Research areas:
Cancer therapeutics
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Inorg. Chem. Front. 2022, 9, 5840-5852
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The research group's flagship area is design and syntheses of nutrient conjugated and hypoxia active anticancer agents. The group is interested to develop the small molecules that are selective towards cancer cells exploiting the higher metabolic rate of cancer cells. The work encompasses the fight against resistance by making complexes with bio acitve ligands. The ligands are most important in our design as they have to be active against desired protein targets (viz. VEGFR-2. Src, HCK, EGFR, TIe-2). The idea is to develop complexes that upon de-metallation releases the ligand to wreck more damage to the cancer cells so that just when the cell thought it got rid of the toxic metal it faces the wrath of the organic part of the molecule, the ligand, which is stand alone active inside cells through a different pathway than the metal complex itself.
The target variance by change of ligand design generates newer variations using well studied pharmacological motifs. Design includes making pro-drugs that upon metabolism in liver or in reducing environment in hypoxia would become more active. Then the compounds are studied for their potential against the target proteins using microcalorimetry and various spectroscopic techniques. Then comes the more interesting part to unravel their pathways of cytotoxicity along with dissemination of the relevant downstream pathways. Our interest in such changes comes from the impetus to understand the mechanistic pathway to improve the efficacy and reduce resistance. The target molecules for modification includes nitrogen mustard, nitrosoureas, NSAIDs and tyrosine kinase inhibitors.
We have succeeded in the recent past in making compounds that kill cancer stem cells, a small and rare population in almost every cancer causing their relapse. Interested students may look for our work on Ru(II) and Pt(II) compounds that are better than the clinical Pt(II) drugs in resisting sequestration and efflux by proteins having thiol donors (ATP7B). These complexes are resistant to thiols that are otherwise efficient to extract the metal from clinical drugs like cisplatin and oxalipaltin. Thus such complexes provide insight into the inhibition of sequestration of anticancer agents by metal transporters and helps to generate complexes that efficiently kill cancer cells including cancer stem cells, the cells responsible for the recurrence of cancer.
The target variance by change of ligand design generates newer variations using well studied pharmacological motifs. Design includes making pro-drugs that upon metabolism in liver or in reducing environment in hypoxia would become more active. Then the compounds are studied for their potential against the target proteins using microcalorimetry and various spectroscopic techniques. Then comes the more interesting part to unravel their pathways of cytotoxicity along with dissemination of the relevant downstream pathways. Our interest in such changes comes from the impetus to understand the mechanistic pathway to improve the efficacy and reduce resistance. The target molecules for modification includes nitrogen mustard, nitrosoureas, NSAIDs and tyrosine kinase inhibitors.
We have succeeded in the recent past in making compounds that kill cancer stem cells, a small and rare population in almost every cancer causing their relapse. Interested students may look for our work on Ru(II) and Pt(II) compounds that are better than the clinical Pt(II) drugs in resisting sequestration and efflux by proteins having thiol donors (ATP7B). These complexes are resistant to thiols that are otherwise efficient to extract the metal from clinical drugs like cisplatin and oxalipaltin. Thus such complexes provide insight into the inhibition of sequestration of anticancer agents by metal transporters and helps to generate complexes that efficiently kill cancer cells including cancer stem cells, the cells responsible for the recurrence of cancer.
Biomimetics and catalysis
RSC Advances, 2014, 4, 35233-35237 J Mol Catal A, 2014, 395, 186-194 J Mol Catal A, 2015, 407, 93-101
The literature in the area of biomimetic complexes show that the general approach to mimic oxidative metalloenzymes involves designing metal complexes with similar donor environment as the enzyme to activate molecular oxygen and oxidize a specific substrate. This method is very helpful in understanding biological systems and disseminate important mechanistic information of enzymatic conversions to design efficient catalysts. It should be borne in mind that nature has multiple constraints while designing a metalloenzyme viz. the designed enzyme has to function in cellular environment, it should have a metal that is available for uptake, it should not participate in undesirable reactions, the geometry of the protein active site hosting the metal should be such that the desired redox chemistry is feasible. In contrast in the laboratory while designing a catalyst we preferably are performing the reaction in a pot which does not have most of the above constraints faced by nature and hence we are free to choose the metal and ligand with the basis that the designed catalyst has good redox activity suitable for that particular oxidation process and functions efficiently. This is the primary impetus to the area of biomimetics in our group. Interested students are welcome to join as PhD student or postdoctoral fellows to work in this area.
Targeting Kinases
Curcumin, an excellent Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) inhibitor, has been studied for a long time to understand it role in treatment of cancer, microbial infection, inflammation, hyperlipidemia, and progressive neurodegenerative disorders. Its importance against cancer is also emphasized from the large number of clinical trials, as kinase inhibitors and as a potentially modifiable scaffold in chemotherapeutics including photodynamic therapy. Only a handful of work with curcumin has been done to design compounds with specific targets in mind (viz. DYRK2, NF-kb, GSK-b, Akt). A few major drawbacks of curcumin and many of its derivatives is extremely poor cellular stability and sparing aqueous solubility at desired pH. The students in AM Lab design derivative of curcumin that are stable inside human cells and investigate their pathway of action via inhibition of Src family kinases in collaboration with the signalling lab. Recent results show that certain potent derivatives of curcumin are stable in cellular environment for more than 24 h in the desired pH range and selectively inhibit certain kinases at nano molar concentrations We hope to tell you more on this soon. It seems in spite of so many controversies, the gift of mother nature "CURCUMIN" is an excellent modifiable scaffold to design molecules that would specifically inhibit particular protein targets. We are looking for students who would take organic synthetic challenges involving 3-6 step organic synthesis and also be ready to study biochemistry of the enzyme inhibition mechanism.@JBC2021 10.1016/j.jbc.2021.100449
