Open Access Repository of Indian Theses

REDDY, V. LOKA

vi 
 
 
Abstract 
The marine environment is known to be rich sources of 
biologically active compounds due to their tremendous biodiversity.  A 
quantitative analysis of marine organisms demonstrated that more 
than 20,000 compounds have been isolated from marine 
microorganisms, micro/macro algae and invertebrates.  Among 
marine seaweeds, the members of Phaeophyceae (marine brown algae) 
have been one of the richest and most promising sources of bioactive 
primary and secondary metabolites, with a broad range of 
physiological and biochemical characteristics.  Several species of 
macro algae growing abundantly in the shallow waters of Gulf of 
Mannar Marine Biosphere Reserve (GoMBR; 80 49’–90 15’ N latitude 
and 780 11’–790 30’ E Longitude), which is one of the world’s richest 
regions from marine bio diversity perspective and the first marine 
Biosphere Reserve in South east Asia. 
In the present thesis abundantly available fifteen species of 
seaweeds were collected and washed thoroughly with fresh water and 
cleaned carefully to remove the extraneous matter.  They were shade 
dried, powdered and extracted with a mixture of dichloro methane and 
methanol (1:1 ratio). All the crude extracts were evaluated against 
gram positive and negative bacteria, brine shrimp, and anti-
proliferative activities on different cell lines.  Based on the preliminary 
investigations, it was found that the brown seaweed, Stoechospermum 
marginatum, exhibited multiple biological activities.  These 
observations have given me a clue that the secondary metabolites that 
are produced by S. marginatum, may have a beneficial molecule/s, 
which may possess potent anti-cancerous/anti-proliferative 
properties. Keeping in view, an extensive study was conducted on the 
vii 
 
brown seaweed, S. marginatum for isolation of bioactive substances.  
Bioassay directed fractionation and purification led to the successful 
isolation of ten bioactive spatane diterpinoids from a brown seaweed, 
S. marginatum.  These structures were determined by analyzing 1H, 
13C NMR and FAB-MS.   
The anti-proliferative/cytotoxic activities of these isolated 
compounds were investigated in different cancer cell lines and found 
that one of the spatane diterpinoids, 5 (R), 19 - diacetoxy -15,18 (R 
and S), dihydro spata-13, 16 (E)- diene (DDSD) has exhibited most 
significant cytotoxic properties against all the cell lines, i.e., Histiocytic 
lymphoma (U937), Acute monocytic leukemia (THP-1), Colon 
adenocarcinoma (COLO205), Promyelocytic leukemia (HL60), Human 
lung carcinoma (A549), Human breast cancer (MCF7) and mouse 
melanocarcinoma (B16F10) with IC50 values of 5.6, 14.21, 36.15, 
40.96, 26.35, 32.34 and 3.45 µg/mL, respectively.  It is evident from 
the results that the mouse melanocarcinoma (B16F10) cells were 
relatively more sensitive to the isolated compound, DDSD. 
Interestingly, the DDSD has exhibited fewer symptoms on the human 
peripheral blood mononuclear cells (PBMC) and mouse fibroblast cell 
lines (BALB/3T3 and NIH/3T3) with IC50 values of 90.18, 69.08 and 
59.80 µg/mL, respectively.  This data indicated that DDSD may 
selectively inhibit the viability of mouse melanoma cells, which is a 
highly desirable property of potential anticancer agents.  Light and 
florescence microscopy studies provide direct evidence that, the 
compound DDSD exhibited apoptotic activity on several cancerous cell 
lines.    
        The molecular mechanism of DDSD mediated apoptosis was also 
investigated for the first time in in vitro and in vivo B16F10 melanoma 
mouse models. Induction of apoptosis in B16F10 cells was 
viii 
 
characterized by colony forming inhibition, wound healing inhibition, 
cell membrane blebbing, chromatin condensation, DNA fragmentation, 
which leads to cell growth inhibition in a concentration-dependent 
manner. Data indicate that DDSD induced the generation of ROS, 
consequentially caused alteration in Bax/Bcl-2 ratio that disrupted 
the inner mitochondrial transmembrane potential (∆Ψm) resulting in 
cytochrome c redistribution to the cytoplasm and activation of 
caspase-mediated apoptotic pathway.  Flow cytometric analysis clearly 
indicated that the DDSD inducing phosphatidylserine externalization 
and mediated “S-phase” arrest in cell cycle.  In addition, results also 
found that DDSD induced apoptosis through deregulating PI3K/AKT 
signalling pathway.  The anti-tumor activity of DDSD was evaluated in 
C57BL/6 mice bearing B16F10 melanoma.  It effectively inhibited 
tumor growth (volume and weight) in a dose dependent manner, yet 
without apparent toxic effects.  Morphology and apoptotic status of 
tumor tissues in the treated mice were assessed by microscopy and 
TUNEL assay, respectively. 
        It was concluded from the experimental data that Spatane 
diterpinoid (DDSD) compound exhibits potent anti-proliferative effect 
in B16F10 cell lines in vitro.  Present experiments proved that DDSD 
induced intrinsic mitochondrial apoptosis pathway by generating ROS 
and inactivation of PI3K/Akt pathway involving modulating expression 
of Bcl-2 family proteins, leading to apoptosome mediated activation of 
caspase cascade. Based on in vivo antitumor activities against B16F10 
subcutaneously grafted murine melanoma, it appears to be a more 
promising therapeutic compound for melanoma cancer treatment with 
no side effects. The present in vitro and in vivo results demonstrated 
that the DDSD molecule may emerge as efficacious agent for 
therapeutic use 


English

IN VITRO-IN VIVO EVALUATION OF CYTOTOXIC AND APOPTOTIC MECHANISM OF SPATANE DITERPINOIDS ISOLATED FROM THE BROWN SEAWEED,STOECHOSPERMUM MARGINATUM

J., SOUJANYA

 i 
 
 
SYNOPSIS 
Synthesis, Conformation and Glycosidic Bond Stabilities of Septanoside Sugars 
Supriya Dey 
Department of Organic Chemistry, Indian Institute of Science, Bangalore-12, India 
 
Seven-membered cyclic sugars, namely, septanoses and septanosides, are less commonly known 
sugar homologues.  Synthesis of septanoses arise an interest due to their configurational and 
conformational features and the attendant possibilities to explore their chemical and biological 
properties.  Septanosides derivatives, mostly, deoxy-septanosides were synthesized, by many 
synthetic methodologies, such as, Knoevengal condensation, ring-closing metathesis, Bayer-Villeger 
oxidation and ring-expansion of 1,2-cyclopropanted glycals as key steps.  Apart from septanosyl 
monosaccharides, septanoside containing di- and tri-saccharides were also performed using 
glycosylation and ring expansions.   
Another area of sustained interest is the studies of the stabilities of glycosidic bonds.  Acid- and 
enzyme-catalyzed hydrolysis of glycosidic bond were investigated intensely in the case of 
pyranosides and furanosides.  The explanation of the hydrolysis of such stereomeric sugars were 
rationalized on the basis of stereoelectronic effects, such as, (i) antiperiplanarity; (ii) synperiplanarity 
of lone-pair of electrons involed in the hydrolysis process; (iii) steric effects; (iv) field and 
hyperconjugative effects; (v) conformational effects; (vi) disarming torsional effects and (vii) 
substituent effects.  Chapter 1 of the thesis describes a survey of (i) synthesis of deoxy-septanosides 
and septanoside-containing di-and tri-saccharides and (ii) acid-catalyzed hydrolysis of 
glycopyranosides.   
 
