Sanjay Dutta , Ph.D.

Principal Scientist
Organic & Medicinal Chemistry
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Research Focus

The focus of our laboratory is in interdisciplinary science in translation research involving chemical biology which will have an impact on the health and diseases.

Research Interest

Currently four different research areas are there in our laboratory

  1. Antivirals against (Hepatitis C Virus)
  2. DNA damage and Cancer
  3. Targeting the mTOR pathway for (Lipogenesis and Lipid accumulation)
  4. Development of Novel Antibacterials

 

1. Objective: My laboratory at CSIR-IICB at Kolkata is involved in the development of novel antivirals targeting Hepatitis C Virus RNA and the liver specific delivery of these antivirals.

Hepatitis C Virus (HCV) infection is one of the major liver diseases and is a global health concern. HCV infection affects almost 180 million people worldwide which represent almost 3% of the world population. HCV mainly effects liver, pathophysiological symptoms associated with this disease is liver cirrhosis, liver failure and hepatocellular carcinoma.  Absence of vaccine and inability to detect virus load in acute condition is major reason for liver transplantation. Recent studies have shown that the Internal Ribosome Entry Site (IRES) RNA of 5’-untranslated region (UTR) is a target for antiviral development due to the highly conserved region of HCV with unique structural features. Till date absolute therapy of Hepatitis C virus is problematic. There is an urgent need for the development of antivirals targeting HCV infection. My laboratory at IICB-Kolkata is engaged in the discovery and development of novel antivirals targeting Hepatitis C virus RNA.

2. Objective: Reduction of lipogenesis and lipid accumulation by glycomimetic-quinoline conjugates via mTOR pathway in Hepatocytes

Principal Investigator: Dr. Sanjay Dutta, Senior Scientist, CSIR-Indian Institute of Chemical Biology, Kolkata. Co-Investigator: Dr. Partha Chakrabarti, Principal Scientist, CSIR-Indian Institute of Chemical Biology, Kolkata

(ChemBioChem 2018, 19, 1720–1726)

Abstract: Nonalcoholic fatty liver disease (NAFLD), which is characterized by excess accumulation of triglyceride in hepatocytes, is the major cause of chronic liver disease worldwide and no approved drug is available. The mechanistic target of rapamycin (mTOR) complexes has been implicated in promoting lipogenesis and fat accumulation in the liver, and thus, serve as attractive drug targets. The generation of non- or low cytotoxic mTOR inhibitors is required because existing cytotoxic mTOR inhibitors are not useful for NAFLD therapy. New compounds based on the privileged adenosine triphosphate (ATP) site binder quinoline scaffold conjugated to glucose and galactosamine derivatives, which have significantly low cytotoxicity, but strong mTORC1 inhibitory activity at low micromolar concentrations, have been synthesized. These compounds also effectively inhibit the rate of lipogenesis and lipid accumulation in cultured hepatocytes. This is the first report of glycomimetic quinoline derivatives that reduce lipid load in hepatocytes. (ChemBioChem 2018, 19,1720–1726).

3. Quinoxaline based small molecules targeting DNA

(Angew. Chem. Int. Ed. 2016, 55, 7733-7736, doi:10.1002/anie.201511881.)

Abstract: Small molecules that intercalate DNA have tremendous therapeutic potential. Typically, DNA intercalators do not alter the overall DNA double-helical structure, except locally at the intercalation sites. In a previous report, we showed that a quinoxaline-based intercalator with a mandatory benzyl substitution (1d) induced an unusually large circular dichroism signal upon DNA binding, suggesting the formation of intercalated DNA superstructures. However, no detailed structural studies have been reported. Using atomic force microscopy, we have probed the nature of the superstructure and report the formation of a plectonemically oversupercoiled structure of pBR322 plasmid DNA by 1d, where close association of distant DNA double-helical stretches is the predominant motif. Without the benzyl moiety (1a), no such DNA superstructure was observed. Similar superstructures were also observed with doxorubicin (dox), a therapeutically important DNA intercalator, suggesting that the superstructure is common to some intercalators. The superstructure formation, for both intercalators, was observed to be GC-specific. Interestingly, at higher concentrations (1d and dox), the DNA superstructure led to DNA condensation, a phenomenon typically associated with polyamines but not intercalators. The superstructure may have important biological relevance in connection to a recent study in which dox was shown to evict histone at micromolar concentrations. (Biochemistry 2018, 57, 5557−5563).

