were 
rearranged to 3-alkylidene oxindoles selectively by using mild base with good 
yields.  
 
 
 
 
 
 


English

SYNTHESIS OF STRUCTURALLY DIVERSIFIED SPIROOXINDOLE AND 3-ALKYLIDENE OXINDOLE HETEROCYCLES VIA ARYNE AND ALKYNE INSERTION; TOTAL SYNTHESIS OF SPINDOMYCIN-B

Vanipenta, Yamini

FORMAL TOTAL SYNTHESIS OF MANDELALIDE A AND SYNTHETIC STUDIES OF TIANCHIMYCIN A AND MADEIROLIDE A

GADDAM, SASHIVINAY KUMAR

 Page XIV 
 
Targeted Delivery of shRNA to Cancer Cell 
Abstract 
Novel targeted delivery for shRNA was developed by exploiting bacterial minicells. In this 
work, shRNA against VEGF A was packaged in minicells. These minicells were linked with 
folic acid for active targeting of tumor cells via folate receptor in vitro and in vivo. In order to 
achieve this, E.coli PB114 was selected as a minicell producing strain. Subsequently, E.coli 
PB114 was transformed with pEZ43G-D in order to confirm segregation of plasmid DNA 
into the minicells. Minicells were purified from E.coli PB114 pEZ43G-D by a combination of 
ceftriaxone lysis and filtration. Ultrapure minicells have been obtained by this new method. 
Total number of minicells was found to be 3.81 × 1010 minicells/ml from 200 ml of starting 
culture. Cancer cell lines, LNCaP, HeLa and KB have been selected as positive control 
whereas A549 was selected as negative control in terms of folate receptor overexpression. 
shRNA expression vectors, psNIPERDH1A1 and psNIPERDU6A2, were transfected in 
selected cell lines and gene expression of VEGF A was analyzed by reverse transcriptase PCR 
in order to validate gene silencing of VEGF A. Both the expression vectors were found to 
downregulate VEGF A mRNA but psNIPERDU6A2 silenced VEGF A more efficiently, 
hence psNIPERDU6A2 was selected for in vitro and in vivo delivery. In vitro delivery was 
studied by delivering 109 minicells from each the group, 1) FAminicellspSUPERneoScramble 2) 
minicellspsNIPERDU6A2, 3) FAminicellspsNIPERDU6A2 in selected cell lines and expression of VEGF 
A was analysed by RT-PCR.  Expression of VEGF A did not changed in any of the group in 
A549 cell line. In contrast, expression of VEGF A reduced significantly in 
FAminicellspsNIPERDU6A2 treated group when compared with other two groups in positive 
control cell lines. Moreover, uptake of folic acid conjugated minicells was found to be 
through receptor mediated endocytosis. Tumor xenograft of A549, LNCaP and KB cells were 
developed in immunosuppressed C57 BL6 mice. Animals were divided in four groups and 
treated with 1) Saline, and 109 of respective minicells 2) FAminicellspSUPERneoScramble 3) 
minicellspsNIPERDU6A2, 4) FAminicellsPSNIPERDU6A2 intravenously. There was a gradual increase 
in the tumor volume till the end of treatment in all four groups of A549 xenograft. Whereas in 
case of LNCaP and KB xenograft, there was a significant decrease in tumor volume in 
FAminicellspsNIPERDU6A2 treated group as compared to other groups. Similarly, expression of 
VEGF A was found to be same in all the groups when compared with the saline treated group 
 Page XV 
 
in A549 xenograft. On the contrary, significant downregulation of VEGF A was found in 
FA
minicellsPSNIPERDU6A2 treated LNCaP and KB xenograft. Finally, In vivo biodistribution 
study of FITC loaded FAminicellspsNIPERDU6A2 revealed majority of fluorescence localize in the 
tumor followed by liver and heart. These results suggest that majority of 
FAminicellspsNIPERDU6A2 were distributed in tumor tissue which can be attributed to both 
passive and active targeting of FAminicellspsNIPERDU6A2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


COTTONSEED OIL - A SOURCE OF IONIZABLE POLYOLS TO DEVELOP WATERBORNE POLYURETHANE AND ITS COPOLYMER DISPERSIONS FOR COATING APPLICATIONS

Reddy, V. Veerabhadra

“Developing a novel synthetic methodologies and their application to the total synthesis of Ternatusine A, Nojirimycin analogues, Boronolide,Anamarine, 8-epispicegerolide