In a programme, it was desired to identify a new methodology for the synthesis of 2-deoxy-2-C-
septanosides.  Synthesis of various septanosides from 2-hydroxy glycals, namely, oxyglycals, 
involves intermediates, such as, vinyl halide (III) and diketone (IV) (Scheme 1).  These 
intermediates were identified as precursors for the synthesis of desired 2-deoxy-2-C-septanosides.  
 
 
 
 ii 
 
 
Scheme 1 
 
In this context, bromo-oxepine III was examined using Pd-catalyzed C-C bond forming 
reactions, namely, Heck, Suzuki and Sonogashira reaction for the formation of hither-to unknown 
septanoside, branching out at C-2.  Heck coupling and Suzuki coupling reaction of bromo-oxepine 
was performed using activated alkenes, acrylates and substituted boronic acid, respectively, in 
presence of Pd(OAc)2, to furnish 2-deoxy-2-C-alkyl/aryl septanoside derivatives (Scheme 2). 
 
Scheme 2 
 
Sonogashira reaction of bromo-oxepine was performed using acetylenes in presence of 
Pd(PPh3)2Cl2 as catalyst and CuI as co-catalyst in DMF:THF:Et3N (5:3:2) solvent mixture to furnish 
2-deoxy-2-C-alkynyl septanoside derivatives (Scheme 3). 
 
Scheme 3 
R = Ph, SiMe3, C6H13
OBnO
BnO
BnO OBn
OMe
R
OBnO
BnO
BnO OBn
OMe
Br
Pd(PPh3)2Cl2, CuI
DMF:THF:Et3N (3:2:1)
98 oC, 72 h
 
 
 iii 
 
 
One of the 2-deoxy-2-C-alkyl septanoside derivative was converted to the corresponding protecting-
group free 2-deoxy-2-C-alkyl septanoside, using hydrogenolysis (Pd/C, H2) and NaBH4-mediated 
reduction. 
 
Scheme 4.  Reaction conditions: (i) Pd-C (10 %), H2, MeOH, 24 h; (ii) NaBH4, MeOH, 0 oC-rt, 3 h. 
 
Chapter 2 presents details of the synthesis of 2-deoxy-2-C-alkyl/aryl/alkynyl septanoside 
derivatives from a bromo-oxepine.  
 
Continuing the efforts to extend the ring-opening of oxyglycal derived gem-dihalo-1,2-
cyclopropanted sugar, a Lewis acid-catalyzed ring-opening was considered important.  The presence 
of an additional substituent in C-2 of oxyglycal switches reactivity as compared to glycals.  For 
example, ring-opening of glycal derived gem-dihalo-1,2-cyclopropane generates 2-C-branched 
pyranoside, whereas corresponding oxyglycal generates oxepines even when both the reactions were 
performed under a mild basic condition, illustrating a sufficient reactivity difference between a 
glycal and an oxyglycal.  Thus, ring-opening reaction of gem-dichloro-1,2-cyclopropanted oxyglycal 
in the presence of a Lewis acid, hither-to unknown, was examined.  In this event, it was found that 
ring-opening reaction led to chloro-oxepine derivatives in the presence of AgOAc, using alcohol as 
nucleophiles.  Primary, secondary, unsaturated and aromatic alcohols were used in the ring-opening 
reaction.  The ring-opening reaction was stereoselective and only α-anomer was obtained in a good 
yield in each case (Scheme 5).  The counter-anion also reacted in an instance, so as to furnish O-
acetyl chloro-oxepine during the ring-opening reaction.   
 
Scheme 5 
 
 iv 
 
 
 
 
The course of the reaction in the absence of alcohol led to afford only the O-acetyl chloro-oxepine 
(Scheme 6).  
 
Scheme 6 
O
BnO
OBn
OBn
Cl
Cl
BnO
AgOAc:NaOAc (1:1)
PhCH3, reflux, 48 h, 78 %
OBnO
BnO
BnO OBn
Cl
OAc
 
 
It became pertinent to compare the result this work with that of AgOAc-catalyzed ring-opening 
of glycal derived gem-dihalo-1,2-cyclopropanated sugar, which led to C-furanoside derivative, as 
reported by Harvey and co-workers.  The sequence of reactions involved were protonation of the 
endo-cyclic oxygen, followed by ring-opening to generate resonance stabilized allylic ion, which 
rearranged to C-furanoside.  In contrast, oxyglycal derived gem-dihalo-1,2-cyclopropane studied 
herein led to chloro-oxepine exclusively, without subsequent rearrangement.  Ring-opening of glucal 
derived gem-dihalo-1,2-cyclopropanated sugars, followed by cyclization to C-furanoside were likely 
to have occurred, due to isomerisation of less-substituted endo-cyclic double bond at C2-C3 of 
oxepine to C1-C2 unsaturated vinyl ether. Such a reaction was related closely to the acid-catalyzed 
rearrangement in less-substituted oxepine systems.  On the other hand, gem-dichloro-1,2-
cyclopropanated oxyglycal  derived chloro-oxepine did not undergo such an isomerisation, possibly 
due to unsaturation being present at highly substituted C2-C3 carbons (Scheme 7).  Thus, the 
presence of an additional oxy-substituent at C-2 in oxyglycal derived cyclopropane derivative plays a 
major role to control the reactivity, as compared to glycal derived cyclopropane derivatives.   
 
 v 
 
 
Scheme 7 
 
The observation that D-oxyglycal derived cyclopropanes afforded only halo-oxepines, 
without undergoing further reactions, was confirmed further by the following reactions: (i) RuCl3-
NaIO4 mediated oxidation; (ii) NaBH4 reduction and (iii) Pd/C mediated hydrogenolysis (Scheme 8). 
 
Scheme 8 
 
Chapter 3 describes details of the ring-opening reactions of oxyglycal derived gem-dihalo-
1,2-cyclopropane to exclusive formation of chloro-oxepine in the presence of AgOAc. 
It was planned further to synthesize a 1,7-linked-α-D-diseptanoside, through the oxyglycal 
route.  Ring-opening of oxyglycal derived gem-dihalo-1,2-cyclopropanated derivative with 6-
hydroxy glycal led to 1,7-α-linked disaccharide unit.  The following reactions were performed in 
order to synthesize 1,7-linked-α-diseptanoside 2: (i) cyclopropanation of the glycal double bond; (ii) 
ring opening of the gem-dihalo cyclopropane; (iii) RuO4 mediated oxidation; (iv) NaBH4 reduction 
 vi 
 
 
and (v) hydrogenolysis using Pd/C, H2 (Scheme 9).  Similar methodology was used for the synthesis 
of monoseptanoside, namely, n-pentyl-D-glycero-D-galacto-septanoside.  
Scheme 9 
O
BnO
OBn
OBn
Cl
Cl
BnO OHO
HO
HO OH
OH
O
1  
 
Oxyglycal route was also used for the synthesis of 2-chloro-2-deoxy septanoside 3, using 
hydrogenolysis (Pd/C, H2) and NaBH4 mediated reduction of chloro-oxepine (Scheme 10). 
Scheme 10 
 
A kinetic study of the hydrolytic stabilities of mono-and diseptanoside was undertaken using an 
acid-catalysis, in a subsequent investigation.  In the course of studies, it was observed that glycosidic 
bond in the reducing-end hydrolyzed twice faster than that at the non-reducing end, whereas 
glycosidic bond in monosaccharide 1 hydrolyzed 1.5 times faster than of reducing-end glycosidic 
bond in diseptanoside 2.  Further, it was found that the replacement of the C-2 hydroxyl group by a 
chloride group reduced the rate of hydrolysis (Table 1).   
 vii 
 
 
Table 1. First order rate constants and thermodynamic parameters for the acid-catalyzed hydrolysis 
of glycosidic bond in septanosides 1, 2 and 3. 
 