We are developing DNA damaging novel small molecules which target different cancer cells. We are working on the elucidation of DNA damage pathways triggered by the small molecules.

Credentials

  • Research Associate, (2011-2012), The Scripps Research Institute, La Jolla, California,USA (Prof M. G Finn)
  • Post-doctoral Research Scholar (2007-2010), University of California-San Diego, California, USA (Prof. Thomas Hermann)
  • Ph.D (2007) Organic Chemistry/Bio-organic Chemistry, University of Missouri, Columbia MO, USA (Prof. Kent S. Gates)

Patents & Publications

PUBLICATIONS

  1. Khondakar Sayef Ahammed, Ritesh Pal, Jeet Chakraborty, Ajay Kanungo, Polnati Sravani Purnima, and Sanjay Dutta* “DNA Structural Alteration Leading to Antibacterial Property of 6-Nitroquinoxaline Derivatives” J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00599 • Publication Date (Web): 07 Aug 2019.
  2. Abhi Das*, Gopinatha Suresh Kumar and Sanjay Dutta* “Interaction of aloe active compounds with calf thymus DNA” J Mol Recognit. 2019, e2786, 1-9, doi/10.1002/jmr.2786
  3. Tridib Mahata, Jeet Chakraborty, Ajay Kanungo, Dipendu Patra, Gautam Basu* and Sanjay Dutta* “Intercalator induced DNA superstructure formation: doxorubicin and a synthetic quinoxaline derivative” Biochemistry 2018, 57, 5557−5563
  4. Subhadeep Palit,# Sanghamitra Mukherjee,# Sougata Niyogi,# Anindyajit Banerjee, Dipendu Patra, Amit Chakraborty, Saikat Chakrabarti, Partha Chakrabarti* and Sanjay Dutta* “Quinoline-glycomimetic conjugates reducing lipogenesis and lipid accumulation in hepatocytes” ChemBioChem, 2018, DOI: 10.1002/cbic.201800271.( #These authors contributed equally.)
  5. Carlos A. Sanhueza, Michael M. Baksh, Benjamin Thuma, Marc D. Roy, Sanjay Dutta, Cathy Preville, Boris A. Chrunyk, Kevin Beaumont, Robert Dullea, Mark Ammirati, Shenping Liu, David Gebhard, James E. Finley, Christopher T. Salatto, Amanda King-Ahmad, Ingrid Stock, Karen Atkinson, Benjamin Reidich, Wen Lin, Rajesh Kumar, Meihua Tu, Elnaz Menhaji-Klotz, David A. Price, Spiros Liras,M. G. Finn,*and Vincent Mascitti* Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor J. Am. Chem. Soc. 2017, 139, 3528-3536.
  6. Tridib Mahata, Ajay Kanungo, Sudakshina Ganguly, Eswar Kalyan Modugula, Susobhan Choudhury, Samir Kumar Pal, Gautam Basu,* and Sanjay Dutta* The Benzyl Moiety in a Quinoxaline-Based Scaffold Acts as a DNA Intercalation Switch.  (Angew. Chem. Int. Ed. 2016, 55, 7733-7736, doi:10.1002/anie.201511881.)
  7. Ajay Kanungo,‡ Dipendu Patra,‡ Sanghamitra Mukherjee, Tridib Mahata, Prakas R. Maulika and Sanjay Dutta* Synthesis of a Visibly Emissive 9-nitro-2,3-dihydro-1H-pyrimido[1,2-a]quinoxalin-5-amine Scaffold with Large Stokes Shift and Live Cell Imaging, RSC Adv., 2015, 5, 70958-70967. DOI: 10.1039/C5RA12960E. ( ‡These authors contributed equally.)
  8. Rynearson KD, Dutta S, Tran K, Dibrov SM & Hermann T. Synthesis of oxazole analogs of streptolidine lactam (2013) Eur. J. Org Chem., 7337-7342.
