2-Methoxyestradiol and analogs as novel antiproliferative agents: Analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding

Abstract

2-Methoxyestradiol (2-MEO), a metabolite of estrogen, is an attractive lead compound for the development of novel antitumor and anti-inflammatory agents, because it embodies antiproliferative and antiangiogenic activities in one molecule. However, the affinity of 2-MEO for the estrogen receptor would lead to undesirable side effects. As a prelude to the design of 2-MEO-like compounds with an optimal activity profile, we assayed 2-MEO and a series of analogs for their ability to cause G1 cell-cycle arrest (by measuring inhibition of DNA synthesis in human cultured airway smooth muscle) and to inhibit binding of [3H]estradiol at the estrogen receptor (ER; from rat uterine smooth muscle). One c..