Synthesis and biological evaluation of B-ring analogues of (−)-rhazinilam

• Published in: Bioorganic & medicinal chemistry 2006-04, Vol.14 (7), p.2314-2332
• Main Authors: Décor, Anne, Monse, Barbara, Martin, Marie-Thérèse, Chiaroni, Angèle, Thoret, Sylviane, Guénard, Daniel, Guéritte, Françoise, Baudoin, Olivier
• Format: Article
• Language: English
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Sciences; Crystallography, X-Ray; Cytotoxicity; Drug Screening Assays, Antitumor; General aspects; Humans; Indolizines - chemical synthesis; Indolizines - chemistry; Indolizines - pharmacology; Lactams - chemical synthesis; Lactams - chemistry; Lactams - pharmacology; Medical sciences; Microtubules - drug effects; Models, Molecular; Molecular Conformation; Organic chemistry; Pharmacology. Drug treatments; Rhazinilam; Stereoisomerism; Structure-Activity Relationship; Structure–activity relationships; Tubulin; Tubulin - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.11.011

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-16α analogues have the same conformation as rhazinilam, whereas C-16β 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, 6aα, 6bα, 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.