2. Academic Validation
  3. Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8 S Configuration

Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8 S Configuration

  • ACS Med Chem Lett. 2020 Jan 2;11(2):108-113. doi: 10.1021/acsmedchemlett.9b00302.
Tyler A Johnson 1 2,  Joseph D Morris 1,  David A Coppage 2,  Colon V Cook 1,  Lauren N Persi 1,  Marcos A Ogarrio 1,  Taylor C Garcia 1,  Nicole L McIntosh 1,  Erin P McCauley 2,  Joseph Media 3,  Mani Maheshwari 3,  Frederick A Valeriote 3,  Jiajiu Shaw 4,  Phillip Crews 2
Affiliations

Affiliations

  • 1 Department of Natural Sciences & Mathematics, Dominican University of California, San Rafael, California 94901, United States.
  • 2 Department of Chemistry & Biochemistry, University of California, Santa Cruz, Santa Cruz, California 95064, United States.
  • 3 Josephine Ford Cancer Center, Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202, United States.
  • 4 21st Century Therapeutics, 440 Burroughs, Suite 447, Detroit, Michigan 48202, United States.
PMID: 32071675 DOI: 10.1021/acsmedchemlett.9b00302
Abstract

Reinvestigation of mycothiazole (1) revealed picomolar potency (IC50 = 0.00016, 0.00027, 0.00035 μM) against pancreatic, (PANC-1), liver (HepG2), and colon (HCT-116) tumor cell lines. Reevaluation of 1 provided [α]D data indicating Vanuatu specimens of C. mycofijiensis contain the 8S enantiomer of 1 and not the 8R configuration previously reported. Semisynthesis provided 8-O-acetylmycothiazole (2), 8-oxomycothiazole (8), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a, 9b), and MND3 (10) with IC50 = 0.00129, >1.0, >1.0, >1.0, >1.0 μM, respectively, against PANC-1 cell lines. These results highlight the significance of the penta-2,4-dien-1-ol residue as a key structural feature of 1 required for its cytotoxicty against tumor cell lines.

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