Biomimic Synthesis and Bactericidal Activity of Depsipeptides Template-directed from Marine Natural Cyclic Peptides

Chuanguang Qin(钦传光),*, Shuai Liu(刘帅), Caixia Lu(鲁彩霞)，Gaowei Ouyang(欧阳高伟)

Northwestern Polytechnical University, Xi’an 710072, China

Recently, more and more cyclopeptides and depsipeptides were separated and identified from marine organisms and terrestrial microorganisms. Generally, naturally occurring cyclopeptides and depsipeptides contain unusual amino acids and building blocks. Most of them will offer a new frontier in both synthetic organic chemistry and biological activities. In particular, unique unusual structures will offer the challenge of exploitation of novel synthetic methods, reactions, reagents, catalysts, etc. However, practically, it is rather difficult to isolate a larger amount of naturally occurring cyclopeptides and depsipeptides because of minute constituents in organisms, difficulty of collection of organisms, and resistance of laboratory culturing. Thus, the limits of the quantity preclude the precise structure determination as well as clarification of detailed biological activities. In fact, the proposed structures of many cyclic peptides have been revised by synthetic works. Thus, the total synthesis is still playing a final means for the structure determination of naturally occurring cyclopeptides and depsipeptides just like several decades ago. Furthermore, the efficient large-scale production of naturally occurring cyclopeptides and depsipeptides by synthesis will offer an opportunity to investigate their biological activities in detail. One of the characteristic features of cyclic peptides will be their conformational rigidity and stability in vivo, in contrast to their linear counterparts. In addition, unusual amino acid and non-amino acid moieties of naturally occurring cyclopeptides and depsipeptides will offer the lead structures of new biologically useful compounds. On the basis of our previous work on total solid-phase synthesis of cyclic peptides, we establish and develop totally novel chemical approaches to synthesize diverse cyclopeptides and depsipeptides derivated from the marine natural product Loloatins and Kahalalides by on-resin head-to-tail cyclization. This powerful and universal total solid-phase synthesis strategy will be applicable to the parallel preparation or one-bead one-peptide (OBOP) library of naturally occurring acylated depsipeptides and the artificial mimic derivatives for systematic research into their biological activities and the structure-activity relationship (SAR) of potent lead antibiotic compounds or antitumor therapeutic agents.

Acknowledgment: This work was financially sponsored by the National Natural Science Foundation of China (20672086，21572180) and the Natural Science Basic Research Plan in Shaanxi Province of China (2012JZ2002).