A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs.
Angew Chem Int Ed Engl
; 63(12): e202318784, 2024 03 18.
Article
in En
| MEDLINE
| ID: mdl-38291557
ABSTRACT
Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75â
mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Depsipeptides
/
Antineoplastic Agents
Language:
En
Journal:
Angew Chem Int Ed Engl
Year:
2024
Type:
Article
Affiliation country:
China