Open AccessReinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8S Configuration
Author(s) -
Tyler A. Johnson,
Joseph D. Morris,
David Coppage,
Colon V. Cook,
Lauren N Persi,
Marcos A. Ogarrio,
Taylor C Garcia,
Nicole L. McIntosh,
Erin P. McCauley,
Joseph Media,
Mani Maheshwari,
Frederick A. Valeriote,
Jiajiu Shaw,
Phillip Crews
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00302
Subject(s) - semisynthesis , potency , stereochemistry , chemistry , cell culture , residue (chemistry) , nitrosobenzene , microbiology and biotechnology , biochemistry , biology , in vitro , genetics , catalysis
Reinvestigation of mycothiazole ( 1 ) revealed picomolar potency (IC 50 = 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 8 S enantiomer of 1 and not the 8 R configuration previously reported. Semisynthesis provided 8- O -acetylmycothiazole ( 2 ), 8-oxomycothiazole ( 8 ), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a , 9b ), and MND3 ( 10 ) with IC 50 = 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.