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Synthesis of Novel Heterocycles via Palladium Catalyzed Reactions
No full textAll solvents were distilled prior to use. Petroleum ether refers to fraction boiling in the range 60-80 °C. DMF and DCM were dried over CaH2, distilled, and stored over 3Å
molecular sieves in sealed container. THF was distilled over sodium and benzophenone. All the reactions were carried out under argon or nitrogen or oxygen atmosphere and
anhydrous conditions unless otherwise stated. Analytical thin-layer chromatography (TLC) was performed on Silica gel 60 F254 aluminium TLC sheets. Visualization of the
developed chromatogram was performed by UV absorbance or iodine exposure. For purification, column chromatography was performed using 100-200 mesh or 230-400 mesh silica gels. All the reagents including PdCl2, Pd(OAc)2, PdCl2(PPh3)2, Pd(PPh3)4 were purchased from Aldrich, Merck, Alfa-Aesar etc. 1H and 13C NMR spectra were recorded using a Brüker Advance 300 or 600 MHz using tetramethylsilane (TMS) as internal standard. Chemical shifts (δ) were given from TMS (δ = 0.00) in parts per million (ppm) with the residual protons of deuterated solvent used [CDCl3: 1H NMR δ =
7.26 ppm (s); 13C NMR δ = 77.16 ppm (t)]. Coupling constants (J) were expressed in Hertz (Hz) and spin multiplicities were given as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet) and br (broad). All 13C NMR spectra were obtained
with complete proton decoupling. Mass spectra were recorded in ESITOF or JEOL JMS600 or GCMS-SHIMADZU-QP5050A DI-EI mass spectrometer. Infrared spectra were
obtained on JASCO FT/IR-4200 infrared spectrometer as neat or KBr plate. Crystallographic data were obtained using Brüker Kuppa Apex 2 instrument
SYNTHESIS, BIOPHYSICAL AND BIOLOGICAL STUDIES OF FEW HETEROCYCLIC SCAFFOLDS AND PEPTIDES
No full textRegioselective Synthesis of Quinazolinone-/Phenanthridine-Fused Heteropolycycles by Pd-Catalyzed Direct Intramolecular Aerobic Oxidative C¢H Amination from Aromatic Strained Amides
No full textA new route for the expedient synthesis of specific
regioisomer of quinazolinone- and phenanthridine-fused
heterocycles through a palladium-catalyzed regioselective
intramolecular oxidative C¢H amination from cyclic strained
amides of aromatic amido–amidine systems (quinazolinones)
has been developed. The amine functionalization of an aromatic
C¢H bond from a strained amide nitrogen involved in
aromaticity has been a challenging work so far. The fusion
of two heterocyclic cores, quinazolinone and phenanthridine,
can occur in two different ways (linear and angular),
but under the conditions reported here, only linear type
isomer is exclusively produced. This approach provides a variety
of substituted quinazolinone- and phenanthridine-fused
derivatives in moderate to excellent yields. Moreover, such
fused molecules show excellent fluorescent properties and
have great potential to be a new type of fluorophores for
the use in medicinal and material science
Unraveling the Interaction of Silver Nanoparticles with Mammalian and Bacterial DNA
No full textThe focus of this study was to understand and
unravel the interaction of silver nanoparticles (AgNPs) with
different types of Deoxyribonucleic acid (DNA), mammalian
and bacterial, having different base pair compositions. Binding
of spherical silver nanoparticles (AgNPs) to Calf thymus (CT)
DNA, Escherichia coli (EC) DNA and Micrococcus lysodeikticus
(ML) DNA has been studied to gain insights into their mode
of interaction and specificity. Interaction of AgNPs with
synthetic DNA has also been carried out. On the basis of
absorption, thermal melting, isothermal calorimetry and
viscosity studies, we could establish the mode of binding and
specificity of the synthesized silver nanoparticles with
mammalian and bacterial DNA. Thermal melting (Tm) studies indicated a decrease in the Tm of all the DNAs, confirming
the destabilization of DNA stacks on interaction with AgNPs. Comparative interaction studies with single stranded (ss) and
double stranded (ds) DNAs further confirmed the specificity of the particles toward ds DNA. On the basis of the results we could
confirm that the synthesized AgNPs could be used for selective detection of DNA through their DNA binding mechanism. In
addition, the AgNPs−DNA complexes exhibited distinct differences in the SERS spectra making it an interesting SERS platform
