Asymmetric syntheses and Wnt signal inhibitory activity of melleumin A and four analogues of melleumins A and B.
Guided by nature: A flexible and epimerization-free approach for the asymmetric syntheses of melleumin A and four analogues of melleumins A and B was developed, which allowed confirming the stereochemistry at C-4 of melleumin A, and revealed that the unnatural 4-epi-melleumin B possesses a modest inhibitory activity on Wnt signaling. The first total synthesis of melleumin A and four analogues of melleumins A and B is described. The N-acyl L-Thr-Gly/beta-hydroxy-gamma-amino acid coupling/macrolactamization strategy allowed the efficient assembly of the three segments being free of epimerization. While the Jouin-Castro method with minor modification allows a rapid entrance to the key syn-beta-hydroxy-gamma-amino acid segment, required for the synthesis of melleumin A, an extension of our malimide-based methodology using a changed N-protecting group affords a flexible access to several anti-beta-hydroxy-gamma-amino acids, and hence analogues of melleumins A and B. Among them, unnatural 4-epi-melleumin B (2 a) exhibits a modest inhibitory activity on Wnt signaling. The total synthesis of melleumin A allowed confirmation of its full structure.
Luo
Jie-Min
JM
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
Dai
Chao-Feng
CF
Lin
Shu-Yong
SY
Huang
Pei-Qiang
PQ
D002460:Cell Line; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013237:Stereoisomerism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D047630:Depsipeptides; D051153:Wnt Proteins; C539389:melleumin A; C539390:melleumin B