 
 
 
 
 
 
 
 
 
a non-reducing end of 2.  
A computational study was conducted, in order to gain further insight into the hydrolysis, using 
B3LYP/6-311G* level theory in the Gaussian 09 program packages.  Calculations using the PCM 
solvent model with water as the solvent showed that the orientation of hydroxylmethyl group plays 
an important role.  In the case of 1, the gg conformer was calculated stable by 2.12 kcal/mol, as 
compared, to tg-conformer.  In the gg conformation, the optimal positioning of the dipole C7-O7 
stabilized the oxo-carbonium ion in the transition state (Figure 1).  Also, hydroxyl group at C4 
stabilized the transition state, through non-covalent interaction (Figure 1).  The transition state for 
the hydrolysis of 1 was found to present activation barrier (∆G#) of 19.9 kcal/mol, which was in good 
agreement with value for 1 (∆G# = 23.26 kcal/mol), as calculated from Erying plot (Table 1).  On the 
other hand, inductive effect of the chloride group, as well as, the tg-orientation of the hydroxymethyl 
group appeared to contribute to the slower rate of the hydrolysis.  
 
Figure 1. gg- and tg-conformations in the ground state of 1.  
 
Compound 
 
Rate of hydrolysis 
(kobs) (104 s-1) 
   
ΔH# 
(kcal/mol)
 
ΔS# 
(cal/mol K) 
 
ΔG# 
(kcal/mol) 
35 oC 45 oC 85 oC 90 oC    
1 2.34 5.61 - - 12.95 −32.88 23.26 
2 1.54 
- 
3.31 
1.36a 
- - 13.18 −33.17 23.56 
3 - - 0.418 2.12 72.44 −123.60 27.90 
OHO
HO
HO OH
OH
OMe
1 gg tg
 viii 
 
 
Chapter 4 describes synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy 
septanoside and their acid-catalyzed hydrolysis studies. 
 
Solid-state and solution phase conformation of septanosides are rare at present even when 
solid-state structures of pyranoside and furanosides are known commonly, that provide rich 
information of covalent and non-covalent interactions.  In this context, single crystal X-ray structural 
analysis of septanosides, namely, n-pentyl-2-chloro-2-deoxy-α-D-manno-sept-3-uloside 4 and p-
bromo phenyl 4,5,7-tri-O-benzyl-β-D-glycero-D-talo-septanoside 5 were analyzed.  It was observed 
that the solid-state structure of 4 adopted twist-chair conformation, namely, 5,6TC3,4, whereas 5 
adopted O,1TC2,3 conformation (Figure 2).  An analysis of non-covalent interactions revealed that a 
dense network of O−H···O and C−H···O stabilized the crystal lattice of 4, whereas O−H···O and 
C−H···π stabilized the crystal lattice of 5. Chapter 5 describes the detailed analysis of X-ray crystal 
structure of two septanoside derivatives including non-covalent interactions responsible for the 
stabilization of crystal lattice. 
 
 
 
  
 
4           5 
Figure 2. ORTEP of 4 and 5 with displacement ellipsoids, at a 10 % and 50 % probability level. 
 
In summary, the thesis established the following major results: (i) synthesis of 2-deoxy-2-C-
alkyl/aryl septanoside from a bromo-oxepine, using organometallic C-C bond forming reactions; (ii) 
the ring-opening reaction of oxyglycal derived gem-dihalo-1,2-cyclopropane in the presence of 
AgOAc and the effect of additional C-2 oxy-substituent in the reactivity, in comparison to glycal; 
(iii) an oxyglycal route for the synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy 
septanoside and their acid-catalyzed hydrolysis studies and (iv) solid-state X-ray crystal structural 
analysis and computational analysis of the conformation and non-covalent interactions associated 
with the stabilization of crystal lattice. 
Overall, the studies presented in the thesis provide a new insight into the synthesis, acid-
catalyzed hydrolysis and solid-state structural analysis of septanoside derivatives.  
O6
C1
C2
C3 
C4 
C5 
C6
C7 
C8 
C9 
C10  C11 
C12
O1
O3
O4
O5
O7
ClO1
 ix 
 
 
The following publications and presentations were based on the Thesis work: 
 
1. Dey, S.; Jayaraman, N. “Branching out at C-2 of Septanosides. Synthesis of 2-deoxy-2-C-
alkyl/aryl septanosides from a bromo-oxepine”, Beilstein J. Org. Chem. 2012, 8, 522-527. 
 
2. Dey, S.; Jayaraman, N. “Exclusive Ring Opening of gem-dihalo-1,2-Cyclopropanated Oxyglycal 
to Oxepines in AgOAc”, Carbohydr. Res. 2014, 389, 66-71. 
 
3. Dey, S.; Jayaraman, N. “Dense Network of O−H···O and C−H···O Interactions in the Solid-state 
Structure of n-Pentyl-2-Chloro-2-Deoxy-α-D-manno-Sept-3-Uloside”, Carbohydr. Res. 2014, 
Revised manuscript submitted. 
 
4. Dey, S.; Jayaraman, N. “Glycosidic Bond Hydrolysis in Septanosides: A Comparison of Mono-, 
Di- and 2-Chloro-2-Deoxy-Septanosides”, Manuscript submitted.  
 
5. Dey, S.; Jayaraman, N. “Solid-state Structure of p-Bromo Phenyl 4,5,7-Tri-O-benzyl-β-D-glycero-
D-talo-septanoside: Stabilization of the crystal lattice by a network of O−H···O, C−H···O and C−H··· 
π interactions”, Manuscript to be submitted. 
 
6. Dey, S.; Jayaraman, N. “Studies of 1,2-Unsaturated Sugars Through Expansion, Shifts and 
Rearrangements”, Oral presentation in 26th International Carbohydrate Symposium, July 2012, 
Madrid, Spain.  
 
7. Dey, S.; Jayaraman, N. “Studies of 1,2-unsaturated sugars through expansions and 
rearrangements”, Poster presentation in International Meeting on Chemical Biology, May 2013, 
IISER-Pune, India. 
 
