Chemical synthesis, docking studies and biological effects of functionalized 1,3-diaryl-2-propen-1-ones on human colon cancer cells

BJP Bangladesh Journal of Pharmacology Research Article Chemical synthesis, docking studies and biological effects of functionalized 1,3 1,3-diaryl diaryl-2-propen propen-1-ones on human colon cancer cells This article was downloaded by you on: Jul 21, 2017 A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2015; 10: 230-40 Journal homepage: www.banglajol.info Abstracted/indexed in Academic Search Complete, Agroforestry Abstracts, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index ISSN: 1991-0088 Chemical synthesis, docking studies and biological effects of functionalized 1,3-diaryl-2-propen-1-ones on human colon cancer cells Guo-Min Zhu1 and Guo-Dong Huang2 1 Department of Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China. 2 Article Info Abstract Received: Accepted: Available Online: 20 January 2015 20 February 2015 17 March 2015 DOI: 10.3329/bjp.v10i1.21699 Cite this article: Zhu GM, Huang GD. Chemical synthesis, docking studies and biological effects of functionalized 1,3-diaryl-2propen-1-ones on human colon cancer cells. Bangladesh J Pharmacol. 2015; 10: 230-40.g A series of 1, 3-diaryl-2-propen-1-ones was synthesised in order to obtain a new type of anti-cancer drug, designed with hybrid features to inhibit colon cancer activated receptor. Based on computational modelling and docking studies, potential inhibitors were synthesised and their biological activity evaluated. The structures of newly synthesized compounds were confirmed by 1HNMR, 13CNMR and Mass spectrometry. All analogues were evaluated for in vitro cytotoxicity against human colon (caco-2) cancer cell lines. Compounds 1b, 1f-1h, and 2i showed significant cytotoxicity. Chalcones 1b, 1f and 1g were identified as the most potent and selective anti-cancer agents with IC50 values <1 µg/mL and 1.5 µg/mL, against caco-2 cell line, respectively. In conclusion, this finding confirms the suitability of indolyl chalcone analogues as candidates for further investigation towards the management of colon cancer related diseases. Introduction Various research groups have focused on chemoprevention and working on development of new lead molecules. Usually early detection and focus on improvement of currently used drugs can be very helpful for curbing the disease. From the available literature it's clear that the quinoline ring system and their fused derivatives are significant structural units and present as substructure in various alkaloids, therapeutics and synthetic analogues, which exhibit good biological activities (Larsen et al., 1996; Roma et al., 2000). Various quinolines derivatives are reported as anti-malarial, anti -inflammatory, antiasthmatic, antibacterial, anti-hypertensive and platelet derived growth factor receptor tyrosine kinase (PDGF-RTK) inhibiting agents (Dube et al., 1998). A large variety of quinolines are reported to exhibit substantial anti-cancer activities (Alkasomi et al., 2010) Quinoline derivative act as anti-cancer agents through a variety of mechanisms for example; cell cycle arrest in the G2 phase (Kim et al., 2005) inhibition of topoisomerase (Ching et al., 2008) and tubulin polymerization inhibition (Alkasomi., 2009) Another mechanism of action is the inhibition of tyrosine kinases (Mulvihill et al., 2008). These results encourage us to design the molecules containing quinoline ring with different functional group to assess their biological activity. Medicinal chemists are tirelessly exploring for a better and more suitable cancer therapeutics. Chal-cones (1, 3diaryl-2-propen-1-ones), constituting an enone system between two aromatic rings are an important class of natural products which are considered as precursors for various flavonoids and exhibit interesting pharmacological activities (Stu et al., 1971). Chalcones, originating from natural and synthetic routes possess several biological activities, such as cytotoxic (Modzelewska et This work is licensed under a Creative Commons Attribution 3.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor. 231 Bangladesh J Pharmacol 2015; 10: 230-240 al., 2006) anti-malarial (Dominguez et al., 2005), antileishmanial (Boeck et al., 2006) anti-inflammatory (Yang et al., 2007), anti-HIV (Cheenpracha et al., 2006), antifungal (Svetaz et al., 2004) and as tyrosine kinase inhibitors (Neryr et al., 2004). Because of very high pharmacological interest, these molecules have attracted medicinal chemists to design and synthesize further large number of chalcones with different functional groups. In the recent years, the development of anticancer agents was achieved by structural modification of chalcones to increase their bioavailability and to study the effect of various substituents on aryl or heteroaryl rings (Meng et al., 2007). potent and selective anti-cancer agents with IC50 values 7.4 µg/mL and 7.8 µg/mL, against human colon (Caco2) cell line, respectively. Based on computational modelling and docking studies, potential inhibitors were synthesised and their biological activity evaluated. Materials and Methods Chemistry and instrument Melting point was determined on a Toshniwal melting point a p p a r a t u s a n d i s uncorrected. IR spectra were recorded on a PerkinElmer 1719 FT-IR spectrophotometer. NMR spectra were obtained in acetone-d6, DMSO-d6 and pyridine-d5 on a Bruker Avance, 300 MHz instrument using TMS as internal standard. The chemical shift values are reported in ppm and coupling constants in Hz. ESI-MS spectra were recorded on a Perkin Elmer Turbo Mass/Shimadzu LCMS. TLC analyses were carried out on precoated silicage l60 F254 plates (Merck) using solvent system, hexane: ethyl acetate (7:3). The compounds were visualized by either exposure of TLC plates to I2 vapours or by spraying with vanillin- sulphuric acid reagent, followed by heating at 110°C for 15 min. Si-gel, 60-120 mesh (spectrochem) was used in the column chromatography for the purification of metabolites. HPLC analyses were carried out on waters spherisorb ODS2 (250 x 4.6 mm i.d., 10 µm) column using binary gradient elution with acetonitrile and water mobile The heteroaryl rings are widely distributed in nature and possess a variety of significant biological activities. The indole ring is an important moiety in many pharmacologically active compounds in which some studies related reported for anti-cancer effectiveness (Grugni et al., 2006). Some of the individual a (...truncated)