Synthesis, conformational analysis and biological evaluation of the lactam analogue of the cyclodepsipeptide apratoxin A

Apratoxin A, a cyclodepsipeptide isolated from a marine cyanobacterium, demonstrates potent cytotoxicity against cancer cell lines by a unique mechanism. A lactam analogue of apratoxin A, named as amidapratoxin A, was efficiently synthesized over 22 linear steps in 2.1% overall yield for the first time. The further conformation analysis was conducted by NMR techniques and computer-based molecular modeling. The results showed that the orientation of the benzene ring in tyrosine moiety, the iso-butyl in isoleucine moiety and hydroxyl group in Ahtmna moiety are quite different from that of apratoxin A, which might result in a significant decrease of the cytotoxicity. While further investigation is on the way, these results provide increased understanding of conformation-activity relationship for apratoxin family members which is an important complement to structure-activity relationship.

Graphical abstractDownload high-res image (142KB)Download full-size imageApratoxin A is a cyclodepsipeptide with potent cytotoxicity against several human cancer cell lines. To further explore the conformation-activity relationship of apratoxin family members, we designed a lactam analogue of apratoxin A named as amidapratoxin A and completed its first synthesis with a concise approach. Amidapratoxin A showed three orders of magnitude less inhibitory potency compared to apratoxin A. Based on the molecular modeling with constraints from the NMR data, we presented the structural model of amidapratoxin A in solvent and illustrated that the orientation variation of the benzene ring in tyrosine moiety, the iso-butyl in isoleucine moiety and hydroxyl group in Ahtmna moiety may play critical role in cytotoxicity decrease. While further investigation is underway, the results above provide an important reference for structural optimization and efficient synthesis of apratoxin A.