Analogues of 9-oxo-9H-xanthene-4-acetic acid (XAA) bearing small, lipophilic 5-substituents are among the most dose-potent compounds yet reported with the capability of causing hemorrhagic necrosis of implanted colon 38 tumors in mice. To further extend structure-activity relationships among this class of compound, a series of XAA derivatives bearing two small lipophilic groups at various positions have been prepared and evaluated. The 5,6-disubstituted compounds in particular show consistently high levels of both dose potency and activity, suggesting this is the optimal configuration among substituted 9-oxo-9H-xanthene-4-acetic acids. The 5,6- dimethyl and 5-methyl-6-methoxy are the most effective analogues, showing in vivo colon 38 activity comparable to that of FAA at 10-15-fold lower doses and superior activity to FAA at the respective optimal doses, and the former has been selected for detailed evaluation.

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Selective epoxidation of the methoxy alkene mixture (IX) from oxidative decarboxylation of 12-methoxypodocarpa-8,11,13-trien-19-oic acid (I) provides a method of obtaining a high yield of the exocyclic alkene (VII) from the mixture. Isolation of the 3α,4α-epoxide (X) during the epoxidation allows the formation of C 3 oxygenated derivatives of 12- methoxypodocarpa-8,11,13-trien-19-oic acid. ��� Methods for opening the epoxide ring of (X) and of the 4α,5α- and 4α,19-epoxides, (XI) and (XII), have been examined, and the structures of the products from rearrangement of each epoxide with boron trifluoride have been assigned.

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