8. Dey, S.; Jayaraman, N. “Branching out at C-2 of septanosides. Synthesis of 2-deoxy-2-C-
alkyl/aryl septanosides from a bromo-oxepine”, Oral presentation in 27th International Carbohydrate 
Symposium, Jan 2014, IISc, Bangalore, India.  
 
 x 
 
 
9. Dey, S.; Jayaraman, N. “Ring Opening of Cyclopropanated Oxyglycals: (i) Branching out at C-2 
of Septanosides and (ii) Studies of Ring Opening Reactions”, Oral presentation on Pfizer Symposium 
on Organic Chemistry, Prof. D.K. Banerjee and Prof. A. Srikrishna Memorial Award Lectures, Jan 
2012, IISc-Bangalore, India.  
 
 


VAPOUR-LIQUID EQUILIBRIUM (VLE) MEASUREMENT AND PREDICTION FOR PROCESS EQUIPMENT DESIGN

Pulipati, Lokesh

SYNTHESIS AND EVALUATION OF HYBRID HETEROCYCLES

AS NOVEL ANTITUBERCULAR AGENTS AND TOTAL SYNTHESIS OF ENIGMOL

Bejugam, Santhosh Kumar

SYNTHETIC APPROACHES TO PENTENOMYCINS, SOME CARBASUGARS AND

AMINOCARBASUGARS FROM CARBOHYDRATES

Shanigaram, Balaiah

Abstract
vi
Abstract
Introduction
In the recent years, the predicted exhaust of fossil fuels actuated the world to search for an
alternative source of energy for their increased necessity. Only the renewable energies will be
able to compensate the demand. Optoelectronics is the best alternative of energy which includes
photovoltaics, OLEDS, etc. The sun is the infinite source of renewable energy. So the most
affordable technology to get more energy is the photovoltaics, the emerging technology in the
field of optoelectronics. Another way of conserving the energy is to use it efficiently with less
energy to produce more light. Here OLEDs comes into the picture. Developing efficient
materials for Optoelectronics is the challenging task. Theoretical methods have been playing
significant role to model efficient optoelectronic material. This thesis is organised in to five
chapters.
Chapter 1
This Chapter includes introduction and classifications of various optoelectronic devices such
as silicon solar cells, DSSC and OLED and materials involved in these devices. Further various
DFT methodologies which are used to successful design of the materials for these applications
are discussed in detail. The main role played by these materials and computational explanation
for the suitability of the molecules for the applications are discussed.
Chapter 2
This chapter describes a study of the molecules TCNQ and F4-TCNQ surface doped on
hydrogen-terminated Si (111) surface [H-Si(111)], with emphasis on the role of van der Waals
interactions in stabilizing the molecular adsorption orientations and the binding energy using
density functional theory(DFT).
Abstract
vii
Figure 1
The most stable spatial configuration of the adsorbed molecules predicted with and without
including the dispersion energy in a low concentration dopant system is same though the
magnitude of the binding energy is much larger in the former case. On the other hand in the case
of increased dopant concentration the adsorption orientations predicted with and without the
inclusion of dispersion energy are different and so is the magnitude of the binding energy. It is
conclude that inclusion of dispersion energy term is important for correct prediction of the spatial
configurations of the adsorbed molecules in surface transfer doping of semiconductors. Finally it
is observed there is a charge transfer from H-Si(111) to dopant as shown in Figure 1.
Chapter 3
In this chapter, opto-electronic and charge transport properties of the six Anthracene-
Oxadiazole derivatives (1a-1c and 2a-2c) (Scheme 1) which show promising charge transport
properties in OLED are studied using DFT and TD-DFT methodologies. Estimated
reorganization energies, charge transfer integrals witness the importance of these molecules as
emitters and charge transporters in the OLED device development. For a good charge transporter
well stacked crystal structure is required.
O
N
N
R
1a:
1b:
O
NN
R
2a:
2b:
2c:1c:
R=
R=
R=
R=
R=
R=
O O
O
O
Scheme 1
Figure 2 FMOs of 1a
Abstract
viii
Chapter 4
This chapter dealt with the two A-D-A type TPA derivates (TPA1 and TPA2) with different
number of anchoring carboxylic acid groups showing different efficiencies in DSSCs. Their
photo voltaic performance difference is explained by DFT, TD-DFT and periodic DFT
calculations.TD-DFT data is well harmonized with experimental UV-Vis absorption data.
Periodic DFT calculations were carried out on nanocrystaline TiO2 modeled with a slab of 5x8
super cell of TiO2(101) anatase phase and the dyes were tethered on to the surface in different
adsorption modes such as bi-dentate bridging mode(BB), mono-dentate(BB) and two mono-
dentate modes (M-M) (Figure 3) among which two mono-dentate mode(M-M) show strong
adsorption energy which could be reason for high efficiency in DSSC. From the isosurface plots
of highest occupied molecular orbital (HOCO) and least unoccupied crystal orbital (LUCO) of
the dyes adsorbed on to the TiO2(101) there is a charge transfer clearly observed from dyes to
TiO2(101) surface.
Figure 3 Crystal orbitals of TPA1 (BB mode) and TPA2 (BB and M-M mode)
Chapter 5
In this chapter, a new class of helically folded quinolinemolecules has been suggested
possessing the charge transfer property. Five quinoline derived tetramer molecules F4- F7
(Scheme 2) has been designed appended with donor OPV (oligo(p-penylene vinylene) as donor
HOCO
LUCO
HOCO
LUCO
HOCO
HOCO
Abstract
ix
varying in number and position on Q4 ring and –COOH group as acceptor. The detailed
computational investigation has been carried out to predict the charge transfer and charge
delocalization behavior of folded molecule and its corresponding linear form. The folded form of
each molecule shows the higher intensity of charge transfer as compare with corresponding
linear form. LUMO in folded form is delocalized over the entire quinoline tetramer unlike the
linear form where it is localized only on the fourth quinoline ring and –COOH region. This
theoretical investigation demonstrates that helical quinoline ring act as a conjugate bridge during
the charge transfer from donor to acceptor which breaks in the linear form. Owing to a higher
intensity and presence of conjugation in charge transfer for such kind of foldamers may have
significant use in the field of material science.
N NH
O
N
N H
O N
N
H
O
N
C O O H
N H
R 1
O
O C H 3
O C H 3
O C H 3
O C H 3
R 2
R 3
R 4
R 5
1) R1 = OPV, R2=R3=R4=R5=H (F4)
2) R2=R3=OPV, R1=R4=R5=H (F5)
3) R1= CH3, R2=R3=R4=OPV R5=H                  (F6)
4) R1= CH3, R2=R3=R4=R5=OPV                      (F7)
Scheme 2


Electronic Structures of Molecules Showing Optoelectronic

Properties: Computational studies using DFT and

Periodic DFT Methodologies

JENA, BIGHNANSHU KUMAR

SYNTHESIS OF PALMEROLIDE A, SACROLIDE A, AND ASPERGILLIDE D

Adiyala, Praveen Kumar Reddy

SYNTHESIS OF PYRROLO[2,1-C][1,4]BENZODIAZEPINE (PBD)

PRODRUGS, DEVELOPMENT OF NEW METHODS FOR SYNTHESIS OF HETEROCYCLIC LIBRARIES AND TOTAL SYNTHESIS OF PINOLIDE

Nandigama, Satish Kumar

Synopsis 
vi 
 
The thesis entitled “Stereoselective Total Synthesis of Trichoderic acid and 
Development of Catalyst-free Green Methodologies on or in Aqueous Medium” has 
been divided into three chapters. 
Statement of Problem 
CHAPTER I: Stereoselective first total synthesis of Trichoderic acid   
Introduction : The isolation of a bisabolane-type sesquiterpene, trichoderic acid (1) 
reported by Wu et al in 2011, from the culture broth of Trichoderma sp. PR-35, an 
endophytic fungus isolated from Paeonia delavayi. It has been evaluated for its 
antibacterial and antifungal activities in addition to this the extract also shown biological 
properties such as: sedative, analgesic, and anti-inflammatory agent, and also a remedy 
for cardiovascular.  
O
H
H
OH
OH
Trichoderic acid (1)
 
Methodology (Retrosynthetic analysis): The stereoselective total synthesis of 
Trichoderic acid (1) starts from commercially available 3-methylcyclohex-2-enone. The 
key steps involved in this synthesis were stereoselective reduction, alfa-methylation of 
lactone and trans-witting coupling by Horner-Emmons Reagent obtain Trichoderic ester.  
 
