Synthesis And Biological Evaluation Of 2-oxo-substituted-arylimidazolines

Combretastatin A-4, one of the most potent agents of Combretum Caffrum, has been found to strongly inhibit the polymerization of tublin by binding much more avidly than colchicine to the same site on tublin. The structural simplicity and its strong cytotoxicity against a variety of human cancer cells, including multi-drug resistant cancer lines, make it very attractive for the development of new drugs. Numerous studies on the structure-activity relationships of Combretastatin A-4 have established that the cis-orientation between the diaryl groups is essential for strong cytotoxicity. This prompted the design and synthesis of a number of cis-restricted analogues of CA-4. Among these, Ohsumi et al. reported that a five-membered heterocyclic ring flanked between the two benzene rings provided tolerable congeners for the bioactivity of CA-4. Till now, several cis-restricted CA-4 analogues with five-membered heterocycles have been described and some of them showed very potent cytotoxicity and significant anticancer activity. In order to further explore the structure-activity relationships of cis-restricted CA-4 analogues with five-membered heterocycles and find new analogues with superior pharmacological properties and lower toxicities, Herein we obtained a series of 2-oxo-N,3,4-trisubstituted-phenylimidazoline-l-carboxamides and 2-oxo-3,4-disubstituted-phenylimidazolines by replacing the five-membered heterocycle with imida-zolin-2-one and modifying the structure of aryl. Also their anticancer activities in vitro were evaluated.The 2-oxo-N,3,4-trisubstituted-phenylimidazoline-l-carboxamides and 2-oxo-3,4-disub-stituted-phenylimidazolines were synthesized by reaction of a-amino-acetophenone hydro-chlorides with arylisocyanates in toluene. Compared with other known synthetic methods of 2-oxo-substituted-arylimidazolines, this new method is more simple and provides higher yield. By this method, twenty-seven 2-oxo-N,3,4-trisubstituted-phenylimidazoline-l-carbox-amides and nine 2-oxo-3,4-disubstituted-phenylimidazolines were afforded.All compounds prepared in this study were tested for their cytotoxicity against PC-3 (prostate cancer), A549 (lung cancer), HO-8910 (ovarian carcinoma), Hela (cervical carcinoma) and 4 leukemic cell lines (HL60, K562, P388 and resistant HL60). The cytotoxicdata showed that compound ly, one of the synthesized products, displayed a promisingselective activity against 4 tested leukemic cells, including resistant HL60 leukemic cell (IC50=2.95?0.55M).To evaluate the anticancer mechanisms of ly, morphology examination and cell cycle analysis were performed in leukemic cells challenged with ly. Results showed that ly caused cell cycle arrested in G2/M phase, and induced cell apoptosis.Further mechanism study and anticancer activity of ly in vivo are currently underway.