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 v...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1997-01, Vol.40 (2), p.236-241
Main Authors: Ali, Syed M, Hoemann, Michael Z, Aubé, Jeffrey, Georg, Gunda I, Mitscher, Lester A, Jayasinghe, Lalith R
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Drug Screening Assays, Antitumor
General aspects
Medical sciences
Melanoma, Experimental - drug therapy
Mice
Microtubules - drug effects
Paclitaxel - analogs & derivatives
Paclitaxel - chemical synthesis
Paclitaxel - chemistry
Paclitaxel - pharmacology
Pharmacology. Drug treatments
Solubility
Structure-Activity Relationship
Taxoids
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm960505t