Design and synthesis of bifunctional isothiocyanate analogs of sulforaphane

correlation between structure and potency as inducers of anticarcinogenic detoxication enzymes

Gary H. Posner, Cheon Gyu Cho, Julianne V. Green, Yuesheng Zhang, Paul Talalay

Research output: Contribution to journalArticle

Abstract

Thirty-five bifunctional isothiocyanates were synthesized as structural analogs of sulforaphane [(-)-1-isothiocyanato-4(R)-(methylsulfinyl)butane] that was recently isolated from broccoli as the principal and very potent inducer of detoxication (phase 2) enzymes in mouse tissues and murine hepatoma cells (Hepa 1c1c7) in culture (Zhang, Y.; Talalay, P.; Cho, C.-G.; Posner, G. H. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 2399-2403). Determination of the potency of each analog in inducing NAD(P)H:quinone reductase, a phase 2 detoxication enzyme, has allowed generalizations concerning the relation of structure and activity. The most potent analogs were bifunctional derivatives in which the isothiocyanate group was separated from a methylsulfonyl or an acetyl group by three or four carbon atoms, and in some of which these groups were conformationally restricted. Among these analogs, the bicyclic ketoisothiocyanate (±)-exo-2-acetyl-6-isothiocy-anatonorbornane (30) was a very potent inducer (comparable to sulforaphane) of quinone reductase in hepatoma cells, and it also induced both quinone reductase and glutathione transferases in several mouse organs in vivo. This and related bicyclic ketoisothiocyanates represent potent phase 2 enzyme inducers that are relatively easily synthesized and that may be more stable metabolically than the natural sulfoxide sulforaphane.

Original languageEnglish (US)
Pages (from-to)170-176
Number of pages7
JournalJournal of Medicinal Chemistry
Volume37
Issue number1
StatePublished - 1994

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NAD(P)H Dehydrogenase (Quinone)
sulfoxide
Hepatocellular Carcinoma
Enzymes
Isothiocyanates
Brassica
Glutathione Transferase
NAD
Carbon
Tissue
Derivatives
Atoms
sulforafan
isothiocyanic acid

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design and synthesis of bifunctional isothiocyanate analogs of sulforaphane : correlation between structure and potency as inducers of anticarcinogenic detoxication enzymes. / Posner, Gary H.; Cho, Cheon Gyu; Green, Julianne V.; Zhang, Yuesheng; Talalay, Paul.

In: Journal of Medicinal Chemistry, Vol. 37, No. 1, 1994, p. 170-176.

Research output: Contribution to journalArticle

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