Heterocycl. Commun. 2016; aop *Corresponding author: Rahis Uddin, Department of Chemistry, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi 110025, India, e-mail: rahisuddin@jmi.ac.in Raquib Alam: Department of Chemistry, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi 110025, India Md. Aftab Alam: Department of pharmacy, School of Medical and Allied Science, Galgotias University, Greater Noida 201301, UP, India Amulya K. Panda: Product Development Cell, National Institute of Immunology, New Delhi 110067, India Preliminary Communication Raquib Alam, Md. Aftab Alam, Amulya K. Panda and Rahis Uddin* Design, synthesis and cytotoxicity evaluation of novel (E)-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1- (pyridin-3-yl)prop-2-en-1-ones as anticancer agents DOI 10.1515/hc-2016-0042 Received March 16, 2016; accepted June 1, 2016 Abstract: (E)-3-(3-Aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin- 3-yl)prop-2-en-1-ones 4a–i have been synthesized and eval- uated for their in vitro cytotoxicity against a panel of three human cancer cell lines Caco-2, MIA PaCa-2, MCF-7 and a normal NIH-3T3 cell line. Compound 4g is cytotoxic with the IC 50 value of 15.32±0.62 μm against the Caco-2 cell line. Keywords: chalcones; Claisen-Schmidt condensation; cytotoxic activity; pyrazoles. Although there has been considerable progress in reduc- ing cancer incidence in the United States, the number of cancer patients continues to increase [1]. Chemotherapy is one of the most effective approaches used for treating cancer patients. However, the lack of selectivity and devel- opment of drug-resistance reduces the efficacy of cancer chemotherapy [2]. Therefore development of effective and safe anticancer agents with high potency and less toxic- ity is a major focus for researchers across the world. The heterocyclic compounds containing a pyrazole ring have received considerable attention owing to their diverse chemotherapeutic potential [3–5]. Important pyrazole- based antitumor drugs available in the market include ruxolitinib and crizotinib [6]. Celecoxib is a typical model of pyrazole-based diaryl heterocyclic small molecule [7] with antitumor activity against prostate tumors in experi- mental models [8–10]. Chalcones show anti-cancer activity [11–28] apparently due to their inhibition of tubulin [15], thioredoxin reductase [17], VEGF [18], mTOR [19] topoi- somerase-I/II [20], 5α-reductase [21], sirtuin-1 [22], JAK/ STAT signaling pathways [23], MMP-2 [24], cathepsin-K [25], Wnt [26], B-Raf [27] and NF-κB [28], among others. On the basis of the interesting biological activity pro- files of pyrazoles and chalcones, we were inspired to syn- thesize some pyrazolic chalcones as potential anticancer agents. Synthesis is outlined in Scheme 1. Pyrazolic chal- cones were prepared from the corresponding 3-aryl-1-phe- nylpyrazol-4-carboxaldehydes 3a–i [29–33] which, in turn, were synthesized from the heterocyclic substrates 2a–i [30] (see Supplementary Material). The Claisen-Schmidt condensation of compounds 3a–i with 3-acetylpyridine in methanolic NaOH afforded the desired (E)-3-(3-(aryl)- 1-phenyl-1H-pyrazol-4-yl)-pyridin-3-yl)prop-2-en-1-ones 4a–i. Compounds 3a–i and 4a–i were characterized by spectral methods and elemental analysis. In vitro cytotoxicity of compounds 4a–i was measured by an MTT [(3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- 2H-tetrazolium bromide)] assay against a panel of three a: R = H b: R = 4-F c: R = 4-Cl N N N O 1 3 6 7 Me O i N H N Me ii N N H O iii NH H 2 N 1a–i 2a–i 3a–i 4a–i 2 5 4 R R R R g: R = 4-NO 2 h: R = 4-Me i: R = 4-OMe d: R = 3-Br e: R = 4-Br f: R = 3-NO 2 Scheme 1 Conditions: (i) EtOH, H 2 SO 4 , reflux; (ii) POCl 3 /DMF, 80°C, then NaHCO 3 /H 2 O; (iii) 3-acetylpyridine, MeOH, NaOH, r.t. Brought to you by | University of California - San Diego Authenticated Download Date | 7/18/16 8:20 PM