Thioholgamides: Thioamide-Containing Cytotoxic RiPP Natural Products

Area of Science:

• Natural Product Chemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Thioviridamide is a unique ribosomally synthesized peptide with anticancer activity.
• The search for novel anticancer agents often involves exploring natural products and their analogs.

Purpose of the Study:

• To identify and characterize new thioviridamide analogs.
• To evaluate the cytotoxic potential of newly discovered compounds against cancer cell lines.

Main Methods:

• Genome mining to identify related gene clusters.
• Chemical screening, cultivation, and isolation of natural products.
• Structural elucidation using spectroscopic methods.
• Cytotoxicity assays against a panel of cancer cell lines and microorganisms.

Main Results:

• Identification and isolation of two new thioviridamide analogs, thioholgamides A and B.
• Thioholgamides A and B possess distinct structural features, including amino acid substitutions and a modified N-capping moiety.
• Thioholgamides exhibit potent submicromolar cytotoxicity, with thioholgamide A showing an IC50 of 30 nM against HCT-116 cells.
• A proposed biosynthetic gene cluster for thioholgamides was identified.

Conclusions:

• Thioholgamides A and B represent a new class of thioviridamide analogs with significant cytotoxic properties.
• The findings suggest a promising avenue for the development of novel anticancer therapeutics derived from natural products.
• Further investigation into the biosynthesis and mechanism of action of thioholgamides is warranted.