G, Chaithanya Kumar

ZERO DIVISOR GRAPHS OF POSETS
A Thesis submitted to the
University of Pune
for the degree of
Doctor of Philosophy
in Mathematics
By
Ms. Anagha Uday Khiste
Under the guidance of
Dr. Vinayak V. Joshi
Department of Mathematics
University of Pune
Pune 411 007
(INDIA)
February, 2014
Abstract
In 1988, Beck [10] introduced the notion of coloring of a commutative
ring R. Let G be a simple graph whose vertices are the elements of R
and two vertices x and y are adjacent if xy = 0. The graph G is known
as the zero divisor graph of R. He conjectured that, the chromatic
number (G) of G is same as the clique number !(G) of G. In 1993,
Anderson and Naseer [1] gave an example of a commutative local ring
R with 32 elements for which (G) > !(G).
Further, this concept of zero divisor graphs is well studied in alge-
braic structures such as rings, semigroups; see Anderson et. al. [1, 2],
F. DeMeyer et. al. [14, 15], LaGrange [31, 32], Redmond [53, 54],
and in ordered structure such as lattices, meet-semilattices, posets and
qosets; see Alizadeh et. al. [9], Estaji and Khashyarmanesh [17], Halas
and Langer [21], Joshi et. al. [27, 28, 29], Lu and Wu [37], Nimbhorkar
et. al. [48, 49, 68].
In this Thesis, we deal with the basic properties such as connectivity,
diameter, girth (gr), eccentricity (e), radius (r), center, cut-set, clique
number (!), chromatic number (), domination number () etc. of the
iv
vzero divisor graph of a poset and its complement. This Thesis contains
four chapters.
In the rst Chapter, we relate lattice properties of a distributive lat-
tice L with graph properties of the corresponding zero divisor graph,
Gf0g(L). Cycles in Gf0g(L) are investigated. Also an algebraic and a
topological characterization is given for the graph Gf0g(L) to be tri-
angulated or hyper-triangulated. Further, we study edge chromatic
number 0 of Gf0g(L).
In Chapter two, we study the zero divisor graph of a Boolean poset.
We determine the diameter, radius, center, eccentricity and domination
number of the zero divisor graph of a Boolean poset.
It is easy to observe that the non-isomorphic posets may have iso-
morphic zero divisor graph. In view of this, the following problem is
worth to study.
Problem 2: Find the class P of posets for which G(P ) = G(Q) if
and only if P = Q for P;Q 2 P .
We partially answer this problem by proving that the class of Boolean
posets is contained in P .
One of the main problems in the theory of zero divisor graphs is
the realization of zero divisor graphs. LaGrange [32] characterized the
graphs which are realizable as zero divisor graphs of Boolean rings
while Lu and Wu [37] considered this problem for general posets. In
this Chapter, we also considered the realization problem for Boolean
posets.
vi
Chapter three deals with (GI(L))
c, the complement of the zero-
divisor graph GI(L) with respect to a semiprime ideal I of a bounded
lattice L. We have obtained necessary and sucient conditions for
(GI(L))
c to be connected and also determined its diameter, radius,
center and girth. Further, we have calculated the vertex chromatic
number of (GI(L))
c, where L = 2n. Also a form of Beck's conjecture
is proved for GI(L) when !((GI(L))
c) <1. In the last section of this
Chapter, we study the cut-sets in (GI(L))
c.
The fourth Chapter is devoted for the study of matrices over lat-
tices. The concept of matrices over Boolean algebra was rst studied
by Luce [38]. He proved that the set of matrices over a Boolean al-
gebra forms a lattice ordered semigroup with zero. Rutherford [55]
studied the eigenvalue problem for Boolean matrices. Further, this
concept was generalized for more general class of distributive lattices
by Tan in [60, 62], see also [30, 40, 61]. Redmond [53] introduced the
concept of zero divisor graphs over a non-commutative ring. Among
non-commutative rings, matrix rings have received special attention in
[11, 13, 42]. Motivated with the work of Redmond [53] about zero divi-
sor graphs of non-commutative rings, we have studied the zero divisor
graphs of matrices over lattices.
In this Chapter, we study the basic properties such as connectivity,
diameter and girth of the zero divisor graph  (Mn(L)) of nn matrices
over a lattice L with 0. Further, we consider the zero divisor graph
 (M2(Cn)) of 2  2 matrices over an n-element chain Cn. We have
vii
determined the domination number of  (M2(Cn)). Also we have shown
that Beck's Conjecture is true for  (M2(Cn)). Further, we have proved
that  (M2(Cn)) is a hyper-triangulated graph.
Lemmas, Theorems, Remarks and Denitions are numbered con-
sequently in each chapter without making distinction between them.
Figures are sectionally numbered. References and Index are given at
the end of the Thesis. References are listed alphabetically and yearwise.
The end of the proof is indicated by the symbol 2.
Place: Pune Ms Anagha U. Khiste
Date: 28th February 2014.
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BIBLIOGRAPHY ix
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Studies towards the synthesis of bio-active lactones: Phostriecin, Portentol and Thermolides

G.K., KIRAN

Synopsis 
i 
 
ELECTROCHEMICAL SYNTHESIS OF INORGANIC MATERIALS AND 
THEIR APPLICATION AS ANODES FOR Li-ION BATTERIES 
A Synopsis 
The major concern of materials chemistry is to synthesize materials with a predetermined 
structure, morphology and orientation.  The conventional ceramic method results in the 
formation of thermodynamically stable phases. Many low temperature methods have been 
introduced in order to synthesize the desired materials in novel structures, controlled 
morphology and growth direction. Among these, electrosynthesis is an ambient 
temperature technique. Since the reaction takes place within the electric double layer 
close to the electrode, the products are deposited as thin and thick films or coatings with 
good adherence to the substrate. Further, the potential gradient at the electric double layer 
is of the order 10
5
 V cm
-1
. Under this gradient the reactant moieties are highly polarized 
and thereby product obtained could potentially be different from that obtained by 
chemical synthesis. Thus phase selection, morphology and crystal growth can be 
kinetically and thermodynamically controlled by the use of electrochemistry. 
Lithium ion batteries are presently the prime energy source for portable electronic 
devices. They have a long life span, high energy density and are environmentally safe. 
With the exception of LiFePO4 and anatase TiO2, lithium ion batteries do not show any 
memory effects. Carbonaceous materials such as graphite, cokes and graphitized carbons 
are commercially used as anode materials in Li-ion batteries. Recently 3d transition metal 
oxides have been extensively studied as anode materials because of their high specific 
capacity, high volumetric energy density and safety. The mechanism of action of metal 
oxide anodes differs from that of carbonaceous materials. In place of the well known 
reversible intercalation mechanism, metal oxide anodes involve a conversion process in 
Synopsis 
ii 
 
which Li2O forms during charge and decomposes during discharge along with the 
concomitant reversible reduction of the transition metal oxide.  
In general, preparation of metal oxide anodes for Li-ion batteries involves a two-step 
process. 
1. Synthesis of the required metal oxide at high temperature. 
2. Fabrication of the electrode by smearing or spin coating of metal oxides 
slurries on a suitable substrate along with carbon powder as conducting 
additive and a polymer binder. 
In this thesis, we combine the one-step electrosynthesis of films and coatings of 
inorganic materials with their application as anodes for lithium ion batteries. This thesis 
consists of eight chapters. A brief description of each chapter is given below. 
Chapter 1: Introduction 
In the first chapter, special emphasis is given to contemporary concerns in materials 
chemistry. A detailed discussion on employing electrochemistry to address these concerns 
is presented. A brief description on electrodeposition of transition metal oxides and their 
application in Li-ion batteries is given.  
Chapter 2: Electrodeposition of crystalline and amorphous CaCO3 on stainless steel 
substrates in the presence of complexing agents 
Highly crystalline calcite CaCO3 was deposited by cathodic reduction of a calcium 
bicarbonate bath in the presence of different aminecarboxylic acids as complexing agents. 
In presence of 5 mole% Sr, the coatings obtained were X-ray amorphous. In the absence 
of Sr, the powder X-ray diffraction (PXRD) patterns of the as-deposited coatings obtained 
from the bath with [DTPA]/[Ca
2+
] ratio < 1, (DTPA: diethylenetriaminepentaacetic acid) 
Synopsis 
iii 
 
