Efficient synthesis of piperazine-2,6-dione and 4-(1 H -indole-2-carbonyl)piperazine-2,6-dione derivatives and their eva
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Med Chem Res (2013) 22:4600–4609 DOI 10.1007/s00044-012-0438-7
ORIGINAL RESEARCH
Efficient synthesis of piperazine-2,6-dione and 4-(1H-indole-2carbonyl)piperazine-2,6-dione derivatives and their evaluation for anticancer activity Sandeep Kumar • Nikhil Kumar • Partha Roy Sham M. Sondhi
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Received: 23 June 2012 / Accepted: 18 December 2012 / Published online: 16 January 2013 Ó Springer Science+Business Media New York 2013
Abstract Condensation of iminodiacetic acid 1 with various amines i.e., cyclohexanamine, 1-(3-aminopropyl)imidazole, pyridin-2-ylmethanamine, pyridin-3-ylmethanamine, pyridin-4-ylmethanamine, 2-morpholinoethanamine, thiophen2-ylmethanamine, 2-(thiophen-2-yl)ethanamine, furan-2-ylmethanamine, 2-(pyrrolidin-1-yl)ethanamine, and 1-(3-aminopropyl) pyrrolidin-2-one 2a–k under microwave irradiation gave the corresponding piperazine-2,6-dione derivatives 3a–k in quantitative yields. Piperazine-2,6-dione derivatives 3a–k on condensation with 1H-indole-2-carboxylic acid under microwave irradiation gave the corresponding 4-(1H-indole-2-carbonyl)piperazine-2,6-dione derivatives 4a–k in quantitative yields. All the synthesized compounds (3a–k & 4a–k) were purified by crystallization and characterized by spectroscopic means. On screening at a concentration of 10 lM, compounds 3k, 4e, 4i breast (T47D), 4j lung (NCI H-522), 3i colon (HCT-15), 4e ovary (PA-1), and 4g liver (HepG-2) exhibited good anticancer activity. Keywords Microwave synthesis Piperazine dione derivatives Anticancer activity
Introduction Diketopiperazine derivatives form an important class of heterocyclic compounds due to their biological activities
and have attracted attention of the researchers working in the area of medicinal chemistry (Poster et al., 1981; Toshiharu et al., 1990; Folkes et al., 2001; Ong et al., 2003; Martins and Carvalho, 2007). Diketopiperazine derivatives exhibiting antitumor (Boger et al., 2000, Loughlin et al., 2000), antiviral (Sinha et al., 2004), antifungal (Houston et al., 2004; Tuntiwachwuttikul et al., 2008), antibacterial (JhaumeerLaulloo et al., 2003; Abraham, 2005), antiaggregatory (Pons et al., 1998), antileishmanial (Hazra et al., 2007), and antiinflammatory (Shvedaite et al., 1999) activities are well documented in literature. Diketopiperazine derivatives also act as plasminogen activator inhibitor-1 (PAI-1) (Bryans et al., 1996), thrombin inhibitor (Cody et al., 1999) and topoisomerase-II inhibitors (Grauslund et al., 2007). Besides, these are known to exhibit phototoxic activity (Molesworth et al., 2010). In search of potent antitumor molecules we have synthesized and evaluated several molecules containing thiazoline, N-substituted cyclic imides, benzimidazole, acridine, amidine & bis amidine, and pyrimidine moieties (Sondhi et al., 2009a, b, 2010a, b, 2011, 2012). In view of the literature cited above, references cited therein, and our background in this area it was considered worthwhile to synthesize diketopiperazine derivatives using iminodiacetic acid and heterocyclic amines under microwave
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