ORIGINAL RESEARCH An efficient L-proline catalyzed synthesis of pyrazolo[3,4- e][1,4]thiazepine derivatives and their in vitro cytotoxicity studies A. Srikanth • S. Sarveswari • V. Vijayakumar • P. Gridharan • S. Karthikeyan Received: 1 May 2014 / Accepted: 2 July 2014 Ó Springer Science+Business Media New York 2014 Abstract Herein, we have developed a mild and efficient synthesis of pyrazolo[3,4-e][1,4]thiazepine derivatives through an L-proline catalyzed multi-component reaction. The synthesized compounds were subjected to in vitro cytotoxicity studies toward pancreas (PANC1), renal (ACHN) and colon (HCT116), non-small cell lung (H460), lung (CALU1), and normal breast epithelium (MCF10A) cell lines and almost all the compounds were found to exhibit good to moderate activity. The compounds 4a, 4d, 4f, 4h, and 4k were found to possess prominent cytotoxic activity toward all cell lines tested. Of the compounds tested, 4f and 4k were found to possess activity equal to the control used toward all tested cell lines with 52.7–80.6 % GI values. Keywords 1, 4-Thiazepines Á L-Proline catalysis Á Cytotoxicity studies Introduction The multi-component reactions (MCR) were reported to dispatch in a single step, hence they were very useful to synthesize the desired pharmacophore (Weber, 2002; Ra- machary and Barbas, 2004; Sunderhaus and Martin, 2009; Jiang et al., 2010). It was found that proline has enormous applications in the field of organo-catalysis (Yadav et al., 2004; Janey et al., 2005; Alcaide et al., 2006; Marquez and Metzger 2006; Mabry and Ganem, 2006: Kumar and Ma- urya, 2007; Li et al., 2010) and has also been described as a ‘‘universal catalyst’’ and ‘‘the smallest enzyme’’ (Mov- assaghi and Jacobsen, 2002), because of its existence in the amphoteric nature, and its ability to perform orchestrated chemical transformations (Ogston, 1958). Chemotherapy acquired a more important role in cancer treatment due to the intracellular barrier crossing property of drugs (Ber- nardi, 1999; Slamon et al., 2001; Neoplasm, 2003; Oh et al., 2010). Hence, the design and synthesis of new lead molecule which could essentially interact with the bio- logical targets has been a major challenge for medicinal chemists and life scientists (Schreiber, 2000; Blundell et al., 2002; Burke and Schreiber, 2004). In spite of the existence of a large number of anti cancer drugs in clinical trials, it is necessary to design a target oriented synthesis for the development of new drugs which have fewer side effects. Over the past few years, many efforts were taken to synthesize thiazepine fused bioactive molecules (Tu et al., 2009; Shi et al., 2012). Thiazepine moiety with aryl and hetero-aryl system was reported as an important category of compounds with potential pharmacological properties, in particular the C–S bond present in thiazepine moiety has an important role in their anti cancer activity (Gunter et al., 1994; Crescenza et al., 1999; Pei et al., 2002; Marcaccini et al., 2003; Venkatesan et al., 2004; Chen and Shi, 2011; Electronic supplementary material The online version of this article (doi:10.1007/s00044-014-1153-3) contains supplementary material, which is available to authorized users. A. Srikanth Á S. Sarveswari (&) Á V. Vijayakumar Á S. Karthikeyan Centre for Organic and Medicinal Chemistry, VIT University, Vellore 632 014, India e-mail: sarveswari@gmail.com P. Gridharan Department of Oncology, HCS & HTS, Piramal Life Sciences Ltd. Guregaon (E), Mumbai 400063, India S. Karthikeyan Industrial Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632 014, India 123 Med Chem Res DOI 10.1007/s00044-014-1153-3 MEDICINAL CHEMISTR Y RESEARCH