Modifications of benzylphenoxy ethanamine antiestrogen molecules: Influence affinity for antiestrogen binding site (AEBS) and cell cytotoxicity

The antiestrogen binding site (AEBS) is a membranous protein complex that h as been shown to be intimately linked with the antiproliferative and antire troviral effects of certain antiestrogenic compounds such as tamoxifen (Tx) . Various specific ligands of AEBS derived from benzylphenoxy ethanamine an d a new benzoyl structure were synthesized either by modification of the am inoether side chain or by halogen substitution at the meta-, ortho-, and pa ra position on the benzoyl group. Using the MCF-7 cellular strain and its R Tx6 variant (a clone selected for its antigrowth resistance to tamoxifen), it was shown that under high drug concentrations the cytotoxicity of the li gands was directly correlated with their affinity for AEBS. In agreement wi th previous observations made on triphenylethylenic ligands, modification o f the basic ethanamine side chain modulated the ligand affinities. Chloride in meta increased ligand efficacy, whereas chloride substitution in ortho and para decreased it. Effects on AEBS-positive MCF-7 cells were drug conce ntration- and time-dependent, whereas they were unspecific on the AEBS-nega tive RTx6 cell line. These cytotoxic effects were confirmed in the absence of estrogen receptor on human AEBS-positive uterine cervix cell carcinoma H eLa cells, but were non-specific on rat fibroblastic AEBS-negative (low con centration) NRK cells. The cytotoxicities of these ligands are related to t heir affinities for AEBS. (C) 1999 Elsevier Science Inc.