Synthesis, biological evaluation, and molecular modeling studies of novel heterocyclic compounds as anti-proliferative a

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Med Chem Res DOI 10.1007/s00044-013-0556-x

ORIGINAL RESEARCH

Synthesis, biological evaluation, and molecular modeling studies of novel heterocyclic compounds as anti-proliferative agents Anurag Chaudhary • P. P. Sharma • Gautam Bhardwaj Vaibhav Jain • P. V. Bharatam • Birendra Shrivastav • R. K. Roy

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Received: 30 November 2012 / Accepted: 18 February 2013 Ó Springer Science+Business Media New York 2013

Abstract Two novel series of heterocyclic compounds have been synthesized. In first series, isatin was allowed to react with substituted aromatic/cyclic carbonyl compounds to get desired mannich bases (2a–e). In second series, 4,5disubstituted oxazoles (6a–p) were synthesized. Eight compounds (2c, 6a, 6e, 6f, 6i, 6j, 6m, and 6n) were screened for anticancer activity in 60 cell lines. Compound 2c, 1-[(4,7,7trimethyl-3-oxobicyclo[2.2.1]heptan-2-yl)methyl]indoline-2, 3-dione, showed maximum activity and thus, selected for further evaluation at five dose level screening. Furthermore, molecular docking studies of compounds 2c into the colchicine-binding site of tubulin, revealed possible mode of inhibition by the compound.

A. Chaudhary (&) Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University, NH-58, Meerut Bypass Road, Meerut 250005, India e-mail: [email protected] P. P. Sharma Department of Pharmaceutical Science, Gurukul Kangri University, Haridwar 249404, India G. Bhardwaj Department of Pharmacy, IILM College, Gr. Noida, India V. Jain P. V. Bharatam Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, Mohali 160062, Punjab, India B. Shrivastav School of Pharmaceutical Sciences, Jaipur National University, Jaipur 302025, India R. K. Roy Dr. K.N. Modi Institute of Pharmaceutical Education and Research, Modinagar 201201, India

Keywords DAMA-colchicine Combretastatin A-4 Anticancer Molecular docking

Introduction Malignant tumor is one of the most serious threats against human health in the world, and the clinical prognosis remains relatively poor. Therefore, it needs to develop the new therapeutic strategies for the improvement of drugs that are currently in use. There has been more and more interest in the search for antitumor compounds with high efficacy and low toxicity in recent years. There are three major approaches in the drug discovery: empiric screening, rational design of new compounds, and chemical modification of known compounds with established pharmacological actions. During the course of identifying compounds active for the prevention and treatment of cancer, stilbene derivatives, such as plant micro-components resveratrol and combretastatin A-4 (CA-4, Fig. 1), have emerged to hold promise for their potent in vitro and in vivo anticancer bioactivities (Murias et al., 2005; Pettit et al., 2005; Latruffe et al., 2002; Bhat and Pezzuto 2001; Ciolino and Yeh 2001; Pettit et al., 1998; Jang et al., 1997; Pettit et al., 1989; Lin et al., 1988). The anticancer potential of CA-4 is attributed

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