Scheme 1. Retrosynthetic analysis of Trichodericacid 
Synopsis 
vii 
 
Results and discussion:
 
Conclusion: In conclusion, successful synthesis of trichoderic acid (1) was accomplished 
from 3-methyl cyclohexenone by stereoselective reduction, Horner-Emmons Reagent and 
intramolecular oxa-Michael reactions as key steps. 
CHAPTER II: This chapter describes the development of new synthetic 
methodologies on azaarenes under catalyst-free conditions on water. These azaarene 
derivatives were evaluated for biological properties as well as photophysical 
properties. 
Section A:  
A catalyst-free one-pot three-component approach for the synthesis of 2-(1-aryl-2-
(azaaryl)ethyl)malononitriles via sp3 C-H activation of 2-methyl azaarenes.  
Combinatorial libraries of 2-(1-aryl-2-(azaaryl)ethyl)malononitriles derivatives have been 
synthesized by catalyst-free one-pot three-component protocol and employing water as a 
solvent. Simple reaction, open air reaction and easy isolation are added advantages of this 
Synopsis 
viii 
 
method. The method is applicable for aryl as well as heteroaryl system and provides a 
convenient access for the synthesis of novel quinoline derivatives. All the 2-(1-aryl-2-
(azaaryl)ethyl)malononitrile derivatives were evaluated for their antimicrobial activity 
against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, and 
Bacillus cereus) and Gram-negative bacteria (Pseudomonas aeruginosa). Some of the 
compounds exhibited good antibacterial activity against both Gram-positive pathogens 
and Gram negative species.  
   
O CN
CNN
R1
N
CN
CN
R1
R2
R2
++ H2O
reflux, 100 oC
30 examples
1 2 3 4
       
Scheme 2. Catalyst-free one-pot three-component synthesis of 2-(1-aryl-2-
(azaaryl)ethyl)malononitriles 
 
Section B: A domino green method for the rapid synthesis of novel fused isoquinoline 
derivatives via Knoevenagel/Michael/cyclisation reactions on aqueous media and their 
photophysical properties  
An expedient, eco-friendly and green-protocol have been developed for the synthesis 
of novel 4-imino-2-aryl-4H-pyrido[2, 1-a]isoquinoline-3-carbonitrile derivatives via 
Knoevenagel/Michael/cyclisation reactions in one-pot under catalyst-free condition on 
aqueous medium. These products exhibited UV-Vis absorption and photoluminescence 
properties.   Structure of the product was confirmed by single x-ray crystallography. 
Synopsis 
ix 
 
                  
Scheme 3. Catalyst-free one-pot three-component synthesis of 4-imino-2-aryl-4H-pyrido[2,1-
a]isoquinoline-3-carbonitrile derivatives  
CHAPTER-III: This chapter describes the development of new synthetic 
methodologies for catalyst-free Michael addition/Friedel-Crafts alkylation of 
pyrazolone and tetrahydroisoquinoline with β-nitrostyrenes. These protocols are 
eco-efficient and eco-friendly using water as a reaction meadium, this chapter is 
further divided into two sections. 
Section A: 
A Catalyst Free Michael Addition of 3-Methyl-2-Pyrazolin-5-one to β-nitrostyrenes 
"On Water": A Green protocol for facile synthesis of 4-(1-aryl-2-nitroethyl)-3-
methyl-1H-pyrazol-5-ol  
A highly efficient and green protocol has been developed for the synthesis of 4-(1-aryl-2-
nitroethyl)-3-methyl-1H-pyrazol-5-ol via Michael addition of 3-Methyl-2-Pyrazolin-5-
one with β-nitrostyrenes under catalyst-free conditions on aqueous medium. A series of 4-
(1-aryl-2-nitroethyl)-3-methyl-1H-pyrazol-5-ols have been synthesized in good to 
excellent yield. C-alkylated product was observed exclusively with 3-Methyl-2-
Pyrazolin-5-one without formation of N-alkylated product. 
      
Scheme 4. Michael addition of 3-methyl-2-pyrazolin-5-one to the β-nitrostyrenes. 
Section B: 
Synopsis 
x 
 
Efficient and eco-friendly protocol for the synthesis of novel 6-substituted 
Tetrahydroquinolines via C6-functionalisation of Tetrahydroquinolines with 
chromene acetals and β-nitrostyrenes in aqueous meadium 
 A facile, novel and eco-efficient method has been developed for the C6-functionalisation 
of unprotected tetrahydroquinoline (THQ) with chromenes and β-nitrostyrenes to afford 
novel 6-substituted tetrahydroquinolines in aqueous medium.  
 
Scheme 4. Synthesis of C6-functionalized THQ derivatives. 
 
 
 
 
 
 


Stereoselective total synthesis of Trichoderic acid and

development of catalyst-free green methodologies on or in

aqueous medium

Madamsetty, Vijay Sagar

SYNOPSIS 
  
Synopsis 
 
Introduction 
The daunting disease of cancer owe its origin to numerous complex genetic and 
non-genetic factors, both intrinsic and extrinsic.  Despite the century old efforts from 
scientists and physicians across the globe for finding cure for this deadly disease, long 
term cure without any relapse of tumor remains elusive.  The hallmarks of most, if not 
all, types of cancer include: self-sufficiency in growth signals, resistance to growth 
suppressors, evading apoptosis, limitless proliferation, inducing angiogenesis, invasion 
& metastasis, reprogramming energy metabolism and lastly, evading the host’s immune 
system. Clinical success of most of the contemporary cancer therapies are limited due to 
non-availability of highly tumor specific drug delivery systems leading to adverse side 
effects on various non-cancerous healthy body tissues, insufficient bioavailability of 
many potent cancer therapeutics, drug resistivity, and the poor physicochemical 
properties of many anti-cancer drugs. To overcome these challenges, chemotherapeutic 
drugs (single or combination) or genetic drugs are often delivered selectively to the 
diseased site with the help of ligand coated liposomal or polymeric drug delivery 
systems for targeting drugs to cancer cells via receptors over expressed selectively on 
the exo-surfaces of  cancer cells. The current thesis embodies design, synthesis, physico-
chemical characterizations, bio-activity evaluations of two novel ligand-coated 
liposomal drug delivery systems for treatment of pancreatic cancer and lung carcinoma. 
Furthermore, the findings of the present thesis demonstrate for the first time that 
liposomally targeted chemotherapy, when used in combination with in vivo dendritic 
cell (DC), targeted DNA vaccination elicits markedly enhanced overall survivability of 
orthotopic pancreatic and lung carcinoma-bearing mice.  
Statement of the problem 
Cancer has long been considered to be a profoundly complex disease with 
second highest mortality rate treatable only with blunt approaches that frequently do as 
much damage to the patient as to the tumor. Pancreatic cancer is often detected late, 
spreads rapidly, and has a poor prognosis. After diagnosis, 25% of people survive one 
year and 5% live for five years.  In an estimated 53,070 new cases of pancreatic cancer, 
41,780 death of pancreatic cancer patients have been reported in 2016.  Lung cancer is 
Synopsis 
 
