Acc. Chem. Res. 1991,24,235-243
bration under basic conditions. Conversion into the thiopyranone 122 followed by treatment with sodium iodide generated the sulfonium ylide 123, which rearranged to form the sulfur-bridged cytochalasan 124 (65%) together with minor isomeric products.38 Further modification gave rise to zygosporin E (125)99(Scheme XIV). Another approach to the 11-membered-ring system of the cytochalasans based on fragmentation of keto toluene-p-sulfonates has been described.a
Conclusion Intramolecular Diels-Alder reactions of 3-acylpyrrol-2(5H)-ones would appear to provide useful access to macrocyclic compounds including [lllcytochalasans, although improved methods are required for stereose(39) Vedejs, E.; Wittenberger, S. J. J . Am. Chem. SOC.1990, 112, 4357-4364. (40) Clark, D. A.; F'uchs, P. L. J. Am. Chem. Soc. 1979,101,3567-3576.
235
lective 13-membered-ring formation. Conformational factors affecting the endo-exo selectivities of these reactions have not been elucidated, although it is likely that they are under kinetic control. Further work on other approaches to cytochalasan synthesis is expected, thus making these complex, biologically active molecules, and their analogues, more readily available for chemical and biological study. Further insights into the processes involved in their biosynthesis are of interest. Is an enzymically mediated Diels-Alder reaction in~olved?~~~~~ I thank all m y eo-workers who have been involved i n cytochulasan synthesis including S. J. Bailey, A. P. Craven, H. Dyke, S. A . Harkin, E . Merifield, R. Sauter, 0. Singh, P.G . Steel, D . J.Tapolczay, S. M. Vather, J. P. Watts, and J.W . F. Whitehead. Z also thank the SERC, ICI Phurmaceuticals, and the Wellcome Research Laboratories f o r support of parts of this program. (41) Turner, W. B. Postepy Hie. Med. Dosw. 1974,28,683. (42) Probst, A.; Ta", C. Helu. Chim. Acta 1981, 64, 2065-2077.
Calicheamicins: Discovery, Structure, Chemistry, and Interaction with DNA MAYD. LEE,GEORGE A. ELLESTAD, and DONALD B. BORDERS* Medical Research Diuision, Lederle Laboratories, American Cyanamid Company, Pearl River, New York 10965 Received March 20,1991 (Revised Manuscript Received July 1, 1991)
Introduction The enediyne class of antitumor antibiotics represented in Chart I by calicheamicin 71' (l),lesperamicin Al (2): dynemicin A (3): and neocarzinostatin (4)4 are some of the most potent antitumor agents ever discovered. Calicheamicin yI1is over lo00 times more potent than adriamycin, a clinically useful antitumor antibiotic, when tested in murine tumor models. The remarkable biological properties of this class of compounds appear to be a consequence of their ability to interact with cellular DNA and initiate double-stranded May D. Lea was bom h Talwan In 1949 and bnmlgratd to Canada wlth her famlty In 1987. After rscdvlng a B.Sc. degree from the Unlverslty of WUsh COhwnMa and a Ph.D. from the Unlverslty of Illnols (wlth K. L. Rlnehart), &e spent a portdoctoral year wlth Y. Kkhl (Haward). She Jdned the Mdcal Rswerch DMsbn of Amerlcen Cyanamld In 1977 as a research chembt In the natural products dbcovery program, where she lo currently a ~ a r leader. p Her research Interest has focusad on the screenhrg, Isoletion, -y active mlcroblal metabdites. and 8tructmI elucldetbn of bM (Isorgo A. Ekstad was born In Coallngn, CA, In 1034. After recelvlng B.Sc. and M.Sc. degree8 In fore8Q and chamlatry (19561968) from Oregon State UnhwsHy, ha obtakrsd a Ph.D. (1982) In orgnnk chemlotry at UCLA wtth 1.A. Wwnan. He then spent a pwlod wtth W. B. Whalky at the Unlverslty of London. In 1984 ha jolned Ledorla Laboratorles In the Msdical Research DMsbn, Amerkan Cyanamld, where he lo cwently a Reward Fsfkw In the Infedous Dkase and Moka*rr Bbbgy Research Sectton. HI8 research Interest8 are focuaed on natural products cbmlotry, dnqIDNA Interactkns, and mechanlom of antlbktlc actlvlty. Donald B. Borders Is the Department Head for the Mkroblal Chemlotry Department In the hkdlcal Research Dtvbkm of Amerkan Cyanamld. He was born In 1932 In Lwnapo#t. IN. He recelvd a B.S. (1954) and M.A. (1068) In chambtry from Indlana Unlverslty and a Ph.D. (1983) In Organlc Cheml8try from the Unlverslty of Illnole (wlth K. L. Rhhart). From 1982 to 1964 ha was a research chembt for Rohm and Haas Company and then JdMdLederb Laboratorb$, a Mvldon of A m w h n Cyanamld. His research Mererta have beon In the bobtbn, structue determinatbn,and biosynttiesb of natual product$.