exhibit all the reflections corresponding to calcite CaCO3. At [DTPA]/[Ca
2+
] ≥ 1, the 
PXRD pattern shows only the 104 reflection, which is indicative of a 104 out of plane 
orientation. Mineral calcite generally shows rhomboidal morphology, which was 
observed when EDTA (ethylenediaminetetraacetic acid) was used as a complexing agent. 
In presence of DTPA, platelet morphology was observed. Amorphous CaCO3 coatings 
show floral and dumbbell morphologies 
Chapter 3: Electrodeposition of MCrO3 (M = La, Dy, Nd, Pr, Gd and Y) perovskite 
oxide coatings on stainless steel substrates  
One of the significant challenges of the effective use of functional oxide materials in 
device applications is to obtain them in the form of thin films or thick coatings. In this 
work, we show cathodic electrodeposition technique as a cost effective method for 
fabrication of perovskite chromite coatings.  Amorphous precursor hydroxide coatings of 
M (M = La, Pr, Nd, Gd, Dy, Y) and Cr were co-deposited on stainless steel electrode by 
cathodic electrodeposition from a nitrate bath. These precursor coatings were further heat 
treated to obtain MCrO3 perovskite oxide coatings. Heat treatment of La-Cr hydroxide 
precursor coatings at 600 °C and 800 °C resulted in coatings of La2CrO6 and LaCrO3 
phases respectively. The other M-Cr hydroxides on heating at 800 °C for 2 hours formed 
respective single phase MCrO3 perovskite coatings. Interestingly, the SEM images of heat 
treated perovskite coatings show different morphologies with varying M in MCrO3 (M = 
La, Pr, Nd, Gd, Dy and Y). 
Chapter 4: Effect of orientation on the reversible discharge capacity of 
electrodeposited Cu2O coatings as lithium-ion battery anodes 
Electrodeposited Cu2O coatings with 111 out-of-plane orientation were found to have the 
lowest reversible discharge capacity as anodes for Li-ion cells. This is attributed to the 
low surface energy and the consequent high thermodynamic stability of the 111 crystal 
Synopsis 
iv 
 
face of Cu2O. In contrast the 200 oriented coating has a higher reversible discharge 
capacity, owing to its polar nature and high surface energy. The highest reversible 
discharge capacity was observed for unoriented coatings, emphasizing the critical role 
played by grain boundaries in the conversion electrodes. The morphology of crystallites 
in the electrodes recovered after cycling is different in the three cases suggesting that the 
nature of reversible chemical conversion is guided by physical attributes of the precursor 
Cu2O crystallites. 
Chapter 5: Electronic structure calculation for Lithium insertion in Cu2O 
The successful use of metal oxides as conversion anodes in Li-ion batteries invokes the 
formation and subsequent reductive decomposition of Li2O. Given the standard reduction 
potential of Li/Li
+
 couple, the reduction of Li2O to Li is a thermodynamic challenge. 
There is as yet no evidence either by experiment or theory that such a process is feasible. 
In this chapter we investigate the interaction of Li
+
 ions with a matrix of Cu2O 
computationally using the first principles based DFT + U methodology. This study 
indicates that alloying of Cu and Li takes place more readily than Li2O formation in the 
early part of the charge cycle. We surmise that capacity fading observed in oxide 
conversion anodes is likely the result of irreversible accumulation of Li2O, and reversible 
alloying plays a greater role in the charge-discharge process than has been generally 
acknowledged.    
Chapter 6: Electrochemical impedance studies of capacity fading of electrodeposited 
ZnO conversion anodes in Li-ion battery  
Electrodeposited ZnO coatings suffer severe capacity fading when used as conversion 
anodes in sealed Li cells. Capacity fading is attributed to (i) the large charge transfer 
resistance, Rct (300 – 700 ) and (ii) the low Li
+
 ion diffusion coefficient,  DLi
+
 (10
-15 
– 
10
-13 
cm
2
 s
-1
). The measured value of Rct is nearly ten times higher and DLi
+
 ten to 
Synopsis 
v 
 
hundred times lower than the corresponding values for Cu2O, which delivers a stable 
reversible capacity. 
Chapter 7: Electrochemical behaviour of NiO conversion anodes in Li-ion batteries: 
Effect of crystallite size and nonstoichiometry 
Conversion anodes comprising non-stoichiometric black NiO suffers severe capacity 
fading in Li-ion batteries. We attribute this capacity fading to (i) its small crystallite size 
(~8 nm), and (ii) high charge transfer resistance (Rct). In contrast the stoichiometric green 
NiO anodes deliver a stable capacity of 280 mAh g
-1
 over 50 charge-discharge cycles. 
The comparatively higher capacity of green NiO can be explained from its (i) negligible 
Rct values, and (ii) large crystallite size (~104 nm). 
Chapter 8: Conclusions 
In this chapter, the conclusions of the thesis have been summarized. The inherent 
limitations of this thesis and the future scope of research regarding the electrodeposition 
of other inorganic materials and their application as electrodes for Li-ion batteries are 
discussed.  


ELECTROCHEMICAL SYNTHESIS OF INORGANIC MATERIALS AND THEIR APPLICATION AS ANODES FOR Li-ION BATTERIES

Mullagiri, Kishore

Synopsis 
 
i 
 
Synopsis 
The work carried out in the research tenure has been compiled in the form of a thesis entitled 
“Design and Development of Indole and Biphenyl Linked Heterocycles as Potent 
Anticancer Agents”. The main aim of this work is design and synthesis of biologically 
active trimethoxyaroyl indole-benzimidazole conjugates, arylindole-glyoxamides, arylamino 
linked biphenyl propenones and aryl (biphenylamino) Propenone-quinazolinone conjugates 
and evaluated for their anticancer activity and apoptosis inducing ability. The thesis has been 
divided into four chapters. 
❖ CHAPTER I: This chapter gives the general introduction about cancer chemotherapy, 
DNA interchlators, tubulin polymerization inhibitors and objectives of the present work. 
❖ CHAPTER II: This chapter describes the desige and synthesis of trimethoxyaroyl indole-
benzimidazole conjugates and evaluated their cytotoxicity against a panel of four human 
cancer cell lines. Further, the apoptosis inducing ability of these derivatives was 
confirmed by Hoechst staining, measurement of mitochondrial membrane potential ROS 
generation and Annexin V-FITC assays. 
❖ CHAPTER III: This chapter deals with the design and synthesis of trimethoxyaroyl 
indole-glyoxamide conjugates and evaluated their cytotoxicity against a panel of four 
human cancer cell lines. 
❖ CHAPTER IV (SECTION-A): This chapter illustrates the synthesis and biological 
evaluation of arylamino linked biphenylpropenones conjugates as tubulin polymerization 
inhibitors. Further these compounds have been evaluated for their ability to induce 
apoptosis. 
❖ CHAPTER IV (SECTION-B): This chapter deals with the design and synthesis of aryl 
(biphenylamino) Propenone-quinazolinone conjugates and evaluated their cytotoxicity 
against a panel of four human cancer cell lines 
 
 
 
