Síntesis y evaluación biológica de nuevas moléculas moduladoras de los receptores de estrógenos

Abstract

Selective Estrogen Receptors Modulators (SERMs) are chemical entities of low molecular weight that interact with estrogen receptors (ERs) and stimulate or inhibit them in different tissues. Tamoxifen and raloxifene are marketed SERMs that have achieved remarkable success in the treatment of breast cancer and osteoporosis respectively, but they have several side effects as endometrial cancer. Therefore, the discovery of new SERMs is of great importance in Medicinal Chemistry. Considering the structural features of most of the SERMs described so far and based on the results obtained from in silico studies on ERs, three families of compounds were selected as SERMs candidates: a) semisynthesized lignan derivatives from two natural dibenzylbutyrolactones through different trasformations, incluiding deprotections of methoxy and methylenedioxi groups, reductions, ring-opening reactions and oxidative cyclizations; b) highly functionalized pyrrol-2-ones obtained from chalcones and isocyanides under microwave irradiation; c) densely substituted pyrazoles prepared from acetophenones, aromatic aldehydes and phenyl hydrazines through a sequence of reactions that includes condensation, heterocyclation and oxidation. All compounds were tested for antiproliferative activity against ERs-positive MCF-7 and T47D breast cancer cell lines and the transcriptional activation activity was also determined in T47D-KBluc cells. In addition, binding studies and in silico ADME-Tox profile prediction were carried out for the most potent compounds. From the obtained results some active compounds were identified as antagonist or partial agonist/antagonist of ER. Lead compounds exhibited good drug-likeness, so they might be potential candidates for the clinical treatment of ERs related diseases and disorders.