cleavage by carbon-centered diradical hydrogen abstraction processes. The elucidation of the chemical structures of 1 and 2 has stimulated intense synthetic efforts in a number of academic laboratories. Similarities between the calicheamicins and the esperamicins were recognized quite early in our studies of the calicheamicins due to the extreme potency of both families of compounds, the presence of a thio sugar in both, and characteristic proton signals of their aglycons. However, the close structural relationships between these two families of compounds were not recognized until the structures of calicheamicin 71' and the esperimicins were published Dynemicin A shares with the calicheamicins in having a 10-membered enediyne ring system, although the remainder of its structure is very different. The chemical structure of the neocarzinostatin chromophore is only remotely related to that of the calicheamicins. The conjugated diacetylenic ring systems of these potent antitumor antibiotics can undergo cycloaromatization (1) (a) Lee, M.D.; Dunne, T. S.;Siegel, M.M.;Chang, C. C.; Morton, G. 0.; Borders, D. B. J. Am. Chem. SOC.1987,109,3464-3466. (b) Lee, M. D.; Dunne, T. S.;Chang,C. C.; Elleatad, G. A.; Siegel, M. M.;Morton, G. 0.; McGahren, W. J.; Borders, D. B. Zbid. 1987,109,3466-3468. (2) (a) Golik, J.; Clardy, J.; Dubay,G.; Groenewold, 0.; Kawaguchi,H.; Konishi, M.;Krishnan,B.; Ohkuma, H.; Saitoh, K.; Do le, T. W. J. Am. Chem. SOC.1987, 109, 3461-3462. (b) Golik, J.; C l d y , J.; Dubay, 0.; Groenewold, G.; Kawaguchi, H.; Koniehi, M.;Krishnan,B.; Ohkuma,H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. SOC.1987,109,3462-3484. (3) Koniehi, M.;Ohkuma, H.; Matawnoto, K.; Tsuno, T.; Kame, H.; Miyaki, T.; Oki, T.;Kawaguchi, H.; VanDuune, 0.; Clardy, J. J. Antibiot. 1989,42, 1449-1452. (4) Edo, K.; Mimgaki, M.; Koide, V.; Seto, H.; Furihata,K.; M e , N.; Iehida, N. Tetrahedron Lett. 1985, 26, 331-334.
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2
3 via carbon-centered diradicals and cause DNA cleavage.6.B The diecovery and the structural elucidation of the calicheamicins and the DNA cleavage chemistry of calicheamicin y t will be presented in the following account. Discovery of the Calicheamicins The calichdcins are produced by the fermentation of Micromonospora echinospora ssp calichensis, a bacterium isolated from a chalky, or caliche, soil sample collected in Texas. They were discovered in the mid1980s in a fermentation products screening program through the use of the biochemical induction assay (BIA), which utilized a genetically engineered strain of Escherichia coli to detect DNA damaging agents.’ Crude preparations of the BIA positive fermentation broths were evaluated in murine tumor models P388 and B16. Only those demonstrating good efficacy were pursued further. A crude preparation of calicheamicin, eatimated to be