the number one cause of cancer deaths in both men and women in the U.S. and 
worldwide. The vast majority (85%) of cases of lung cancer are due to long-
term tobacco smoking. The general prognosis of lung cancer is poor because doctors 
tend not to find the disease until it is at an advanced stage. Five-year survival is around 
54% for early stage lung cancer that is localized to the lungs, but only around 4% in 
advanced, inoperable lung cancer. Lung cancer occurred in 1.8 million people and 
resulted in 1.6 million deaths Worldwide in 2012. Thus, there is an urgent need for 
developing novel and more competent approach for eradicating and enhancing the 
overall survival rate of both pancreatic and lung cancer patients using targeted 
chemotherapy and cancer immunotherapy. 
Objectives of the study 
1. To develop the plectin-1 receptor (plec) targeting  liposomal formulations of 
novel plectin-1 selective KTLLPTP-lipopeptide and to evaluate their therapeutic 
promises in combating orthotopic mouse pancreatic cancer using our newly 
developed approach of combining targeted chemotherapy and direct in vivo DC-
targeted DNA vaccination. 
2. To develop lung cancer targeting liposomal formulations of novel SNIDARAK-
lipopeptide & its non-targeting control NSSSVDKK-lipopeptide and to evaluate 
their therapeutic promises in combating orthotopic mouse lung cancer using our 
newly developed approach of combining targeted chemotherapy and direct in 
vivo DC-targeted DNA vaccination. 
3. Structure-activity studies on the use of liposomes of mono-, di-, and tri-
guanidinylated cationic amphiphiles for systemic co-delivery of potent anti-
cancer drugs paclitaxel (PTX) & CDC20 siRNA co-encapsulated within the 
liposomes of these guanidinylatd amphiphiles using an orthotopic mouse lung 
tumor model. 
Methodologies Used and Sample Results 
Part 1 describes development of the plectin1-targeting liposomal formulations of 
lipopeptide containing phase display derived pancreatic cancer targeting ligan 
KTLLPTP in the head group region (lipopeptide 1) and its nontargeting control 
Synopsis 
 
lipopeptide with SNLHPSD in the head group region (lipopeptide 2). The fluorescently 
labeled liposomal formulations of lipopeptide 1 showed higher cellular uptake in 
pancreatic cancer cells (Pan02, Panc-1, and Miapaca-2) compared to normal NIH3T3 
Cells. Plectin-1 receptor selective cellular uptake process for these liposomal formutions 
were confirmed by antibody saturation. The ex vivo fluorescence values of isolated 
organs revealed that mice injected with NIR-labeled liposomal formulation of 
lipopeptide 1 had strong fluorescence in the orthotopic pancreatic tumor compared to 
other isolated organs. Importantly, combination of i.v. administration of the liposomal 
formulation of lipopeptide-1 containing both curcumin & gemcitabine and genetic 
immunization with in vivo DCs targeting lipoplex of liposomes of mannose-mimicking 
cationic amphiphile (recently developed in our laboratory) & p-CMV-MSLN (a plasmid 
DNA encoding mesothelin expressed in the majority of pancreatic cancer cells) 
regressed and increased survivability of the established orthotopic mouse pancreatic 
tumor model in syngeneic C57BL/6J mice. The findings in CTL assay and cytokines 
assay (IFN-γ & IL-4) clearly demonstrated that the in vivo DCs targeted lipoplexes were 
efficient in inducing cellular and humoral response against pancreatic cancer. 
 
H
N
O
N
H
H3N
O
N
O
H
N
OH
O
N
O
N
H
O
H
N
O
N
H
HO
O
NH3
NH3
N
n-C18H37
n-C18H37
Cl
Cl
Cl
H
Cl
0
500
1000
1500
2000
2500
control naked 
MSLN
Lipo+Luci Lipo+MSLN
I
F
N
-
γ
(
p
g
)
/
1
0
6
 c
e
ll
s
-10
0
10
20
30
40
50
60
70
100:1 80:1 60:1 40:1 20:1 10:1
%
 
 
o
f
 
 
L
y
s
i
s
E:T ratio
control
naked MSLN
lipo-luci
lipo- MSLN
0
0.5
1
1.5
2
2.5
3
control naked 
MSLN 
Lipo+Luci Lipo 
+MSLN
I
L
-
4
 
(
p
g
)
/
1
0
6
 
c
e
l
l
s
0
0.5
1
1.5
2
2.5
3
3.5
4
Control lipo-(cur+gem) lipo-MSLN lipo-(cur+gem)& 
lipo-MSLN%
 O
f
 T
u
m
o
r
 w
e
ig
h
t
 w
.
r
.
t
 b
o
d
y
 w
e
ig
h
t
 
Treatment Groups 
0
20
40
60
80
100
120
14 28 38 48 56 65 75 85 95 105
%
 
o
f
 
S
u
r
v
i
v
a
l
Days after tumor implantation 
control
Lipo-Cur+Gem
lipo-MSLN 
lipo-(cur+gem )& 
lipo_MSLN
1 2 3 4
a
b
c
d e
f
Curcumin, gemcitabine 
MSLN-pDNA 
Co lipids 
+
KTLLPTP
 
 
The Part 2 of the present thesis describes design of a novel lung cancer targeting 
liposomal formulations of SNIDARA-lipopeptide (lipopeptide 1) and its non-targeting 
control lipopeptide with NSSSVDK in the head group region (lipopeptide 2). Further, 
this parts embodies development of a novel liposomal delivery system prepared using 
the above-mentioned lipopeptides for lung cancer targeted delivery of curcumin and 
doxorubicin. The labeled liposomal formulation of lipopeptide 1 showed higher cellular 
Synopsis 
 
