BUTITAXEL ANALOGS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS

N-Acyl analogues 8, 9, and 12-26 of butitaxel (3) were prepared in one or two steps from amines 5 and 6 through Schotten-Baumann acylation. Seventeen novel analogues, consisting of aliphatic carbamates, alicycl ic amides, and heteroaromatic amides, were synthesized. They were eval uated for their in vitro ability to stimulate the formation of microtu bules, their cytotoxicity toward B16 melanoma cells, and their solubil ity in water. The most potent analogue found in this study was N-deben zoyl-N-(2-thenoyl)butitaxel (20), possessing ca. 2-fold better tubulin assembly properties and cytotoxic activity against B16 melanoma cells than paclitaxel. Compound 20 was ca. 25 times more water soluble than paclitaxel.