Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one Analogues as Cytotoxic Agents y VedulaM.Sharma, a, * K.V.AdiSeshu, a C. Vamsee Krishna, a P. Prasanna, a V. Chandra Sekhar, a A. Venkateswarlu, a Sriram Rajagopal, b R. Ajaykumar, b Dhanvanthri S. Deevi, b N.V.S.RaoMamidi c and R. Rajagopalan b a Discovery Chemistry, Dr. Reddy’s Laboratories, Discovery Research, Miyapur, Hyderabad, 500 050, India b Discovery Biology, Dr. Reddy’s Laboratories, Discovery Research, Miyapur, Hyderabad, 500 050, India c Drug Metabolism and Pharmacokinetics, Dr. Reddy’s Laboratories, Discovery Research, Miyapur, Hyderabad, 500 050, India Received 3 December 2002; accepted 10 March 2003 Abstract—A series of 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues were synthesized and evaluated for cytotoxic activityagainsteighthumancancercelllines.Compounds 18, 21, 28, 29, 30 and 31 showedcytotoxicactivitywithGI 50 valuesinthe range of 2.1–8.1 mM concentration. Among these, compounds 21 and 28 exhibited good pharmacokinetic properties. These com- poundswerefurtherevaluatedfortheirinvivoefficacyinmodifiedhollowfibreassay(HFA). # 2003ElsevierScienceLtd.Allrightsreserved. Antimitotic agents are one of the major classes of cyto- toxic drugs for cancer treatment and have attracted attentionrecentlyduetotheclinicalsuccessofTaxol. 1 4 Antimitotic agents arrest the cell division by interfering with the normal microtubule polymerization/depoly- merization process. Although antimitotic drugs such as Vincristine and Paclitaxel gained wide clinical use for thetreatmentofvariouscancers,theysufferfrommany side effects, difficulty in dosing schedule and lack of efficacy against various multidrug resistant cancer cell lines. Therefore, there is a need to discover novel anti- tumor agents with fewer side effects, improved pharma- cokinetic properties and better efficacy with novel mechanismofactions. In 1987, Petit et al., 5 reported the isolation of Com- bretastatin A-1 (CA-1)andB-1(CB-1) from the South African willow tree Combretum caffrum (Com- bretaceae). Both natural products were shown to be significant cancer cell growth inhibitors and antimitotic agents. Later it was found that monophenol derivative of CA-1, Combretastatin A-4 (CA-4) is much more potent in its phosphate prodrug. 6 Current phase-II clinical trials and the uncovering of its very promising anti-angiogenesis effects 7,8 combined with its strong anti-tubulin activity attracted our attention and prompted us to search for similar novel alkaloids of plant origin with a novel ring structure as part of our ongoingcancerresearchprogramme. 9,10 Our search resulted in identification of an interesting compound Septicine (32, Fig. 1), reported in the lit- erature, from the Indian medicinal plant Tylophora asthamatica. 11 The prominent difference between Septicine and Combretastatins (CA-1, CB-1 and CA-4) is that Septicine has a novel additional indo- lizidine ring which is absent in Combretastatins. In this paper we describe the synthesis, cytotoxic activ- ity and structure activity relationship of Septicine (32) and its analogues. Literature search revealed that Septicine has been syn- thesized earlier by different routes. 12 18 We employed the method reported by Bhakuni et al. 17,18 with a few modifications to synthesize analogues as shown in Scheme 1. Appropriately substituted 3-oxo-3-phenyl- propionicacid methyl esters (1) were hydrolyzed to cor- responding 3-oxo-3-phenyl-propionicacids (2), these were condensed with 1-pyrroline 3 19 to give 1-phenyl-2- pyrrolidin-2-yl-ethanones (4). Reaction of 4 with differ- ent substituted phenylacetylchlorides (5)inthepresence of triethylamine yielded 1-phenyl-2-(1-phenylace- 0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00263-4 Bioorganic & Medicinal Chemistry Letters 13 (2003) 1679–1682 *Corresponding author. Tel.: +91-40-23045439; fax: +91-40- 23045438; e-mail: sarmavm@drreddys.com y DRLPublicationNo.274.