1948 J. Med. Chem. 1990, 33, 1948-1954 Chalcones: A New Class of Antimitotic Agents Michael L. Edwards,* David M. Stemerick, and Prasad S. Sunkara Merrell Dow Research Institute, P.O. Box 156300, Cincinnati, Ohio 45215. Received November 3, 1989 A series of chalcones was evaluated as antimitotic agents. One of these, (E)-l-(2,5-dimethoxyhenyl)-3-[4-(di- methylamino)phenyl]-2-methyl-2-propen-l-one) (73), was found to be an effective antimitotic agent at a concentration of 4 nM in an in vitro HeLa cell test system. When evaluated in experimental tumor models in vivo, this compound exhibited antitumor activity against L1210 leukemia and BI6 melanoma. Vincristine and vinblastine are anticancer agents which inhibit microtubule assembly by binding in an irreversible manner to tubulin.’ With the exception of colchicine (l), \ zyxwvutsrqpo 2 CH30 Scheme I O C H O + /- R’ 5 0 II p C C H 3 - R 4 1 6 reversible inhibitors of microtubule assembly**-jare gen- erally not clinically useful, Colchicine’s reversible binding site on tubulin is different from that of the vinca alkaloid^.^ Scheme 11 Recent reports have delineated the SAR of colchicine- &HpR + , @3 - i O - tubulin bindin? and the antimitotic activity of analogues /-- R” of podophyllotoxin,6a-c and stegano~in.~~~~ 7 0 the C ring. The combretastatinsh and compound 2,9b with These studies have shown that the important structural features of the colchicine molecule for binding to tubulin are the methoxy groups of the A ring and the carbonyl of R 9 Dustin, P. Microtubules, 2nd ed.; Springer-Verlag: New York, 1984; Chapter 5 (Microtubule Poisons). (a) Hoebeke, J.; Vannigen, G.; DeBrabander, M. Biochem. Biophys. Res. Commun. 1976,69,319. (b) Arai, T. FEBS Lett. 1983, zyxwvutsrqponm 155, 273. (c) Wheeler, G. P.; Bowdon, B. J.; Temple, C., Jr.; Adamson, D. J.; Webster, J. Cancer Res. 1983,43,3567. (d) Lesieur, I.; Delacourte, A.; Cazin, M. Acta Ther. 1984, IO, 145. (e) Rossi, M.; Link, J.; Lee, J. C. Arch. Biochem. Biophys. 1984,231,470. (f) Geyens, G. M. A.; Nuydens, R. M.; Willeb- rords, R. E.; Vandeveire, F. M. L.; Goosens, F.; Dragonetti, C. H.; Marcel, M. M. K.; DeBrander, M. J. Cancer Res. 1985,45, 433. (9) Lacey, E.; Watson, T. R. Biochem. Pharrnacol. 1985, 34, 1073. (h) Barta, J. K.; Jurd, L.; Hamel, E. Biochem. Pharmacol. 1986, 35, 4013. (i) Barta, J. K.; Powers, L. J.; Danaltess, F.; Hamel, E. Cancer Res. 1986,46,1889. (i) Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.; Schmidt, J. M. J. Nat. Prod. 1987,50, 119. Dustin, P. Microtubules, 2nd ed.; Springer-Verlag: New York, 1984. (a) Fitzgerald, T. J. Biochem. Pharmacol. 1976,25,1383. (b) Andrew, J. M.; Timasheff, S. N. Biochemistry 1982,21, 534. (c) Andrew, J. M.; Gorbunoff, M. J.; Lee, J. C.; Timasheff, S. N. Biochemistry 1984, 24, 1742. (d) Bane, S.; Puett, D.; MacDonald, T. L.; Williams, R. C. J. Biol. Chem. 1984,259, 7391. (e) Ross, M.; Link, J.; Lee, J. C. Arch. Biochem. Biophys. 1984,231, 470. (a) Quinn, F.; Beisler, J. J. Med. Chem. 1981,24, 251. (b) Iorio, M.; Williams, T.; Sik, R.; Chignell, C. J. Med. Chem. 1981,24, 257. (c) Margulis, T. Biochem. Biophys. Res. Commun. 1977, 76 (4), 1293. (a) Cortese, F.; Bhattacharyya, B.; Wolff, J. J. Biol. Chem. 1977,252 (4), 1134. (b) Loike, J . D.; Brewer, C. F.; Sternlicht, H.; Gender, W. J.; Horwitz, S. F. Cancer Res. 1978,38,2688. (c) Kelleher, J. Mol. Pharmacol. 1977, 13, 232. (a) Wang, R.; Rebhun, L.; Kuechan, S. Cancer Res. 1977,37, 3071. (b) Zauala, F.; Guenanr, D.; Robin, J.; Brown, E. J. Med. Chem. 1980, 23,546. Fitzgerald, T. Biochem. Pharmacol. 1976, 25, 1383. 0022-2623/90/ 1833-1948$02.50/0 Scheme 111’ 10 11 12 OReagents and conditions: (a) TMSCl, KCN, ZnC1,; (b) LDA, no B ring, exhibit tubulin binding of the same order as that of colchicine. Sulfhydryl reagents also interfere with microtubule as- sembly108sb and this effect can be inhibited by the presence of colchicine or podophyllotoxin,l*asb suggesting the pres- ence of a sulfhydryl residue a t the colchicine-binding site on tubulin. These results prompted us to examine com- CZHJ; (c) N(Bu),F. (9) (a) Lin, C. M.; Singh, zyxw S. B.; Chu, P. S.; Dempcy, R. 0.; Schmidt, J. M.; Pettit, E. R.; Hamel, E. Molec. Pharmacol. 1989,34,200. (b) Zwieg, M.; Chignell, C. Biochem. Pharmacol. 1973,22,2141. (10) (a) Aikeda, Y.; Steiner, M. Biochemistry 1978, 17 (17), 3454. (b) Lee, V.; Yaple, R.; Baldridge, R.; Kirsh, M.; Himes, R. Biochim. Biophys. Acta 1981,671,71. (11) (a) Ludveiia, R.; Roach, M. Biochemistry 1981,20,4444. (b) Roach, M.; Bane, S.; Ludveiia, R. J. Biol. Chem. 1985,260 (51, 3015. 0 1990 American Chemical Society