NAD(P)H Quinone Oxidoreductase 1 (NQO1)-Bioactivated Pronqodine A Regulates Prostaglandin Release from Human Synovial Sarcoma Cells

Natural products have contributed to the elucidation of biological mechanisms as well as drug discovery research. Even now, the expectation for natural products is undiminished. We screened prostaglandin release inhibitors that had no effect on in vitro cyclooxygenase activity derived from natural p...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2013-04, Vol.76 (4), p.510-515
Main Authors: Nakae, Koichi, Adachi, Hayamitsu, Sawa, Ryuichi, Hosokawa, Nobuo, Hatano, Masaki, Igarashi, Masayuki, Nishimura, Yoshio, Akamatsu, Yuzuru, Nomoto, Akio
Format: Article
Language:English
Subjects:
Benzoquinones - chemistry
Benzoquinones - pharmacology
Humans
NAD(P)H Dehydrogenase (Quinone) - genetics
NAD(P)H Dehydrogenase (Quinone) - metabolism
NAD(P)H Dehydrogenase (Quinone) - physiology
Oxidation-Reduction
Prostaglandins - genetics
Prostaglandins - metabolism
Reactive Oxygen Species
Sarcoma, Synovial - metabolism
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary:Natural products have contributed to the elucidation of biological mechanisms as well as drug discovery research. Even now, the expectation for natural products is undiminished. We screened prostaglandin release inhibitors that had no effect on in vitro cyclooxygenase activity derived from natural product sources and discovered pronqodine A. Using spectral analysis and total synthesis, the structure of pronqodine A was shown to be a benzo[d]isothiazole-4,7-dione analogue. Evaluation of the biological activity of pronqodine A revealed that the NAD(P)H dehydrogenase quinone 1 (NQO1) converted pronqodine A into a two-electron reductive form. The reductive form underwent autoxidation and reversed to its native form immediately with the generation of reactive oxygen species. Further investigations proved that pronqodine A inhibited cyclooxygenase enzyme activity only in the presence of NQO1. Pronqodine A acts as a potential bioreductive compound, inhibiting prostaglandin release in selectively activated NQO1-expressing cells.
ISSN:0163-3864
1520-6025
DOI:10.1021/np300643f