Isothiazoles. Part XV. A mild and efficient synthesis of new antiproliferative 5-sulfanylsubstituted 3-alkylaminoisothiazole 1,1-dioxides

Eur J Med Chem. 2006 May;41(5):675-82. doi: 10.1016/j.ejmech.2006.01.009. Epub 2006 Mar 15.

Abstract

5-Sulfanyl-3-alkylaminoisothiazole dioxide derivatives have been identified as a new class of potent inhibitors of rat aortic myocite proliferation. They were prepared by applying a simple methodology able to introduce a heteroatom on C-5 of the 3-alkylaminoisothiazole dioxide system. 3-Aminosubstituted-5-chloroisothiazole dioxides react smoothly not only with S-nucleophiles but also with N- and O-nucleophiles affording the corresponding 5-heterosubstituted isothiazole dioxides through an addition-elimination reaction. The behavior of 3-alkylamino-4-bromo-isothiazole 1,1-dioxide with S-, N- and O-nucleophiles affording the same products has also been described. On the contrary, the 3-amino-4,5-unsubstituted isothiazole dioxide system reacts easily only with sulfur nucleophiles affording the corresponding 4,5-dihydro-5-sulfanylderivatives through a simple Michael addition reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Alkyl and Aryl Transferases / metabolism
  • Alkylation
  • Amination
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Male
  • Molecular Structure
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Oxygen / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Sulfur / chemistry*
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Thiazoles
  • Sulfur
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase
  • Oxygen