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-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.