Butitaxel analogues: 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, alicyclic amides, and heteroaromatic amides, were synthesized. They were evaluated for their in vitro ability to stimulate the formation of microtubules, their cytotoxicity toward B16 melanoma cells, and their solubility in water. The most potent analogue found in this study was N-debenzoyl-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.