Synthesis of 15-aza-salicylihalamide A analogues

Salicylihalamide A, a potent cytotoxic natural product, was isolated by Boyd and co-workers in 1997 from a marine sponge Haliclona sp. collected from waters around Rottnest Island which is situated 18 km off the coast of southern Western Australia. This compound is characterized by a unique structure as well as by different biological activities with interesting mechanisms of action, displaying cytotoxicity at nanomolar levels against several human tumor cell lines. The majority of SAR studies have been conducted on salicylihalamide derivatives with modified enamide side chains as well as on the 12-membered ring and it has been shown that some small modification of the enamide moiety or of the macrolactone ring are tolerated without substantial loss of cytotoxic activity. For example, the semisynthetic 15-aza-epothilone B was found to exhibit a better therapeutic range than epothilone B because of the stability of the macrolactam. This led us to our hypothesis that the modification of the 12-membered macrolactone in salicylihalamide A to a macrolactam would provide a more stable macrocyclic system and thus would be an interesting target for synthesis and biological evaluation. A key step in the synthesis of the new lactam analogue of salicylihalamide A was a photochemical acylation reaction. In order to prepare the desired E-lactam we have investigated the formation of the macrocyle using a RCM procedure. Conversion of macrolactam into the vinyl iodide followed by Cu catalysed cross coupling with the 2,4-(Z,Z)-heptadienoic amide gave the 15-aza-salicylihalamide A analogue in good yield. Due to its promising bioactivity profile, the first total synthesis of the novel salicylihalamide A lactam analogue was accomplished in 17 linear steps from 2,6-dihydroxybenzoic acid with an overall yield of 0.70%. The new analogue was tested for cell growth inhibition against several leukemia cell lines. The results showed that the 15-aza-salicylihalamide A analogue exhibited antiproliferative effects at sub-micromolar concentrations.