for identifying ds DNA. The optical and physical properties of AgNPs help in differentiating the DNAs of different base pair
compositions through their binding affinity and specificit
Dynamicity and evolution of immune responses during progressive experimental visceral leishmaniasis
No full textVisceral leishmaniasis (VL) or kala-azar, a disseminated infection of the lymphoreticular system, is caused by the protozoan parasite(s) Leishmania donovani and/or L. infantum/chagasi. An estimate of 0.2-0.4 million global VL cases are reported each year with more than 90% of them occurring in India, Bangladesh, Sudan, South Sudan, Brazil and Ethiopia (Alvar et al. 2012). L. donovani infections can lead to clinical manifestations such as persistent low-grade fever, hepatosplenomegaly, cachexia, pancytopenia, and hypergammaglobulinemia or may remain clinically asymptomatic depending on the immune status of the host. Active VL is characterized by suppression of cell mediated immunity (CMI), which is apparent from the unresponsiveness of patients to different delayed type hypersensitivity (DTH) tests (Leishmanin skin test or Montenegro test) as well as the defective lymphoproliferative response of the peripheral blood mononuclear cells (Asad et al. 2015). Recovery from infection following an effective chemotherapy, on the other hand, is associated with a strong cell-mediated DTH response (Ejazi and Ali 2013). Thus, a favorable CMI in response to appropriate treatment marks the successful cure.
Regulatory T cells (Treg cells) are considered as a multitalented master of immune regulation that promotes bystander suppression of effector T cells and infectious tolerance through secretion of regulatory cytokines (Tang and Bluestone 2008). In infectious diseases, IL-10, TGFβ and other immunosuppressive cytokines are secreted from various regulatory cell populations. These cytokines not only suppress the protective immune response but are actively involved in differentiation of induced Treg cells. These cytokines attenuate the antimicrobial activities of macrophage leading to increased probability of parasite survival {Asad and Ali, 2014}. IL-12, which is also known as cytotoxic lymphocytes maturation factor, is a central immunoregulator of initiation and maintenance of Th1 response. IL-12 driven IFN dominated Th1 response promotes healing and parasite clearance. IFN, TNF and IL-12 act as host response, induce microbial activity against promastigotes and amastigotes of L. donovani. These cytokines synergistically generate protective immune responses against VL and their dominancy marks cure of the disease. During active disease, these cytokines are downregulated by elevated IL-10 and TGFβ (Adhikari et al. 2012). The mechanism of immunosuppression during Leishmania
General Introduction
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infection is, however, still poorly understood. Increased mRNA levels of IFNγ in both liver and spleen of the infected subjects (Nylen et al. 2007) emphases a mixed Th1/Th2 response during VL, which was unconventional to other infectious diseases. IL-35 which is a member of the IL-12 family and a heterodimer comprised of Ebi3 (IL-27β) and IL12a/p35 (IL-12β), is secreted by Treg cells and is required for maximal Treg function in vitro and in vivo. IL-35 was shown to inhibit the proliferation of mouse T effector (Teff) cells in vitro (Collison et al. 2010). Nevertheless, its effects on leishmaniasis have not been investigated. Therefore, a comprehensive study of immune cells profile at the site of Leishmania infection, and their modulation is immensely important. In the present study, attempts are made to identify the regulation of immune responses of the T cells and the major Treg cell populations in the L. donovani infected BALB/c mice. BALB/c mice infected with L. donovani strain Ag83 shows a progressive visceral disease mimicking human VL. Here we have studied the involvement of different subsets of CD4+ and CD8+ T cells and the immunoprotective and immunosuppressive cytokine profile of these cells at different time points of infection with the progression of the disease in mice. Moreover, we studied the suppressive activity of Treg cells on immunoprotective responses by co-culturing CD4+ T cells with Treg cells. Further, we used blocking/neutralizing antibodies against Treg cells as well as immunosuppressive cytokines secreted by Treg cells to establish the role played by these cytokines in creating suppressive milieu during the disease progression.