uptake in lung cancer cells (LLC, H460, and A549) compared to normal NIH3T3 Cells. 
The ex vivo fluorescence values  of isolated organs revealed that mice injected with 
doxorubicin loaded  liposomal formulation of lipopeptide 1 had strong fluorescence in 
the orthotopic pancreatic tumor compared to other isolated organs. Findings in the MTT-
assay basedcCell viability studies and annexin-v binding based apoptosis studies 
demonstrated that co-delivery of curcumin and doxorubicin loaded targeted liposomes 
maximally enhanced the anti-cancer effect. The same result was also found during cell 
cycle study where curcumin and doxorubicin delivery via targeting liposome exhibited 
maximum G2/M population. Importantly, combination of i.v. administration of the 
liposomal formulation of lipopeptide-1 containing both curcumin & doxorubicin and 
immunization with in vivo DCs targeting lipoplex of mannose-mimicking cationic 
amphiphile (recently developed in our lab) & p-CMV-MUC-1 (a plasmid DNA 
encoding MUC-1 expressed in the majority of lung cancer cells) regressed and increased 
survivability of the established orthotopic mouse lung tumor model in syngeneic 
C57BL/6J mice. 
Part 3 of the present thesis embodies structure activity studies using different 
liposomal formulations of mono-, di- and tri- guanidinylated cationic amphiphiles 
containing co-encapsulated anti-cancer drugs and genes. PTX (hydrophobic drug) was 
solubilized within the lipid bilayer regions of the liposomes and CDC20 siRNA 
(hydrophilic anti-cancer siRNA) was encapsulated within the aqueous core of the 
liposomal formulations. Bio-activities of the liposomal formulations of these cationic 
guanidinylated amphiphiles were evaluated both in vitro and in vivo. Biodistribution 
studies using FAM-siRNA labeled liposomes revealed orthotopic mouse lung tumour 
selective accumulation of the liposomal formulations in syngeneic C57BL/6J mice.  The 
plasma stability of FAM-siRNA labeled liposomes, MTT-based cytotoxicity assays, 
Annexin-V binding based apoptosis studies and cell cycle arrest at G2M phase were 
studied.  Finally, in vivo tumor inhibition and survival studies were done with the most 
efficient liposomal formulation containg both PTX and CDC20 siRNA in orthotopic 
mouse lung tumor model. Importantly, the findings in these structure-activity studies 
convincingly demonstrated that presence of more positive charge (due to presence of 3 
Synopsis 
 
guanidine groups in the head-group region) can enhance the entrapment efficiency of 
drugs and genes, and increase the plasma stability of the liposomal formulations. 
 
1 2 3 4
0
20
40
60
80
100
120
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
%
of
 su
rv
iv
al
days after tumor implantation 
0
1
2
3
4
5
6
7
8
control lipo-PTX lipo-CDC20 lipo(PTX+CDC20)
%
 O
f T
um
or
 w
ei
gh
t w
.r
.t
bo
dy
 w
ei
gh
t 
0
20
40
60
80
100
120
%I
D 
/m
L o
f P
las
m
a 
18MG
18BG
18TG
0
10
20
30
40
50
60
70
tumor liver kidney heart spleen pancrease blood
%
 o
f I
D
/ i
n 
ea
ch
 o
rg
an
  
18MG
18BG
18TG
B
GAPDH
CDC20 
A
CDC2
0 
18S 
I
II
 
 
Conclusion 
The findings described in the present thesis collectively demonstrate that  use of 
tumor-targeted liposomal drug delivery in combination with in vivo dendritic cell 
targeted DNA vaccination leads to remarkable survivability enhancements in orthotopic 
pancreatic and lung tumor bearing mice. Such combination therapy holds potential for 
future use as a “platform technology” in the war against the dreaded disease of cancer. 


Combating pancreatic and lung cancer by liposomally targeted chemotherapy in combination with in vivo dendritic cell targeted DNA vaccination

