Sixty-five derivatives and analogs of the antitumor agent, mycophenolic acid (1), have been obtained by modifying all positions of the molecule except C-V. None of these compounds was as effective as 1 in suppressing cell division in mouse fibroblasts cultured in vitro. The most active analog (56), in which the MeO of 1 was replaced by EtO, had about 12% of the activity of 1. Although 0-acetate 51, alcohol 20, and aldehyde 30 were equiactive with 1 against transplanted tumors in rodents, presumably because of in vivo conversion into 1, no compound having a greater antitumor effect than that of 1 was obtained.Mycophenolic acid (1), a mold metabolite first isolated in 1896,1 has been shown by several groups2 3to have antitumor properties and the compound is presently undergoing clinical trial. Structure 1 was proposed in 1952s and confirmed in 1957.4 A recent total synthesis5 has confirmed the trans configuration at the double bond.5 1 The present paper reports derivatives and analogs of 1 which were prepared to determine the structural features necessary for antitumor activity.Chemistry.-It was established early that a variety of simple substituted phenols including 7-hydroxyphthalan-l-one and 6-allyl-7~hydroxyphthalan-l-one (2) were devoid of antitumor properties. Compound 5, prepared from 3 by the sequence (a) oxidation with 0s04-NaI04 to give 4, (b) condensation of 4 with Ph3P=C-(Me)CO»Et; and (c) hydrolysis of the resulting ester with MeSO3H-90% HCOTI,6 was also devoid of antitumor properties indicating that most of the structural features of 1 were probably required for biological activity. Accordingly each of the substituents of 1 was modified in turn as described below.Attempted O-acetylation of 5, as a preliminary to further modification of the C-6 substituent unex-
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