Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3-O-sulfamates

J Steroid Biochem Mol Biol. 2005 Feb;94(1-3):239-51. doi: 10.1016/j.jsbmb.2005.01.005. Epub 2005 Feb 24.

Abstract

Sulfamoylated derivatives of the endogenous estrogen metabolite 2-methoxyestradiol (2-MeOE2 (7)), such as 2-methoxy-3-O-sulfamoyl estrone (2-MeOEMATE (1)), display greatly enhanced activity against the proliferation of human cancer cells and inhibit steroid sulphatase (STS), another current oncology target. We explore here the effects of steroidal D-ring modification on the activity of such 2-substituted estrogen-3-O-sulfamates in respect of inhibition of tumour cell proliferation and steroid sulphatase. The novel 17-deoxy analogues of 2-MeOEMATE and the related 2-ethyl and 2-methylsulfanyl compounds showed greatly reduced inhibition of MCF-7 proliferation. Introduction of a 17alpha-benzyl substituent to such 2-substituted estrogen sulfamates also proved deleterious to anti-proliferative activity but could, in one case, enhance STS inhibition with respect to the parent substituted estrone sulfamate. In contrast, selected 17-oxime derivatives of 2-MeOEMATE displayed an enhanced anti-proliferative activity. These results illustrate that enhanced in vitro anti-cancer activity can be achieved in the 2-substituted estrogen sulfamate series and highlight, in particular, the importance of potential hydrogen bonding effects around the steroidal D-ring in the activity of these molecules. The SAR parameters established herein will assist the future design of anti-proliferative and anti-endocrine agents as potential therapeutics for both hormone dependent and independent cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Estrone / analogs & derivatives*
  • Estrone / chemical synthesis*
  • Estrone / pharmacology*
  • Female
  • Humans
  • Kinetics
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • estrone-3-O-sulfamate
  • Estrone