Synthesis, cytotoxic, and DNA binding studies of novel fluorinated condensed pyrano pyrazoles
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MEDICINAL CHEMISTRY RESEARCH
ORIGINAL RESEARCH
Synthesis, cytotoxic, and DNA binding studies of novel fluorinated condensed pyrano pyrazoles S. Bhavanarushi • V. Kanakaiah • E. Yakaiah • V. Saddanapu • A. Addlagatta • J. Vatsala Rani
Received: 19 May 2012 / Accepted: 13 September 2012 Ó Springer Science+Business Media New York 2012
Abstract One pot solvent-free synthetic method is developed for the synthesis of novel pyrano[2,3-c]pyrazole analogs. Cytotoxicity experiments conducted against a pair of cancerous, non-cancerous lung cell lines, and a cervical cell line is described. These compounds are selectively toxic against cancer cells and not normal cells. Molecular mechanism is established for the mode of DNA binding of these compounds using electrochemical and proton NMR methods. Keywords DBU Knoevenagel condensation Pyrano[2,3-c]pyrazole HeLa cells Electrochemical Intercalation
Introduction Potential pharmacologically active compounds have been developed by exploring a wide variety of pyrazoles fused with different heterocycles that are known to contribute to various chemotherapeutic effects like antileukemic (Chou et al., 2007), antitumor (Li et al., 2006), antimicrobial (Holla et al., 2006), and antiviral (Yan et al., 2006) agents. Investigations in the chemistry and biology of 2-pyrones
S. Bhavanarushi V. Kanakaiah E. Yakaiah J. V. Rani (&) Fluoro Organic Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India e-mail: [email protected] V. Saddanapu A. Addlagatta (&) Center for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad 500 607, India e-mail: [email protected]
have been highly intensified with the recognition that they constitute an essential pharmacophore in many naturally occurring and biologically active agents (Dickinson, 1993). Some pyrones are reported to possess cytotoxic effect against a few human cancer cell lines (Marrison et al., 2002). The substituted pyrans can bind to DNA through an intercalative mode wherein the planar aromatic heterocyclic group inserts and stacks between the base pairs of DNA (Barton, 1986). In addition, fluorine is intentionally incorporated into inhibitors because of its lipophilicity and also its comparable size with hydrogen atom. Fluorine-containing molecules display better drug delivery properties. The use of conventional organic solvents in the synthesis of 2-amino-3-cyano-4H-pyrans make the work up procedure complicated and lead to poor yields of products (Singh et al., 1996; Wang et al., 2003; Devi and Bhuyan, 2004). Lately, in addition to the usual synthetic methods, 2-amino-3-cyano-4H-pyrans have also been synthesized under microwave (Lin et al., 2002; Tu et al., 2002) with ultrasound irradiation (Li et al., 2004) in aqueous media (Tong-Shou et al., 2004; Jin et al., 2005) two-component (Kaupp et al., 2003) and three-component (Tong-Shou et al., 2004) condensations, etc. Each of these methods have some merits with at least one of the limitations of low yields, long reaction time, effluen
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