Synthesis and biological action of two glucocorticoid alkylating agents

J Med Chem. 1977 Sep;20(9):1134-9. doi: 10.1021/jm00219a005.

Abstract

Two alkylating glucocorticoids have been synthesized in order to test the possibility of alkylating glucocorticoid receptors. The title compounds are 9alpha-fluoro-11beta,16alpha,17alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-[bis(2-chloroethyl)carbamate] 16,17-acetonide (I) and 11beta,17alpha,21-trihydroxypregn-4-ene-3,20-dione 21-[bis(2-chloroethyl)carbamate] (II), prepared from triamcinolone acetonide and cortisol, respectively, through the reaction of the C-21 hydroxyl group with phosgene and di-2-chloroethylamine in the presence of triethylamine. Both compounds are biologically active as inhibitors of the growth of cultured mouse fibroblasts and are able to compete for the specific binding of radiolabeled triamcinolone acetonide to the L929 cell receptor. The bis(2-chloroethyl)carbamate moiety is capable of reacting with nucleophilic groups as evidenced by the colorimetric reaction with 4-(p-nitrobenzyl)pyridine. Both the interaction with the receptor and inhibition of cell growth by these two glucocorticoids are reversible.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylating Agents / chemical synthesis
  • Alkylating Agents / pharmacology*
  • Animals
  • Binding, Competitive
  • Cell Division / drug effects
  • Fibroblasts / drug effects
  • Glucocorticoids / chemical synthesis
  • Glucocorticoids / pharmacology*
  • Hydrocortisone / analogs & derivatives*
  • Hydrocortisone / metabolism
  • Mice
  • Receptors, Drug
  • Triamcinolone Acetonide / analogs & derivatives*
  • Triamcinolone Acetonide / metabolism

Substances

  • Alkylating Agents
  • Glucocorticoids
  • Receptors, Drug
  • Triamcinolone Acetonide
  • Hydrocortisone