Kaushik, Arun

Preface
At the core of statistics lies the ideas of statistical inferences. Methods of statistical inference
enable the investigator to argue from the observations in a particular sample to the general case;
also help us to understand our world and make sound decisions about how to act. In general, in-
ferences may be classified into two groups based on the logical reasoning used, namely inductive
and deductive. In inductive inference, we are attempting to draw inferences from the particular
to the general. Whereas deductive inference refers to arguments those are certain to be true by
definition and derivation. Further, Inferences may also be classified into two groups based on
the assumptions made about the model for the considered data set, namely parametric and non-
parametric inferences. For more details about parametric and non-parametric inferences, readers
may refer to Rohatgi and Saleh (2003), Walker and Lev (1953), Lehmann and Casella (1998),
Boes et al. (1974), etc. Another classification of the statistical inference, depending upon the in-
terpretation of probability and type of information used for inferences, that leads to two different
paradigms for statistical inference; namely, the classical paradigm and the Bayesian paradigm. In
Classical approach one uses the information available from the sample only and considers the
parameters as unknown constants.
After classification of model based on information in hand, the next step is to estimate the
parameters involved therein. In the statistical literature various classical and Bayesian estimation
techniques are discussed for point estimation problem. These stated inferential procedures are
based on data observed according to specific situations. Mostly, in the field of lifetime study, the
data related to the units (man made or god made) are obtained from the lifetime experiments
where randomly selected units are put on test under a specified condition. The lifetime of the units
are observed. It may be noted that the observation thus obtained will naturally be obtained one
after the other i.e. the life times are ordered observations in natural way. It may be noted here
that the lifetime test as mentioned here will often be time consuming and costly. Thus one can not
afford to wait till all the units put on test fails. Therefore many times, situations do arise when the
Preface
units under study are lost or removed from the experiments while they are still alive i.e., we get
censored data in such cases. If the point at which the experiment terminates is time dependent,
it is called Type-I censoring. If it is unit dependent, it is called Type-II censoring. Depending
on the need and practical considerations, various modified forms of censoring schemes have
been discussed in the literature. Cohen (1965) developed a censoring scheme and named it
progressive Type-II censoring scheme, which facilitates the removals of the units from the test
at certain specified stages before termination of the experiment. For more details about various
censoring scheme see Balakrishnan and Aggarwala (2000), Cohen and Norgaard (1977), Davis
et al. (1979), Viveros and Balakrishnan (1994b), Balakrishnan and Sandhu (1995), etc.
Another situation which is often met in some of the life testing experiment is related to the lim-
itation of the recording exact failure time of the units put on test. In such situations, random lifetime
of interest is known only to lie within an interval instead of being observed exactly. This type of
inspection plan give rise to a new censoring scheme, called interval censoring. Finkelstein (1986)
has discussed many clinical trials and longitudinal studies falling in this category. According to
Jianguo (2006), interval-censored failure time data occurs in many other areas also including de-
mographic, epidemiological, financial, medical, sociological and engineering studies. Aggarwala
(2001) proposed a combination of interval Type-I censoring and progressive censoring and called
it as progressive interval Type-I (PITI) censoring which is having wide applications in clinical trials.
The present piece of work aims to explore the estimation method for PITI censoring scheme
in Classical as well as in Bayesian paradigm for the considered distributions. It is also aimed to
inquire whether censoring scheme have any significant effects on estimators and how much. We
have dealt the Classical and Bayesian point estimation along with interval estimation of the param-
eters for considered life-time models under specified loss functions. For Bayesian computation,
the MCMC techniques with M-H algorithm has been used to study the properties of the posterior
distribution and proposed estimators. Under M-H algorithm, the asymptotic (normal) distribution
of the posterior is considered as the proposal density for sample generation from that posterior.
The whole thesis is divided into 5 chapters. Among them, Chapter 1 provide a basic reading
material so as to equip the reader for understanding the problems discussed in the following
chapters. Although the topics considered have not been discussed in detail, it is attempted to
provide sufficient references so that interested readers can look into the references to have the
complete knowledge of the topics. Finally, we provided the motivation and summary of the present
work.
The Chapter 2 deals with the various estimator for parameters of Generalised Exponential
distribution under PITI censoring scheme when removals follow binomial distribution. We have
checked the performances of the estimators under different considered removals and inspection
plans. Since the ML estimators are not obtainable in explicit algebraic form, therefore, we pro-
pose to use some numerical iterative method, here we have used Newton-Raphson method in
R-environment. Further, we observed that the Newton-Raphson method do not converge all the
x
Preface
times, Therefore, we also used EM-Algorithm to obtain the ML estimates. Estimation of param-
eters under the Bayesian paradigm using non-informative and gamma priors when loss is con-
sidered to be SELF has also been considered. Bayes estimators also have not been obtained
in explicit algebraic form. Therefore, we propose to use of M-H algorithm. Some diagnosis of
M-H algorithm in the present problem is also discussed. We illustrate our proposed methodology
with the two real examples. The first is related to the survival time of patients with Plasma Cell
Myeloma data and the second is regarding to the number of revolutions (in million) before failure
of groove ball bearings. On the basis of examples, we can’t check the performance of estimators,
so we conducted a Monte Carlo simulation study. For the simulation purpose, one need the gen-
eration of samples from specified model under considered censoring scheme. For this purpose
we have developed an algorithm. Comparison of the performances of the various estimates of the
parameters involved in the model along with reliability and hazard functions is made on the basis
of their average absolute bias and mean square error (MSE). The content of this chapter is based
on the author’s paper “A. Kaushik, U. Singh and S. K. Singh (2017). Estimations of the param-
eters of generalised exponential distribution under progressive interval Type-I censoring scheme
with random removals, AUSTRIAN JOURNAL OF STATISTICS.”
In the previous chapter, we have discussed the procedure regarding the PITI censored sample
considering the removals as Binomially distributed. In fact the probability of removal shall vary from
patient to patient, also visit to visit and remains unknown to the experimenter. Thus, one should
consider that the removal probability p to be random following a probability distribution. Keeping
this point in mind, we propose beta-binomial distribution for the number of removals. In this chapter
i.e. Chapter 3, we have discussed the problem of point and interval estimation of the shape and
scale parameters of Weibull distribution based on PITI censoring with Beta-Binomial removals
(PITICBBR). The Bayes estimators have been obtained by considering both symmetrical (SELF)
and asymmetrical (GELF) loss functions. The estimators thus obtained, have been compared with
the corresponding maximum likelihood estimators for their risks through Monte Carlo Simulation
study. Further, expressions for the expected number of total failures (ENTF) have been derived
for PITICBBR censoring scheme. Finally, a real data set has been considered to illustrate the
practical utility of the paper. The content of this chapter is based on the author’s paper “A. Kaushik,
U. Singh and S. K. Singh (2015). Bayesian Inference for the Parameters of Weibull Distribution
under Progressive Type-I Interval Censored Data with Beta-binomial Removals, Communications
in Statistics - Simulation and Computation.”
In the earlier chapters, we have seen that the inspection scheme and removals schemes do
effect the performance of the estimators i.e. censoring scheme play a significant role to obtain the
parameter’s estimates. Abo-Eleneen (2011), Awad (2016) and Cho et al. (2015) compared the
different censoring scheme in the experiments utilizing the entropy. The use of entropy measures
for quantifying the information loss due to censoring has been proposed by Hollander et al. (1987).
Kittaneh and Akbar (2014) discussed the efficiency of Type-I censored sample from Weibull distri-
xi
Preface
bution based on sub-measure of entropy. Kittaneh and El-Beltagy (2015) has compared censored
sample utilizing the entropy. But all these studies are limited to Type-I, Type-II and progressive
censoring. No work has been done in this direction for PITI censoring schemes. Even no one has
attempted for the mathematical expression for Shannon entropy of PITI censored data. Motivated
by the above facts, we are concerned here with the use of entropy for PITI censored data for
comparing different censoring schemes. In Chapter 4, we have discussed Shannon entropy for
the PITI censoring scheme. We have developed the methodology to obtained Shannon entropy
for PITI censored sample. However, the entropy of PITI censored data is not so straightforward,
because of it is having an m-dimensional summation. Here, we noticed that as m increases the
time of computation increases with more faster rate. Hence, we suggest a simple and less time
taking method using Monte Carlo technique to find entropy for considered situation. Finally, we
apply our proposed methodology for computing the entropy for PITI censored samples for three
distributions namely, Weibull, log-normal and GED.
As mentioned earlier, in many life-testing experiments, it is always more economical or practi-
cal to gauge observations PITI censored, than to record their actual measurements. In such situ-
ations, an important question is to determine the associated inspection times appropriately before
conducting the experiment to assess the parameters of interest with least possible reduction in
efficiency as compared to the exact observed situation. In this context, Lin et al. (2009) have de-
veloped some optimum inspection plan for log-normal distribution. They have used maximization
of determinant of Fisher information matrix or minimization of determinant of variance-covariance
matrix criterion for optimization. However, their study was concerned with log-normal distribution
only. Therefore in Chapter 5, we propose a similar study for two parameters Rayleigh distribution
with additional competitive optimality criterion for inspection times. For the above stated objec-
tive, first we derive the expected Fisher information matrix, generalised asymptotic variance, and
asymptotic variance of population mean for a progressively interval Type-I censored sample. Af-
ter that we describe some criteria for choosing inspection times for the optimal spaced inspection
times. Further, we have propose two additional competitive optimality criterion for inspection times.
For the illustration of our methodology, we perform a numerical study. The effect of the number
of inspections and the choice of inspection times based on the asymptotic relative efficiencies
(AREs) of the MLEs of the parameters are assessed. Finally, optimal PITI inspection plan have
been obtained.  
xii


Not a member yet

IN VITRO-IN VIVO EVALUATION OF CYTOTOXIC AND APOPTOTIC MECHANISM OF SPATANE DITERPINOIDS ISOLATED FROM THE BROWN SEAWEED,STOECHOSPERMUM MARGINATUM

VAPOUR-LIQUID EQUILIBRIUM (VLE) MEASUREMENT AND PREDICTION FOR PROCESS EQUIPMENT DESIGN

SYNTHESIS AND EVALUATION OF HYBRID HETEROCYCLES AS NOVEL ANTITUBERCULAR AGENTS AND TOTAL SYNTHESIS OF ENIGMOL

SYNTHETIC APPROACHES TO PENTENOMYCINS, SOME CARBASUGARS AND AMINOCARBASUGARS FROM CARBOHYDRATES

Electronic Structures of Molecules Showing Optoelectronic Properties: Computational studies using DFT and Periodic DFT Methodologies

SYNTHESIS OF PALMEROLIDE A, SACROLIDE A, AND ASPERGILLIDE D

SYNTHESIS OF PYRROLO[2,1-C][1,4]BENZODIAZEPINE (PBD) PRODRUGS, DEVELOPMENT OF NEW METHODS FOR SYNTHESIS OF HETEROCYCLIC LIBRARIES AND TOTAL SYNTHESIS OF PINOLIDE

Stereoselective total synthesis of Trichoderic acid and development of catalyst-free green methodologies on or in aqueous medium

Combating pancreatic and lung cancer by liposomally targeted chemotherapy in combination with in vivo dendritic cell targeted DNA vaccination

Bayesian Inferences for Various Lifetime Models under Progressive Interval Type-I Censoring

506

510