Research Projects

Jan 2009-May 2012: PostDoctoral Fellow at Biomedical and Pharmaceutical Sciences, UNIVERSITY OF RHODE ISLAND, USA where I worked with Prof. K. Parang for the development of anti-cancer and anti-HIV molecules on following projects

Design and synthesis of peptide nanoassemblies for intracellular delivery of biological active molecules

NanoMedicine – Drug Delivery through peptides

The peptide, the naturally available molecules in cells are known to change their morphological structures/forms to bring about the particular action near the cells e.g. peptide rearrange into nanostructures to facilitate transportation across the membrane. The peptide nanoassemblies could be utilized to deliver the drugs and other biological active molecules. We designed different structurally variable linear and cyclic peptides, evaluated their nanoassembly forming properties and their ability to transport the different drugs (nucleoside drugs, anti-cancer drug) inside the cells. Selected new peptides showed characteristic morphological nanoassemblies and imperative efficiency in improved delivery of drugs (Molecular Pharmaceutics, 2013, 10 (2), 488-499).

Design and synthesis of heterocyclic Small molecule as Kinase Inhibitor for anti-cancer drug development

Anti-cancer drugs – designing, synthesis and evaluation

Phosphorylation of many protein substrates occurs in the presence of protein tyrosine kinases (PTKs) that catalyze the transfer of γ-phosphate group from ATP to specific tyrosine residues. PTKs have critical roles in the signal transduction pathways, play important role in the regulation of a wide variety of normal cellular signal transduction pathways and are key modulators of cancer cell invasion and metastasis. The kinase inhibitors act by blocking the phosphorylation of substrates in cancer cells in catalytic site of the enzyme. Crystallographic studies of an ATP mimic, AMP-PNP, bound to c-Src (PDB 2SRC) and complexes of 3-phenylpyrazolopyrimidine derivatives (PPD) as ATP-binding site inhibitors with Hck (PDB 1QCF) and Lck (PDB 1QPE) have revealed that the pyrazolopyrimidine core of PPD mimic the adenine base of ATP in binding to the nucleotide binding site. We are currently investigating the variation of N1 substitution in 3-phenylpyrazolopyrimidineswith different 1,2,3-triazoles containing hydrophobic residues that may interact with amino acids of vacant cavity and contribute to the enhancement of Src kinase inhibitory potency (Bioorg. Med. Chem. Lett, 2011, 1342-46). Further, molecules under investigation include different heterocycles incorporating Indole moiety and other functional variations for improved binding in kinase domain. New covalent kinase inhibitor molecules have shown excellent properties and potent anti-cancer activity against breast, ovarian cancer and leukemia.

Synthesis of Prodrug derivatives of nucleoside and anthracycline based drug molecules for improved pharmacological properties and therapeutic index

Anti-cancer pro-drugs – pharmacological improvement by derivatization

The potential activity of anti-cancer drugs depends upon the availability of drug concentration at the cancer/tumor target site. Generally, most of the nucleoside and anthracycline structure-based drugs (due to undesirable pharmacokinetic and biodistribution) are required at high doses to achieve the required therapeutic effect. Overdose of anticancer drugs leads to side effects (mostly severe) that limit the potential application of such drugs. We are investigating the pharmacological and pharmacokinetic properties modulation by introduction of different conjugation with peptides, lipids, or amino acids (prodrug concept). The modification introduced on Cytarabine (an arabino nucleoside used against leukemia ) by long fatty acid showed comparable anti-cancer activity to parent drug and enhanced pharmacological properties (Eur. J. Med. Chem., 2010, 4601-08). Further investigations are going on towards evaluation of application of synthesized prodrugs. The derivatives synthesized from Doxorubicin has shown excellent pharmacological properties having improved cellular uptake inside the cancer cells along with retention for longer duration giving sustained release of drug leading to improved therapeutic potential of drug (Journal of Medicinal Chemistry, 2012, 1500-1510).

Synthesis of novel carbohydrate-cyclo-peptide (Carbopeptide) as nucleoside mimic for anti-cancer and anti-HIV molecules development

The nucleoside based drug which inhibit the DNA synthesis in cancerous cells or inhibit the reverse transcriptase in HIV infected cells by mimic the naturally occurring nucleosides have been developed by either modifications/alteration in base part or the introduction of modifications/alterations in sugar part. We have developed novel carbopeptide molecules based on introduction of peptide and sugar. New molecules synthesized have cyclic dipeptide attached to modified sugars and indicated moderate anti-HIV properties (Canadian Journal of Chemistry, 2014, 92(12), 1145-49).