Synopsis 
 
ii 
 
Chapter-I 
Introduction 
Cancer, characterized by uncontrolled growth or spread of abnormal cells, posses a 
significant challenge with high rates of diagnosis and mortality. Chemotherapy plays a very 
important role in treatment of solid tumors and is used as an adjuvant to surgical or radio 
therapeutic procedures. Chemotherapy becomes critical to effective treatment because only 
systemic therapy can attack micro metastases. The chemotherapeutic agents target the fast 
dividing abnormal cells and can be categorized into functional sub groups: alkylating agents, 
anti metabolites, antibiotics and antimitotics such as microtubule targeting agents. 
 Microtubules are protein biopolymers formed through polymerization of of α- and β-
tubulin. Tubulin polymerization is reversible and the dynamic assembly and disassembly of 
microtubules are involved in a number of cell functions including cell division, migration and 
shape change. Many natural and synthetic compounds are reported to target the tubulin- 
microtubule system. Anti mitotic agents derived from natural or synthetic products, generally 
exert their effect as microtubule stabilizers or polymerizing agents like taxol, paclitaxel and 
docetaxal which block the microtubule disassembly. They bind at the α-tubulin site in the 
microtubules and are used in the treatment of carcinomas like lung, breast, ovarian and 
bladder. In contrast, microtubule destabilizers such as colchicine, vinca alkaloids, 
combretastatin A-4 and E7010 bind at the β-tubulin site in microtubules and cause the 
depolymerization of microtubules. Many of such agents manifest different limitations in their 
clinical utility, therefore development of new microtubule targeting agents is of significance. 
      Combretastatin A-4 (4a), is another excellent tubulin polymerization inhibitor that binds 
to colchicine binding site of the tubulin and demonstrates cytotoxicity against a broad 
spectrum of human cancer cell lines including MDR cancer cells. However, the in vivo 
efficiency of CA-4 is limited due to poor pharmacokinetics resulting from its high 
lipophilicity and low water solubility. The structural modifications on CA-4 has led to the 
development of a number of new CA-4 derivatives that exhibit potent tubulin polymerization 
inhibitors such as  combretastatin A-4 phosphate (4b-CA4P, Figure 1A) and CA-1 disodium 
phosphate (CA1P-Oxi 4503) as prodrugs. Similarly, amino substituted combretastatin 
Synopsis 
 
iii 
 
derivative (4c-AVE-8063) and serine prodrug of combretastatin amine (4d-Ombrabulin) 
have been developed. These prodrugs of CA-4 are in advanced stages of clinical studies. 
 
 
Figure 1. Tubulin depolimerization inhibitos. 
 
Chapter-II 
Design and synthesis of trimethoxyaryl indol-benzimidazole conjugates as tubulin 
polymerization inhibitors. 
 The main drawback associated with combretastatin A-4 are bioavailability and 
isomerization of the biologically active Z-configured double bond into the inactive E-
configuration during long storage and administration. To overcome this, the ethynyl bridge of 
the stilbene moiety was replaced by a biologically stable keto group (phenstatin) and 
bioisosteric replacement of the (Z)-1,2-ethylene group with a 1,1-ethylene bridge of stilbene 
Synopsis 
 
iv 
 
moiety (isocombretastatin) that resulted in the retention of the biological activity with 
improved physical properties. Phenstatin derivatives and isocombretastatin A-4 (isoCA-4) 
derivatives exhibited substantial anti-cancer activity and its derivatives were easier to 
synthesize than the combretastatins (which require control of geometric selectivity) and have 
greater pharmacological potential due to improved metabolic stability. 
        On the other hand, benzimidazoles are remarkably effective compounds both with 
respect to their inhibitory activity and their favorable selectivity ratio. Extensive biochemical 
and pharmacological studies have confirmed that benzimidazole molecules are effective 
against various strains of microorganisms. Benzimidazoles are regarded as a promising class 
of bioactive heterocyclic compounds that exhibit a range of biological activities. Specifically, 
this nucleus is a constituent of vitamin-B12. This ring system is present in numerous 
antiprotozoal, antihelmintics, anti-HIV4, anticonvulsant, antiinflammatory, antihepatic and 
antineoplastic, antiulcer activities. 
        Considering, the potent bioactivity of the molecules, phenstatin and isocombretastatin 
A-4 some new benzimidazole molecules have been synthesized that incorporate phenstatin 
and indole skeleton evaluated their cytotoxic activity. The promising activity observed 
prompted us to investigate the role of these new compounds in the proliferation and apoptosis 
of the human prostate cancer cell line. 
       The trimethoxy aroyl indole-benzimidazole conjugates 7-9(a‒h), 11(i-k) were 
synthesized in six straight forward reactions. Initially, the commercially available 5-
bromoindole (1) was protected with tert-butylchlorodimethylsilane (TBDMSCl), alkylated 
with iodomethane (MeI) and bromoethane (EtBr) in the presence of sodium hydride and 
DMF to produce corresponding 1- substituted indoles (2a-c) respectively. The products (2a-
c) were further treated with n-butyllithium (n-BuLi) and 3,4,5-trimethoxybenzaldehyde at -78 
oC to furnish the corresponding alcohols (3a-c) with moderate yields. The oxidized products 
5a-c were isolated with good yields from the reaction of 4a-c with 2-iodoxybenzoic acid 
(IBX) in DMSO and after oxidation, the deprotection of TBDMS group with tetra-n-
butylammonium fluoride (TBAF) provided 4a. Next, Vilsmeier reaction of 6a-c with 
phosphoryl chloride (POCl3) and DMF afforded (7a-c) in good yields. Finally, the 
derivatives 7-9(a‒h) and 11(i-k) were generated by condensation of various aldehydes 7a-c 
Synopsis 
 
v 
 
with substituted benzene-1,2-diamine (OPDs) in the presence of sodium metabisulfite 
(Na2S2O5) as shown in Scheme 1. 
 
