Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis

Abstract

By limiting the nitrogen source to glutamic acid, we isolated cyclic peptides from Euglena gracilis containing asparagine and non-proteinogenic amino acids. Structure elucidation was accomplished through spectroscopic methods, mass spectrometry and chemical degradation. The euglenatides potently inhibit pathogenic fungi and cancer cell lines e.g., euglenatide B exhibiting IC 50 values of 4.3 μM in Aspergillus fumigatus and 0.29 μM in MCF-7 breast cancer cells. In an unprecedented convergence of non-ribosomal peptide synthetase and polyketide synthase assembly-line biosynthesis between unicellular species and the metazoan kingdom, euglenatides bear resemblance to nemamides from Caenorhabditis elegans and inhibited both producing organisms E. gracilis and C. elegans. By molecular network analysis, we detected over forty euglenatide-like metabolites in E. gracilis, E. sanguinea and E. mutabilis, suggesting an important biological role for these natural products.

Stereoselective Synthesis of Polyketide Segments of Nemamide A and Euglenatides D–E

“…In 2022, a series of another hybrid natural products euglenatides A–E ( 3 – 7 , Figure 1 ) were discovered by Ganesan and coworkers from biomass extract of E. gracilis , a freshwater unicellular microalga, bearing a gene cluster of NRPSs and PKSs. 4 The structures of these secondary metabolites were established similarly to nemamides where the polyketide frameworks were found to be resembled closely to nemamide A. The saturated chain of these members is two-carbon homologated compared to nemamide A and there is an additional hydroxylated center in the polyketide counterpart for euglenatides A–C ( 3 – 5 , Figure 1 ).…”

“…Euglenatides showed potential inhibitory effect against pathogenic fungi as well as promising cytotoxicity in breast cancer cells lines (IC 50 of 4.3 μM in Aspergillus fumigatus and 0.29 μM in MCF-7 for euglenatide B). 4 Our continual interest 5 in natural product synthesis prompted us to embark on the chemical synthesis of biologically promising nemamides and euglenatides family of secondary metabolites. We initially concentrated into the very similar and architecturally attractive polyketide segments of nemamide A and euglenatides D–E and report herein for the first time a general strategy of their synthesis in a stereoselective manner.…”