A new procedure for the rapid isolation of additional homologues of the cytotoxic linear bistetrahydrofuranoid acetogenins rollinicin and rollinone from Rollinia papilionella, R. sericea, and R. microsepala will be investigated. Several of these acetogenins have shown in vivo activity against the P388 lymphocytic leukemia in mice. Additional homologues will be isolated with the use of a Sephadex column and will be characterized using NMR and mass spectral methods. Since the mechanism of action of these antineoplastic compounds is not known, a structure-activity study will be initiated to determine which functional groups are required to demonstrate cytotoxic activity. The acetogenins, particularly the bistetrahydrofuran moiety, are sensitive to a variety of reaction conditions. Therefore, model compounds will be synthesized and used to develop the reaction conditions to be used to modify the active principles. The bistetrahydrofuran portion of the model compounds will be synthesized via a 'zipper' reaction of an appropriate triepoxide. The triepoxide will be prepared from the corresponding triene which will be constructed via a series of Wittig reactions. The decomposition products of clinical samples of maytansine will be isolated and identified by NMR and mass spectral methods. the identification of these decomposition products may provide some insight into the metabolism of maytansine when administered as an antineoplastic drug. Minor maytansinoids will be isolated from Maytenus rothiana, M. senegalensis, and M. putterlickoides. These maytansinoids will be identified by comparisons to known maytansinoids and by NMR and mass spectral data. New maytansinoids will be screened for cytotoxicity and may be prepared in larger quantities by semi-synthesis from maytansinol for in vivo testing. Modified maytansinoids will also be prepared from maytansinol for further evaluation of the structure-activity relationships in this series of potent antineoplastic agents. Modifications of the side chain ester and ether derivatives will be prepared. Activity-guided fractionation of extracts of Schrebera alata and Gypsophilia paniculata will also be initiated.
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