  9. On the formation and properties of interstrand DNA-DNA cross-links forged by reaction of an abasic site with the opposing guanine residue of 5'-CAp sequences in duplex DNA.  Johnson K. M, Price N. E, Wang J, Fekry M. I, Dutta S, Seiner D. R, Wang Y, Gates K. S  J. Am. Chem. Soc., 2013, 135, 1015-25
  10. Glycomimetic Ligands for the Human Asialoglycoprotein Receptor.  Mamidyala, S.  K.; Dutta, S.; Chrunyk, B. A.; Préville, C.; Wang, H.; Withka, J. M.; McColl, A.; Subashi, T. A.; Hawrylik, S. J.; Griffor, M. C.; Kim, S.; Pfefferkorn, J. A.; Price, D. A.; Menhaji-Klotz, E.; Mascitti, V. and Finn. M.G.  J. Am. Chem. Soc., 2012, 134, 1978–1981.(§These authors contributed equally.)
  11. Synthesis and crystal structure of a novel heterocycle, 2-oxa-4,7-diazabicyclo[3.3.1]non-3-ene.  Dutta, S.; Dibrov, SM.; Ho, BT.; Higginson, C. J.; & Hermann T. J. Chem.Cryst. 2012, 42, 119-129.
  12. Noncovalent DNA Binding Drives DNA Alkylation by Leinamycin: Evidence That the Z,E-5-(Thiazol-4-yl)-penta-2,4-dienone Moiety of the Natural Product Serves as an Atypical DNA Intercalator. Fekry, M.; Szekely, J.; Dutta, S.; Breydo, L.; Zang, H.; Gates, K. S. J. Am. Chem. Soc. 2011, 132.
  13. A crystallographic study of a highly substituted imidazolinone, (3S,4S,5R)-3-(((S)-4-((1H-indol-3-yl)methyl)-5-oxo-4,5-dihydro-1H-imidazol-2-yl)amino)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxypiperidin-2-one  Dutta, S, Dibrov SM, Higginson CJ & Hermann T. J. Chem.Cryst. 2011, 41, 1573-1578.
  14. 1, 3-Diazepanes of Natural Product-Like Complexity from Cyanamide-Induced Rearrangement of Epoxy-δ-lactams. Dutta, S.; Higginson, C. J.; Bao, T. Ho.; Rynearson, K. D.; Dibrov, S. M. And Hermann, T.; Organic Letters, 2010, 12, 360-363.
  15. 1-Cyclohexyl-2-(3-furyl)-1H-benzimidazole-5-carboxylic acid. Dibrov, S.; Dutta, S. and Hermann, T. Acta Cryst. (2009). E65, o2136.
  16. Conformational inhibition of the HCV IRES RNA. Parsons, J.; Castaldi, M. P.; Dutta, S.; Dibrov, S. M.; Wyles, D. L. and Hermann, T. Nature. Chem. Biol, 2009, 5, 823-825. (Reported in News and Views by D. W Begley & G Varani in the same Journal)
  17. Synthesis and Biological Evaluation of New 2-arylcarbonyl-3-trifluoromethylquinoxaline 1,4-di-N-oxide Derivatives and Their Reduced Analogue. Solano, B.; Junnotula, V.; Martin, Adoracion.; Villar, R.; Burguette, A.; Vicente, E.; Silanes, S. P.; Aldana, I.; Mongoe, A.; Dutta, S.; Sarkar, U.; Gates, K. S.     J. Med. Chem., 2007, 50 (22), pp 5485–5492
  18. Interstrand crosslinks generated by abasic sites in duplex DNA. Dutta, S.; Chowdhury, G.; and Gates, K. S. J. Am. Chem. Soc. 2007, 129, 1852-1853
  19. DNA Damage by Fasicularin. Dutta, S.; Abe, H.; Aoyagi, S.; Kibayashi, C.; and Gates, K. S. J. Am. Chem. Soc. 2005, 127, 15004-15005
  20. Biologically Relevant Chemical Reactions of N7-Alkylguanine Residues in DNA. Gates, K. S.; Nooner, T and Dutta, S. Chem. Res. Toxicol, 2004, 17, 839-856
  21. Chemical Properties of the Leinamycin-Guanine Adduct in DNA. Nooner, T.; Dutta, S and Gates, K. S. Chem. Res. Toxicol, 2004, 17, 942-949