ABSTRACT
Breast cancer is the most common cancer suffered by female, and the second highest cause of cancer-related death among women worldwide. At present, hormone therapy is still the main treatment route and can be divided into three main categories: selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). However, breast cancer is difficult to cure even after several rounds of anti-estrogen therapy and most drugs have serious side-effects. Here, we review the literature published over the past five years regarding the isolation and synthesis of analogs and their derivatives.
Subject(s)
Antineoplastic Agents/pharmacology , Aromatase Inhibitors/pharmacology , Breast Neoplasms/drug therapy , Estrogen Receptor Antagonists/pharmacology , Estrogen Receptor Modulators/pharmacology , Estrogen Receptor alpha/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/isolation & purification , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Estrogen Receptor Antagonists/chemistry , Estrogen Receptor Antagonists/isolation & purification , Estrogen Receptor Modulators/chemistry , Estrogen Receptor Modulators/isolation & purification , Estrogen Receptor alpha/metabolism , Female , Humans , Molecular StructureABSTRACT
Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 µM. At 11.2 µM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.
