Synthesis and biological evaluation of B-ring analogues of (-)-rhazinilam |
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Authors: | Décor Anne Monse Barbara Martin Marie-Thérèse Chiaroni Angèle Thoret Sylviane Guénard Daniel Guéritte Françoise Baudoin Olivier |
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Institution: | Institut de Chimie des Substances Naturelles, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France. |
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Abstract: | Three macrocyclic analogues of rhazinilam 1 having a 11- or 12-membered B-ring with an endocyclic carbamate group or an amino-acid residue were synthesized from the natural product. These analogues 3 and 4 displayed a very low activity on tubulin. Thirty N-1 and C-16 substituted analogues of rhazinilam were also synthesized regioselectively from rhazinilam. Stereochemical analyses showed that N-1 and C-16alpha analogues have the same conformation as rhazinilam, whereas C-16beta analogues adopt a different conformation for rings B and D. All N-1 and C-16 analogues were less active than rhazinilam on tubulin, though analogues 5a, 6aalpha, 6balpha, and 6f having the less bulky substituents retained close affinities. A few analogues either active (like 6f) or inactive (like 5o) on tubulin showed significant inhibition of the growth of KB cancer cells. |
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