Synthesis of multifacet nucleoside derivatives for synergistic Anti-HIV microbicidal activity

Medicinal Chemistry of Anti-HIV drugs – designing and synthesis of Nucleoside RT Inhibitors

The nucleoside based reverse transcriptase inhibitors acts by inhibiting the progression of viral RNA to DNA reverse-transcription. For optimum results a combination of different nucleoside drugs is given (synergistic effect or HAART) and due to low plasma half life of nucleoside drugs, the continuous higher doses are required. Based on prodrug concept and drug synergism, we have synthesized different multifacet nucleoside derivative to improve the delivery and obtain the synergism effect. The synthesized derivatives have shown improved properties and comparable (in-vitro) anti-HIV activities (Journal of Medicinal Chemistry, 2012, 4861-4871, Journal of Medicinal Chemistry, 2012, 55 (6), 2672-2687, Molecular Pharmaceutics, 2013, 10(2), 467-476. Chemical Biology Letters, 2014, 1(1), 14-32).

Sept2006-Jan2009: DST-JNC PostDoctoral Fellow at Organic Chemistry, Indian Institute of Science, Bangalore-India where I worked with Prof. Santanu Bhattacharya and in collaboration with Prof. CNR Rao, Jawaharlal Nehru Center for Advanced Scientific Research, Bangalore-India on following nanoscience projects:

Nanomaterials Carbon nanotubes – functionalization for material science applications

Carbon Nanotube derivatization for homogenous incorporation in OrganoGels for applicable thermoresponsive materials

Carbon Nanotube have emerged an excellent nano material with exceptional physical properties and being extensively investigated for various application in material sciences. We synthesized different carbon-nanotube-fattyamide derivatives for homogenous mixing in organogels to improve thermal behavior of gels. The gelation process and the properties of the resulting nanocomposites were found to depend on the kind of SWNTs derivatives incorporated in the gels. While with pristine SWNTs, only a limited amount could be dispersed in the organogels. Scanning electron microscope images of the nanocomposites showed that the texture and organization of the gel aggregates were altered upon the incorporation of SWNTs. The microstructures of the nanocomposites were found to depend on the kind of SWNTs used. Incorporation of functionalized SWNTs into the organogels depressed the sol to gel transition temperature, with the n-hexadecyl chain functionalized SWNTs being more effective than the n-dodecyl chain functionalized counterpart. Rheological investigations of pristine SWNT containing gels indicated that the flow of nanocomposites became resistant to applied stress at a very low wt% of SWNT incorporation. Again more effective control of flow behavior was achieved with functionalized SWNTs possessing longer hydrocarbon chains. This happens presumably via effective interdigitation of the pendant chains with the fatty acid amides of L-alanine in the gel assembly. Remarkably, using near IR laser irradiation at 1064 nm for a short duration (1 min) at room temperature, it was possible to selectively induce a gel-to-sol phase transition of the nanocomposites, while prolonged irradiation (30 min) of the organogel under identical conditions did not cause gel melting. This was the first study related to incorporation of CNT in organogel and have been widely referred (J. Mat. Chem., 2008, 2593-2600).

Nanomedicine - CNT – derivatization and gene delivery applications (Gene therapy)

Development of Cholestrol lipid assisted SWCNT water soluble conjugates for gene delivery towards development of biocompatible biomaterial for application in Gene Therapy

Carbon nanotubes, due to their robust properties, are showing promise in biomedical application. The main problem encountered for CNT application is their insolubility in all bio-suitable media. In a pursuit of making biocompatible material having high efficacy for DNA/siRNA delivery for application in Gene therapy, we synthesized different cholesterol based lipids and achieve the excellent lipid assisted solubility of carbon nanotubes in water. The water soluble non-covalent CNT conjugate so obtained showed very good binding with DNA fragments as evaluated by various bio-physical techniques. Further, in-vitroevaluation of SWCNT conjugates showed efficient delivery of siRNA inside the cells. (Nanotechnology, 2012, 65101 and J. Mat. Chem., 2012,22, 7985-7998).

Synthesis of Gemini-pyrene lipids and application in CNT water solubilization and bacterial infection inhibition

In effort to evaluate biomedical application of single walled carbon nanotubes in biomedical applications, we synthesized various Gemini-pyrene based lipids. The lipids were evaluated for CNT solubility in water and their anti-bacterial potency. The pyrene lipid showed selective activity against S. pyogenes and S. aureus.