Recent research suggests Th17 as an additive to Th1 response. In the absence of Th1 response, Th17 shows some protection against leishmaniasis through an unconventional pathway for activating effector T cell responses {Asad and Ali, 2014}, but to what extent this is true in controlling VL remains unanswered. Involvement of TGFβ in both Th17 cell priming and development of Treg could also be looked upon as an important issue. It is intriguing to note that Th17 cells have close developmental links with CD4+FOXP3+ Tregs. FOXP3 and RORγt can directly interact via a DNA-independent mechanism, and during Th17 cell development FOXP3 is transiently expressed (Zhou et al. 2008). The function of Th17 and Treg cells in VL, including their trafficking and mechanism of action by way of secreting cytokines, are needed to be established for better understanding and control of the disease. Here we have
General Introduction
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studied the profile of Th17 cells and their cytokines during the progression of murine VL and their role as an additive to Th1 response for protection against the disease.
In the absence of a successful vaccine, chemotherapy is the mainstay to combat the disease. Amphotericin B is a proficient anti-leishmanial drug, especially when pentavalent antimonials, the first line treatment against leishmaniasis are globally challenged by the emergence of resistant strains. But AmB treatment is associated with nephrotoxicity, hepatotoxicity and hypokalemia. Due to this, liposomal formulations of AmB have been introduced which are however very costly. Thus, we evaluated a new ergosterol-rich liposomal amphotericin B formulation, KALSOMETM10 for its toxicity, efficacy as well as its immunomodulatory role which is a prerequisite for long time protection. This drug is expected to not only reduce the treatment cost but improve safety and provide life-long protection
Designing Substituted Furan and Pyran Derivatives from Cyclic and Acyclic Precursors: Synthesis and Applications
No full textfocuses on the gold(III)-catalyzed efficient general route to densely substituted chiral 3-formyl furans under extremely mild conditions from suitably protected 5-(1-alkynyl)-2,3-dihydropyran-4-one using H2O as a nucleophile. The reaction proceeds through the initial formation of an activated alkyne–gold(III) complex intermediate, followed by either a domino nucleophilic attack/anti-endo-dig
cyclization, or the formation of a cyclic oxonium ion with subsequent attack by H2O. To confirm the proposed mechanistic pathway, we employed MeOH as a nucleophile instead of H2O to result in a substituted furo[3,2-c]pyran derivative, as anticipated. The similar furo[3,2-c]pyran skeleton with a hybrid carbohydrate–furan derivative has also been achieved through pyridinium dichromate (PDC)
oxidation of a substituted chiral 3-formyl furan. The corresponding protected 5-(1-alkynyl)-2,3-
dihydropyran-4-one can be synthesized from the monosaccharides (both hexoses and pentose) following
oxidation, iodination, and Sonogashira coupling sequences. Furthermore, to demonstrate the potentiality
of chiral 3-formyl furan derivatives, a TiBr4-catalyzed reaction of these derivatives has been shown to
offer efficient access to 1,5-dicarbonyl compounds, which on treatment with NH4OAc in slightly acidic
conditions afforded substituted furo[3,2-c]pyridine
Role of phosphodiesterase in Leishmania survival and infectivity
No full textLeishmaniasis is a vector borne disease caused by various members of the genus Leishmania, a protozoic parasite of the family Trypanosomatidae (order Kinetoplastida). The parasite was described as early as 1756, by Alexander Russell (Hide et al., 2007). In early 1903, L.H.
