Steroid conjugates of dichloro(6-aminomethylnicotinate)platinum(II): effects on DNA, sex hormone binding globulin, the estrogen receptor, and various breast cancer cell lines

ChemMedChem. 2007 Mar;2(3):333-42. doi: 10.1002/cmdc.200600173.

Abstract

Esters of 6-aminomethylnicotinic acid with various steroidal alcohols were treated with K(2)PtCl(4) to give the N,N-chelated dichloroplatinum(II) complex conjugates 4. Their interaction with plasmid DNA was monitored by electrophoretic mobility measurements. Their affinities towards sex hormone binding globulin (SHBG) and towards the nuclear estrogen receptor ER(alpha) were assessed by competitive displacement radioassays. The inhibitory effect of 4 on breast tumour cells MCF-7 ER(+)/ER(-) and MDA-MB-231 was investigated in vitro. Conjugates with 3-O-linked estrogens 4 a,b or 17-O-linked androgens 4 g bound strongly to SHBG. The conjugate complex 4 b, featuring a 3-O-linked estradiol, also bound strongly and agonistically to the estrogen receptor. It also elicited distinct growth retardation of MCF-7 (ER(+)) cells, presumably by a mechanism different from that of cisplatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects*
  • Cell Division / physiology
  • Cisplatin / pharmacology
  • DNA / metabolism*
  • Estradiol / metabolism
  • Female
  • Humans
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / pharmacology*
  • Receptors, Estrogen / metabolism*
  • Sex Hormone-Binding Globulin / metabolism*
  • Steroids / chemical synthesis
  • Steroids / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Receptors, Estrogen
  • Sex Hormone-Binding Globulin
  • Steroids
  • dichloro(6-aminomethylnicotinate)platinum(II)
  • Estradiol
  • DNA
  • Cisplatin