Details

Autor(en) / Beteiligte

• Wang, Zongqiang
• Kasper, Amanda
• Takahashi, Mai
• Morales Amador, Adrian
• Bhattacharjee, Abir
• Kan, Jingbo
• Hernandez, Yozen
• Ternei, Melinda
• Brady, Sean F.

Titel

Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn‐BNP)‐Coupled Metagenomics

Ist Teil von

• Angewandte Chemie (International ed.), 2024-04, Vol.63 (17), p.e202317187-n/a

Auflage

International ed. in English

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products. Mining the untapped chemical diversity encoded by soil microbiomes presents an opportunity to identify additional natural topoisomerase inhibitors. Here we couple metagenome mining, bioinformatic structure prediction algorithms, and chemical synthesis to produce the dual topoisomerase inhibitor tapcin. Tapcin is a mixed p‐aminobenzoic acid (PABA)‐thiazole with a rare tri‐thiazole substructure and picomolar antiproliferative activity. Tapcin reduced colorectal adenocarcinoma HT‐29 cell proliferation and tumor volume in mouse hollow fiber and xenograft models, respectively. In both studies it showed similar activity to the clinically used topoisomerase I inhibitor irinotecan. The study suggests that the interrogation of soil microbiomes using synthetic bioinformatic natural product methods has the potential to be a rewarding strategy for identifying potent, biomedically relevant, antiproliferative agents. By coupling sequence‐tag‐based metagenome mining, bioinformatic structure prediction algorithms, and total chemical synthesis we discovered the synthetic bioinformatic natural product tapcin. Tapcin is a mixed p‐aminobenzoic acid‐thiazole with a rare tri‐thiazole substructure. It has topoisomerase I and II activity and exhibits potent in vitro and in vivo antiproliferative activity.