Donovan and W.B. Leishman independently demonstrated the causative parasite in splenic tissue in autopsies from infected patients in India (Bern & Chowdhury, 2006). The disease on the other hand has been thought to have evolved with the human species and plagued ancient civilizations
(Tuan et al., 2008). Leishmaniasis is caused by approximately 21 species of morphologically similar kinetoplastid protozoa belonging to the genus Leishmania (Croan et al., 1997), which is divided into two subgenera; Leishmania of the Old World and Viannia in the New World (Hide et al). Leishmania spp. are usually transmitted by the bite of an insect vector i.e. sandflies of the
genera Phlebotomus and Lutzomyia. Of 500 known phlebotomine species, only some 30 of them have been identified as vectors of the disease. Each species of Leishmania is adapted to transmission in certain species of sandflies. Only the females feed on blood. The clinical
manifestation ranges from simple cutaneous lesions to life threatening visceral forms. Leishmaniasis has a long history. Designs on pre-Colombian pottery and the existence of thousand-year old sculls with evidence of leishmaniasis prove that the disease has been present in the Americas for a long time. It has also been present in Africa and India since at least the mid-eighteenth century (Allison et al., 1993). Today, an estimated 12 million cases of
leishmaniasis exist worldwide with an estimated number of 1.5 -2 million new cases occurring annually; 1 - 1.5 million cases of cutaneous leishmaniasis and 500 000 cases of visceral leishmaniasis (Desjeux P et al., 1998). With the exception of Antarctica and Australia Leishmania spp. have been reported on every continent. These organisms are primarily endemic in tropical and sub-tropical regions and human disease mainly occurs in Africa, parts of Asia, the
Middle East, Latin America and the Mediterranean region. In Europe, leishmaniasis appears to be spreading northward from its traditional foci. The leishmaniases are considered to be endemic in 88 countries (16 developed countries and 72 developing countries) on four continents. Ninety
percent of cases with cutaneous forms of leishmaniasis occur in Afghanistan, Algeria, Brazil, Iran, Peru, Saudi Arabia and Syria, while ninety per cent of visceral leishmaniasis cases are found in Bangladesh, Brazil, India, Nepal and Sudan. In India, it is a serious problem in Bihar
Target-dependent biogenesis of cognate microRNAs in human cells
No full textExtensive research has established how miRNAs regulate target mRNAs by translation
repression and/or endonucleolytic degradation in metazoans. However, information related to
the effect of target mRNA on biogenesis and stability of corresponding miRNAs in animals is
limited. Here we report regulated biogenesis of cognate miRNAs by their target mRNAs.
Enhanced pre-miRNA processing by AGO-associated DICER1 contributes to this increased
miRNP formation. The processed miRNAs are loaded onto AGO2 to form functionally
competent miRISCs both in vivo and also in a cell-free in vitro system. Thus, we identify an
additional layer of posttranscriptional regulation that helps the cell to maintain requisite levels
of mature forms of respective miRNAs by modulating their processing in a target-dependent
manner, a process happening for miR-122 during stress reversal in human hepatic cell
Spectroscopic and microcalorimetric studies on the molecular binding of food colorant acid red 27 with deoxyribonucleic acid
No full textInteraction of the food colorant acid red 27 with double stranded DNA was investigated using spectroscopic and
calorimetric methods. Absorbance and fluorescence studies suggested an intimate binding interaction between
the dye and DNA. The quantum efficiency value testified an effective energy transfer from the DNA base pairs to
the dye molecules. Minor groove displacement assay with Hoechst 33258 revealed that the binding occurs in the minor
groove of DNA. Circular dichroism studies revealed that acid red 27 induces moderate conformational perturbations
in DNA. Results of calorimetric studies suggested that the complexation process was driven largely by positive
entropic contribution with a smaller favorable enthalpy contribution. The equilibrium constant of the binding was
calculated to be (3.04 ± 0.09) × 104M�1 at 298.15 K. Negative heat capacity value along with the enthalpy–entropy
compensation phenomenon established the involvement of dominant hydrophobic forces in the binding process.
Differential scanning calorimetry studies presented evidence for an increased thermal stability of DNA on binding of acid red 2
Synthesis of various analogues based on Andrographolide and Betulinic acid and evaluation of their anti-cancer potential
No full text“Synthesis of various analogues based on Andrographolide and Betulinic acid
and evaluation of their anti-cancer potential” is divided into three chapters, each chapter is divided
further into two Parts. Part-I of each chapter deals with the general survey of literature on the synthesis
of different analogues of Andrographolide and Betulinic acid, their importance and the biological
activity, which is of interest to us for the design and synthesis of our derivatives. Part-II deals with
detailed methodology developed from our laboratory for the preparation of analogues of
Andrographolide and Betulinic acid. IC50 data of the newly synthesized analogues, experimental
procedures with characterization data, references and copies of spectra of important compounds are
also included in the part-II of each chapter. The following description summarizes the present work as
detailed in part-II of each chapter