Scheme 1: Reagents and conditions: (i) TBDMSCl, NaH, THF, 0 °C-rt, 3 h, 93%; (ii) MeI, 
NaOH,DMSO, 0 °C-rt, 3 h, 95%; (iii) EtBr, NaH, THF,0 °C-rt, 3 h, 95% (iv) 3,4,5-
trimethoxy benzaldehyde, n-BuLi, THF, -78 °C, ,4 h, 73˗75%, (v) IBX, DMSO, 0 °C–rt, 3 h, 
95%; (vi) TBAF, THF, 0 °C-rt, 4 h, 90% (vii) POCl3, DMF, CHCl3, reflux, 12 h, 78-82%; 
(viii) Na2S2O5, EtOH:H2O, 80 °C, 2 h, 68-85%. 
The conjugates 7-9(a‒h) 11(i-k) were evaluated for their cytotoxic activity on a panel 
of different human cancer cell lines such as A549 (lung), HeLa (cervical), MCF-7 
(breast) and DU-145 (prostate) by employing MTT assay. IC50 values are expressed in 
Synopsis 
 
vi 
 
µM and compared with nocodazole as control. Some of the derivatives show 
significant activity against most of the cell lines tested with IC50 values ranging from 
0.54 to 31.86 µM. Among them derivatives 7c-e, 7i, 8b, 8c, 8f-h, 9a, 9b, 9d-f and 9h 
showed considerable activity with IC50 values of <5 µM and majority of derivatives 
show good cytotoxicity against prostate cancer cell line (DU-145). However, 
derivatives 8g and 9f were found to be very active against DU-145 cell line with IC50 
values of 0.68 µM and 0.54 µM respectively. Therefore, the DU-145 cell line was 
chosen as a model cell line for subsequent experiments. 
Chapter-III 
Synthesis and biological evaluation of tirmethoxyaryl indole glyoxamide conjugates as 
potential anticancer agents. 
Indoles are the common components of fragrances and precursors of many 
pharmaceuticals. The amino acid tryptophan is an indole derivative and a precursor of the 
neurotransmitter serotonin and many biological macromolecules in our body. Although 
indole derivatives were used as monomers to synthesis phthalocyanines which can then form 
complexes with different metal ions, and these complexes exhibit some antiprion activities, 
the inhibitory effects of some indole derivatives on the amyloid fibrillation of the hen egg 
white lysozyme (HEWL) were the first example of indole derivatives as small molecules 
studied in the context of amyloidogenesis. Among the indole derivatives tested, indole-3-
acetic acid, indole-3-carbinol and tryptophol had the most inhibitory effects on the amyloid 
formation. Disaggregation of previously formed HEWL amyloid fibrils was also enhanced by 
indole-3-acetic acid. 
On this representation we designed and synthesized aryl indole based glyoxamides 
and evaluated their cytotoxic activity against four human cancer cell lines. 
         The trimethoxy aroyl indole-glyoxamide conjugates 6(a‒j),7(a‒j) were synthesized in 
four straight forward reactions. Initially, the commercially available 5-bromoindole (1) was 
alkylated with iodomethane (MeI) and bromoethane (EtBr) in the presence of sodium hydride 
and DMF to produce corresponding 1- substituted indoles (2a, 2b) respectively. The products 
(2a, 2b) were further treated with n-butyllithium (n-BuLi) and 3,4,5-trimethoxybenzaldehyde 
Synopsis 
 
vii 
 
at -78 oC to furnish the corresponding alcohols (4a,4b) with moderate yields. The oxidized 
products (5a, 5b) were isolated with good yields from the reaction of (4a,4b) with 2-
iodoxybenzoic acid (IBX) in DMSO and after oxidation, products (5a, 5b) were treated with 
oxalyle chloride in dry THF for 3 h a yellow scurvy was formed. To this, add N,N-
diisopropyl ethyl amine and different substituted anilines and allow it for 3h on heating 60 oC  
as shown in Scheme 2. 
 
Scheme 2. Reagents and conditions: (i) MeI, NaOH, DMSO, 0 °C-rt, 3 h, 95%; (ii) EtBr, 
NaH, THF,0 °C-rt, 3 h, 95% (iii) n-BuLi, THF, -78 °C, ,4 h, 73˗75%, (iv) IBX, DMSO, 0 
°C–rt, 3 h, 95%; (v) Oxalyl chloride, THF, rt, 3 h (vi) N,N-diisopropyl amine, substututed 
anilins, 60 °C 3h.  
The conjugates 6(a‒j)7(a-j) were evaluated for their cytotoxic activity on a panel of deferent 
human cancer cell lines such as DU-145 (prostate), A549 (lung), HCT-116 (colon), HepG2 
(liver) and by employing MTT assay. IC50 values expressed in µM and compared with 
nocodazole as control. Some of the derivatives show significant activity against most the cell 
lines tested with IC50 values ranging from 1.24 to 138.03 µM.  
 
Synopsis 
 
viii 
 
Chapter-IV (Section-A) 
Design, synthesis and biological evaluation of arylamino linked biphenylpropenone 
conjugates as tubulin polymerization inhibitors. 
Because of the biaryl configuration, Colchicine and allocolchicinoid derivatives are 
effective binding agents with tubulin. This biaryl configuration is also present in a wide 
range of cytotoxic natural products such as steganacin, steganone, eupomatilone, buflavine, 
dibenzocyclooctadiene lignans and many synthetic derivatives. B. Sridhar and coworkers 
designed, synthesized a new class of nitrovinyl biphenyl compounds .On the basis of 
structure of colchicines and allocolchicines by the modification of B ring, which exhibit to 
obstruct tubulin polymerization and cause mitotic arrest. Compared with colchicine in MCF-
7 and HeLa cells, majorty of these compounds were found to possess potent anticancer 
properties, with IC50 values in the range of 0.05–7 µm. These compounds inhibited tubulin 
assembly by more than 60%, and by the studying of flow cytometry analysis, it indicates the 
growth arrest of cells in the G2/M phase of the cell cycle in a concentration-dependent 
manner. Treatment of cells with resulted in up regulation of cyclin B1 and aurora kinase B 
mRNA levels, corresponding to growth arrest in the G2/M phase of the cell cycle as the 
mode of action. 
 Reddy and co-workers synthesized a series of (Z)-1-aryl-3-arylamino- 2-propen-1-
ones and were evaluated for their anti-proliferative activity against two different human 
tumor cell lines derived from human prostate (DU145) and leukemic (K562) cancers. These 
compounds displayed good anticancer activity with IC50 ranging from 0.06 to100 μM. The 
most active compound (Z)-1-(2-bromo-3,4,5-trimethoxyphenyl)-3-(3-hydroxy-4 
methoxyphenylamino)prop-2-en-1-one exhibited promising activity with IC50 0.06, 0.1 μM 
against DU145 and K562 cell lines respectively. Cytotoxicity data demonstrated that 
presence of a halo group at the ortho position moderately improved the cytotoxic activity of 
the molecules compared to the corresponding ortho-unsubstituted compounds. Further 
studies demonstrated that cells are arrested G2/M phase of the cell cycle and these 
compounds caused microtubule stabilization like paclitaxel and induced apoptosis via 
Synopsis 
 
ix 
 
activation of the caspase family. Therefore (Z)-1-aryl-3-arylamino-2-propen-1-one represents 
a new class of microtubule-stabilizing agents 
On the basis of above literature we designed, synthesized and evaluated a series of 
arylamino linked biphenylpropenone conjugates as shown in scheme 3. 
 
