Synthesis and biological evaluation of B-ring analogues of (-)-rhazinilam.
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.
Décor
Anne
A
Institut de Chimie des Substances Naturelles, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France.
Monse
Barbara
B
Martin
Marie-Thérèse
MT
Chiaroni
Angèle
A
Thoret
Sylviane
S
Guénard
Daniel
D
Guéritte
Françoise
F
Baudoin
Olivier
O
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects
D000470:Alkaloids; D007212:Indolizines; D007769:Lactams; D014404:Tubulin; C009170:rhazinilam