Design and synthesis of bifunctional isothiocyanate analogs of sulforaphane: correlation between structure and potency as inducers of anticarcinogenic detoxication enzymes

J Med Chem. 1994 Jan 7;37(1):170-6. doi: 10.1021/jm00027a021.

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-isothiocyanatonorbornane (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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticarcinogenic Agents*
  • Cyclization
  • Enzyme Induction / drug effects
  • Female
  • Glutathione Transferase / biosynthesis
  • Isothiocyanates / chemical synthesis*
  • Isothiocyanates / pharmacology
  • Liver Neoplasms, Experimental
  • Mice
  • Molecular Conformation
  • Molecular Structure
  • Norbornanes / chemical synthesis*
  • Norbornanes / pharmacology
  • Quinone Reductases / biosynthesis*
  • Structure-Activity Relationship
  • Thiocyanates / chemistry*
  • Thiocyanates / pharmacology
  • Tumor Cells, Cultured

Substances

  • Anticarcinogenic Agents
  • Isothiocyanates
  • Norbornanes
  • Thiocyanates
  • 2-acetyl-6-isothiocyanatonorbornane
  • NADH dehydrogenase (quinone)
  • Quinone Reductases
  • Glutathione Transferase
  • sulforafan