Scheme 3. Reagents and conditions: (i) Pd(OAc)2, K2CO3, DMF:H2O (1:2), 3 h, rt, 
85%, (ii) Ethynyl magnesium bromide, THF, 0 °C-rt, 3 h, 65%, (iii) IBX, DMSO, 0 °C, 2 h, 
75% (iv) Substituted anilines (10a-e), EtOH, 4 h, rt, 80-85%. 
A series of arylamino-biphenylpropenones conjugates 6(a-o) and 7(p-y) were synthesized 
and developed a potent conjugates 6j and 7x which displayed a strong cytotoxic activity with 
IC50 values of 0.9 and 0.7 μM against the human A549 cancer cell lines. Flow cytometry 
analysis indicates that these compounds induce cell cycle arrest at G2/M phase in A549 cells. 
Tubulin polymerization assay showed that they are potent inhibitors of tubulin 
Synopsis 
 
x 
 
polymerization and immunocytochemistry revealed loss of intact microtubule structure in 
cells treated by these conjugates 6j and 7x. In addition, they induce apoptosis in A549 cells 
by studying their effect on Hoechst staining and tunnel assay. Overall, these results 
demonstrate that the arylamino-biphenylpropenones conjugate have the potential to be 
developed as leads and their further amenable structural modifications may produce 
promising anticancer agents for A549 cancer cells. 
Chapter-IV (Section-B) 
Design and synthesis of aryl biphenylamino propenone quinazolinone conjugates and 
evaluated their cytotoxicity. 
In continuation to these efforts on the design of new anticancer agents, a series of 
quinazolinone amino linked biphenyl propenone derivatives have been synthesized and 
evaluated for their cytotoxic activity against four human cancer cell lines. 
Synthesis of quinazolinone amino linked biphenyl propenones  
1. Synthesis of 6-amino-2-methyl-3-phenylquinazolin-4(3H)-ones 
Aminoquinazolinones (5a-e) were prepared as shown in scheme.4. Anthranilic acid (1) on 
reaction with acetic anhydride at 150 oC afford the cyclized product 2-methyl-6-nitro-4H-
benzo[d][1,3]oxazin-4-one (2). This upon reaction with different substituted aryl anilines 
(3a–e) in acetic acid under reflux conditions provide the corresponding 2-methyl-6-nitro-3-
phenylquinazolin-4(3H)-ones (4a–e). Which on further reduced with palladium-carbon 
formed the 6-amino-2-methyl-3-phenylquinazolin-4(3H)-ones (5a-e). 
Synopsis 
 
xi 
 
 
Schem 4. Reagents and conditions: (i) AC2O, 3h, 150 0 °C, 85%, (ii) AcOH, 90  °C  
3 h, 65%, (iii) EtOAc/Pd-C, rt, 3h 90%. 
Synthesis of 1-([1,1'-biphenyl]-2-yl)prop-2-yn-1-ones 
Biphenyl propenones were prepared as shown in scheme 5, a mixture of 2-bromo 
benzaldehyde (1) corresponding boronic acids (2a-e) palladium(II) diacetate, sodium 
carbonate (Na2CO3) and N,N-dimethyl farmamide(DMF):water (2:1) was stirred for 3 hours 
at room temperature to produce [1,1'-biphenyl]-2-carbaldehydes (3a-e). After that, these 
aldehydes (3a-e) were treated with ethynyl magnesium bromide in dry tetrahydro furon 
(THF) at 0 °C to room temperature for 3 hours to produce 1-([1,1'-biphenyl]-2-yl)prop-2-yn-
1-ol 4a-e. Oxidation of 4a-e with 2-iodoxybenzoic acid (IBX) in the presence of dimethyl 
sulfoxide (DMSO) to give 1-([1,1'-biphenyl]-2-yl)prop-2-yn-1-one (5a-e).  
 
Schem 5. Reagents and conditions: (i) Pd(OAc)2, K2CO3, DMF:H2O (1:2), 3 h, rt, 85%, (ii) 
Ethynyl magnesium bromide, THF, 0 °C-rt, 3 h, 65%, (iii) IBX, DMSO, 0 °C, 2 h, 75%  
Synopsis 
 
xii 
 
Condensation of (10a-e) with aminoquinazolinones (5(a-e) from Scheme 4) in ethanol at 
room temperature resulted in the formation of (Z)-6-((3-([1,1'-biphenyl]-2-yl)-3-oxoprop-1-
en-1-yl)amino)-2-methyl-3-phenylquinazolin-4(3H)-ones in good yields. as shown in 
following reaction. 
 
 
 
 
 
 
 
 
 


