rhizoxin and Leukemia-P388

Chemical modification of the side chain in rhizoxin, a potent antimitotic agent, was attempted in order to study structure-activity relationships and also to devise a probe for photoaffinity labeling of tubulin. An OsO4/NaIO4 oxidation gave a nor-rhizoxin 20-al (5) which was converted to 20-ol (6) by a NaBH3CN reduction. Starting from these two compounds as key intermediates, a series of Wittig reaction products 7-2, and of 20-O-acylates 13-21 were prepared and their anti-tubulin activity and cytotoxicity were determined. An aryl azide derivative 23 was synthesized as a photoaffinity analogue.

Topics: Animals; Antibiotics, Antineoplastic; Isomerism; Lactones; Leukemia P388; Macrolides; Molecular Conformation; Structure-Activity Relationship; Tubulin Modulators; Tumor Cells, Cultured

Rhizoxin, isolated from a plant pathogenic fungus which causes rice seedling blight, inhibits the mitosis of the tumor cells in a manner similar to that of Vinca alkaloids as revealed by morphological study and flow cytometry analysis. This new 16-membered macrocyclic lactone showed similar chemotherapeutic effects to those of vincristine against L1210 and P388 leukemia-bearing mice. The drug is also effective against B16 melanoma inoculated i.p. or s.c. Rhizoxin, in contrast to the ansamacrolide, maytansine, was effective against human and murine tumor cells resistant to vincristine and Adriamycin in vitro and in vivo. A maximum 60% increase in life span was obtained in mice inoculated with P388 leukemia resistant to vincristine. Rhizoxin showed greater cytotoxicity in cultured tumor cells than did vincristine. Rhizoxin seems to bear consideration for further development as a new chemotherapeutic agent.

Topics: Animals; Antibiotics, Antineoplastic; Cell Cycle; Cells, Cultured; Drug Resistance; Female; Lactones; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Macrolides; Maytansine; Melanoma; Mice; Microscopy, Electron, Scanning