Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Area of Science:

• Natural Product Chemistry
• Enzymatic Synthesis
• Medicinal Chemistry

Background:

• Tryprostatin A and B are cytotoxic diketopiperazine natural products.
• The indole moiety is crucial for tryprostatin A's biological activity.
• Limited methods exist for late-stage modification of these natural products.

Purpose of the Study:

• To develop an efficient chemoenzymatic method for late-stage modification of tryprostatin B.
• To generate novel tryprostatin analogs with diverse functional groups.
• To explore the structure-activity relationships of tryprostatin derivatives.

Main Methods:

• Utilized a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus.
• Employed chemoenzymatic approach for late-stage functionalization of tryprostatin B.
• Characterized novel analogs using analytical techniques.

Main Results:

• Generated novel analogs with allylic, benzylic, heterocyclic, and diene moieties.
• Demonstrated high regioselectivity for the indole C6 position.
• Achieved significant substrate conversion for multiple analogs.

Conclusions:

• Prenyltransferase-based late-stage diversification provides access to novel natural product analogs.
• This method facilitates structure-activity relationship studies of tryprostatin derivatives.
• The chemoenzymatic approach offers an efficient route to previously inaccessible compounds.