DESIGN AND DEVELOPMENT OF INDOLE AND BIPHENYL LINKED

HETEROCYCLES AS POTENTIAL ANTICANCER AGENTS

KARRA, PURUSHOTHAM REDDY

STUDIES TOWARDS THE SYNTHESIS OF BIOACTIVE LACTONES AND DEVELOPMENT OF NOVEL METHODOLOGY USING Fe/CITRIC ACID

GOMES, JASMINE

Abstract/Synopsis Co-existence of superconductivity and magnetism in Rutheno-cuprates, non-oxide perovskite MgCNi3 and FeSe/Te systems Superconductivity (SC) and ferromagnetism (FM) are two antagonistic states of matter that tend to avoid each other. The mutual interference of these two states below their respective ordering temperatures, superconducting transition temperature (Tc) and magnetic ordering temperature (Tm), and the conditions under which they may co-exist is a matter of fundamental interest. Basically, two different types of superconductivity occur: one is singlet and other is triplet. In the more common and well known singlet superconductivity, the electrons form the cooper pairs, in which the electrons have opposite spin momentum, while in triplet superconductivity the two spins are parallel. In 1959 [Anderson et al Phys. Rev. 116, 898], it was proposed that co-existence of superconductivity and weak ferromagnetism can occur, and the ferromagnetic state can adjust itself, while there is no effect on the superconductivity. This work is planned, in order to resolve the complexity of the co-existence of superconductivity and weak ferromagnetism in rutheno-cuprates, MgCNi3 and Fe-based chalcogenides superconductors. The objective of this research work is to study the exact nature of magnetism and its co-existence with superconductivity in a single thermodynamic frame. Detailed magnetic characterization of weak ferromagnetism and co-existing superconductivity of various rutheno-cuprates including (Gd,Eu,Y)/Ru-1222, YRu-1212, MgCNi3 and FeSe/Te is studied on number of samples and is been put in different chapters of the thesis. It is concluded that weak ferromagnetism adjusts itself in such a way that the same could co-exist with superconductivity at lower temperatures below the magnetic ordering temperature. The thesis opens up a possible fresh scenario to look for search of new superconductors in close vicinity of magnetic order or even co-existing with the same. The present thesis is divided in to eight chapters. Chapter 1 gives brief review of the fundamentals of magnetism and superconductivity in a general way. The chapter also deals with the existing literature review on rutheno-cuprates, non-oxide perovskite MgCNi3 and Fe-based chalcogenides superconductors. Chapter 2 describes the general experimental techniques employed for the synthesis, structural determination, electrical/thermal transport and detailed magnetization (DC/AC) measurements on the samples. In chapter 3 synthesis of parent bulk RuSr2Eu1.4Ce0.6Cu2O10-δ (EuRu-1222) and their structural, transport, and magnetic measurements have been presented. Further, substitutions like Cr and Mn ion at Ru site in EuRu-1222 were also done to study the effect of doping on the superconducting and magnetic properties of the pristine system EuRu-1222. Chapter 4 deals with the detailed study of spin-glass (SG) and cluster ferromagnetism (FM) in RuSr2Eu1.4Ce0.6Cu2O10-δ (EuRu-1222) magneto-superconductor. In chapter 5, the complex magnetism of RuSr2Gd1.4Ce0.6Cu2O10-δ (GdRu-1222) is studied through detailed DC and AC magnetization (frequency and field dependence) and heat capacity measurements. A frequency dependent cusp is observed in AC susceptibility (χac) vs. T measurements, indicating the presence of spin-glass (SG) state. The thermoremnant magnetization (TRM) studies being carried out below spin-glass (SG) state confirmed the presence of spin-glass (SG) state. Chapter 6 deals with the magnetic and thermal behavior of Ru0.9Sr2YCu2.1O7.9 (YRu-1212) and complex magnetism of RuSr2Y1.5Ce0.5Cu2O10 (YRu-1222) magneto-superconductors. Both of these samples are synthesized at National Institute of Materials Science (NIMS), Japan through High Pressure (6 GPa) and High Temperature (1400oC) (HPHT) technique. In chapter 7, synthesis, structural, magnetic and specific heat properties of non-oxide perovskite pure and Boron (10B) doped MgCNi3 superconductor are presented and discussed in detail. In chapter 8, detailed structural, thermal and magnetic properties characterization of Fe-based chalcogenides pure and 3d metal doped FeSe0.5Te0.5 superconductor is presented. Detailed analysis of magnetization studies being presented in the thesis on various rutheno-cuprates had clearly demonstrated that ferromagnetic (FM) clusters are present in these superconductors. Further, two more very recent examples of superconducting ferromagnets are put together in this thesis i.e., MgCNi3 and FeSe0.5Te0.5. Certainly the thesis will invoke the scientific community to accept and find possible theoretical explanations for the co-existing ferromagnetism and superconductivity. 




Elucidation of spatiotemporal variations in functional genes involved in the nitrogen cycle along the west coast of India

P., CHIRANJEEVI

ANNEXURE-I 
 
SYNOPSIS 
1. Introduction 
The increase in global scale urbanization has resulted in significant energy demand and material 
consumption as well as the anthropogenic generation of waste in large quantities. The major 
source of our fuel needs is the petroleum-based refinery, which has a grave impact over energy-
environment nexus. Consequently, alternative and renewable energy sources should be explored 
to gain sustainability. It is estimated that in the next eight years, the average per capita waste 
generation rates per person, will increase from 1.2 to 1.42 kg per day in low and middle 
economic countries. The intrinsic advantage of waste is its biodegradable organic fraction 
associated with inherent net positive energy that could be converted to economically useful 
energy forms, to meet the world’s energy demand. The regulatory requirement for the treatment 
of waste prior to disposal makes waste as renewable feedstock for sustainable renewable energy 
generation. Considerable improvements are required to the existing bioprocess and also efforts 
should be made towards practical applicability at commercial scale.  
2. Statement of Problem 
Waste has potential to meet the world’s growing energy demand, by employing several 
bioprocesses. Dark fermentation, being one of the green and eco-friendly process, received 
significant interest in the recent decade owing to the fact that biohydrogen production through 
renewable waste feedstock can address today’s two most important concerns: energy security, 
climate change through waste remediation. This process of biological hydrogen production will 
compete with conventional hydrogen production in a sustainable and economical way. Yet, the 
process parameters and reactor configuration need to be optimized to increase the production rate 
and yield with diverse wastes at a pilot scale before commercialization. Besides, biohydrogen, an 
additional sustainable option is biodiesel production from waste. Converting solar energy to high 
energy bio-molecules during microalgae cultivation is referred as photo-bioproducts and can be 
cultivated by open pond and specially designed closed systems called photobioreactors. 
Employing mixed microalgae to utilize waste (liquid or gaseous) for biodiesel production is 
more feasible to apply at commercial scale to mitigate gaseous (CO2, CO)  
and liquid wastes (effluents). Prior to commercialization, mixed microalgae require optimization 
towards higher biomass and lipid productions to overcome the limitations. 
Moreover, photo-bioproducts an additional sustainable bioelectricity can be generated from 
photosynthesis process. Photosynthetic conversion of solar energy to chemical energy and 
further to electrical energy using rhizosphere microorganisms of plant root is referred as 
bioelectrogenesis and the system used is plant microbial fuel cell (P-MFC). Based on the 
application requirement, P-MFC can be designed as an eco-electrogenic engineered system 
(EES) specifically used to remediate waste in natural water bodies which are polluted. Yet, it is 
necessary to optimize electrode material, distance of anode to cathode and operation with real 
field effluents for efficient power output and waste remediation before scaling up. 
3. Scope and Objectives of the Research  
The scope of the thesis was designed to study acidogenic and photosynthetic processes for the 
production of biobased products viz., biohydrogen, biodiesel and bioelectricity through waste 
utilization encompassing process upscaling as final objective. Hydrogen production through 
fermentation process is technically simpler, requires low operating costs, is more robust and 
makes it feasible and sustainable to upscale the processes for mass production. Microalgae 
cultivation for biobased products is more advantageous than other biological routes due to rapid 
doubling time of cells, harvesting solar energy and CO2 sequestration capabilities with less land 
use. Rhizosphere mediated electrogenesis employing photosynthetic fuel cell with terrestrial and 
aquatic plants through the photosynthetic process is generating considerable interest in applied 
research in recent times and is also considered important in the context of the biorefinery. 
Furthermore, integrated strategies address the unused carbon in one process to serve as the 
substrate for another process in a cascading biorefinery pathway. In response to finding solutions 
to the challenges and for process understanding, different strategies have been adopted to harness 
bioenergy and value-added products through sustainable biological processes addressing the 
waste remediation (Fig 1). 
 
 
Fig 1: Flow chart depicting the scope of research 
 
With the existing scope in the literature, the thesis was designed and discussed with the 
following broad objectives 
 To enumerate the potential of different waste/wastewaters as feedstock for acidogenic 
biohydrogen production. 
 To comprehend and optimize the critical parameters of the acidogenic process towards 
upscaling and techno-economical feasibility 
 To evaluate photosynthetic process for higher biomass and lipid productivity through 
selective-optimization strategy and process upscaling 
 To design and evaluate the rhizosphere mediated bioelectricity production using 
terrestrial and aquatic plants towards process upscaling 
 To integrate acidogenic and photosynthetic processes in cascading mode to produce 
biobased products with simultaneous waste remediation in a biorefinery framework 
 
 
Scale of operation Biobased productsProcessBiocatalystWaste
Biogenic waste
Acidogenic bacteria 
(mixed)
Acidogenisis 10 m3
BioH2 and Volatile 
fatty acids
Microalgae (mixed) Photosynthesis 50 L Biomass and lipids
Plant rhizosphere 
bacteria (mixed)
Photosynthesis 150 L Bioelectricity
CO2
Sustainable waste remediation
In
te
g
ra
tio
n
4. Structure of the Thesis 
The thesis is divided into six chapters. Chapter 1 presents a general introduction and review of 
literature covering different topics of the thesis; Chapter 2 presents acidogenic biohydrogen 
production optimizing physicochemical parameters, reactor configuration and upscaling the 
process assessing techno-economic feasibility for commercial application; Chapter 3 deals with 
photosynthetic mixed microalgae cultivation by optimizing physicochemical parameters and 
scaling up in an efficiently designed flat-panel photobioreactor for higher production of biomass 
and lipids;  Chapters 4 presents rhizobial catalyzed bioelectrogenesis from terrestrial and aquatic 
plants through photosynthetic CO2 sequestration; Chapter 5 depicts integration strategies of 
acidogenic process with photosynthetic process for bio-based production (biomass, biodiesel and 
bioelectricity) with simultaneous waste remediation; Chapter 6  summarizes research output and 
future scope of the research. 
5. Summary of the Research 
Comprehensive efforts were made towards up-scaling the biohydrogen production process for 
practical application. Biohydrogen production is assessed by a methodical two-phase rapid 
protocol/methodology developed to know the potential of diverse waste/wastewater varying 
different process parameters [inoculum (pretreated and untreated), redox condition and organic 
loading] crucial for biohydrogen production. During these experiments, it was noticed that 
acidogenic redox condition with pretreated inoculum at high organic loading with food waste 
and design synthetic wastewater as substrate showed good results for biohydrogen production. 
In addition, experiments were carried out to enhance biohydrogen production with two reactor 
configurations (biofilm and suspended) with above-optimized conditions. Enhanced 
biohydrogen production with biofilm configured bioreactor was observed due to adherence of 
robust microbes (developed during exposure to different microenvironment) on biofilm matrix. 
Further, the optimized configuration was incorporated in the 10 m
3
 acidogenic biohydrogen pilot 
plant design and was evaluated with food waste as feedstock for biohydrogen production with 
the optimized conditions. Finally, techno-economic analysis for biohydrogen process was 
performed with real field data which showed positive results in socio-economic aspects and is 
environmentally friendly towards practical application of commercial plant. 
 
 
Fig 2: Flow chart depicting biohydrogenesis, photosynthesis and bioelectrogenesis 
integration and scale up operations during research work 
Further research extended with the photosynthetic process includes cultivation of mixed 
microalgae by optimizing physicochemical parameters that show positive influence on biomass 
and lipid productivity with Taguchi method. Among the eight factors, carbon concentration 
individually showed significant positive influence on the biomass productivity (5.26 g/l) 
followed by nitrates, light, temperature, pH, carbon source, Magnesium, and Phosphates. Among 
the four parameters, pH, salinity, and carbon concentration showed significant influence on 
maximizing the lipid synthesis (55% of total lipids). The broader understanding of biomass 
production and lipid biosynthesis for biodiesel production and recovery of bio-based 
products lead to the design of 50 l flat panel photobioreactor (FPBR) for microalgae cultivation 
operated with optimized biomass and lipid conditions towards practical applicability. High 
biomass and lipid production during operating FPBR with optimized biomass condition is best 
Food waste
Anaerobic  
fermentation
H2
Effluents rich in 
volatile fatty acids  
Microalgae 
cultivation 
Eco-electrogenic 
engineering 
systems 
Biomass
Bioelectricity 
Biodiesel
Acidogenic process
Algal cultivation process
Integration
Photosynthetic Fuel cell
P-MFC
Bioelect
ricity 
Light
H2O
CO2
Light
H2O
CO2
Scale of 
operation
10 m3
Scale of 
operation
150 L
Scale of 
operation
50 L
Scale of 
operation
50 L
suitable for outdoor cultivation of mixed microalgae to produce high value-added photosynthetic 
products.  
Photosynthetic fuel cells were explored to tap their potential for power generation 
with Pennisetum setaceum, a perennial grass plant by placing anodes at different regions of the 
rhizosphere. The study concluded that the maximum power was observed with the anode placed 
nearer to the root zone due to maximum plant-microbial and electrode interactions. 
Subsequently, another study was carried out to evaluate the power production by exploring the 
photosynthetic CO2 sequestration by native macrophytes in designed ecological engineering 
system (EES). The power production enumerated the specific advantage of EES as self-
sustainable technology by means of a photosynthetic process with the potential of real field 
applications.    
Integration of acidogenic and photosynthetic processes in a biorefinery framework towards 
maximum resource recovery with simultaneous waste treatment is the sustainable practice for 
process upscaling in an economically viable route (Fig 2). In this direction, acid rich effluents 
from biohydrogen reactor were used as a substrate for microalgal cultivation. Apart from gaseous 
energy (H2) production in the first stage, the integration facilitated liquid energy production in 
the form of biodiesel in the second stage with simultaneous wastewater treatment. In the similar 
way, the effluent from biohydrogen process was also fed to EES embedded with fuel cell 
assemblies. The study made a comprehensive evaluation of photosynthetic hydrophytes, abiotic 
cathode and biotic anode along with microbes (present in sediment and rhizosphere of the 
aquatic plant) with concurrent power generation and wastewater treatment. Biorefinery is 
emerging as a potential route, where a range of products can be valorized from non-edible 
feedstock/biogenic waste. The research output deliberates on ‘waste as a prime target substance 
in the biorefinery that shows a broad range of opportunities for commercial interests’.  
 
 
 
 


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