Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain was written by Sharma, Abhishek;Toy, Weiyi;Guillen, Valeria Sanabria;Sharma, Naina;Min, Jian;Carlson, Kathryn E.;Mayne, Christopher G.;Lin, Shengjia;Sabio, Michael;Greene, Geoffrey;Katzenellenbogen, Benita S.;Chandarlapaty, Sarat;Katzenellenbogen, John A.. And the article was included in ACS Chemical Biology in 2018.Reference of 103-16-2 The following contents are mentioned in the article:
A major risk for patients having estrogen receptor α (ERα)-pos. breast cancer is the recurrence of drug-resistant metastases after initial successful treatment with endocrine therapies. Recent studies have implicated a number of activating mutations in the ligand-binding domain of ERα that stabilize the agonist conformation as a prominent mechanism for this acquired resistance. There are several critical gaps in our knowledge regarding the specific pharmacophore requirements of an antagonist that could effectively inhibit all or most of the different mutant ERs. To address this, we screened various chemotypes for blocking mutant ER-mediated transcriptional signaling and identified RU58668 as a model compound that contains structural elements that support potent ligand-induced inhibition of mutant ERs. We designed and synthesized a focused library of novel antagonists and probed how small and large perturbations in different ligand structural regions influenced inhibitory activity on individual mutant ERs in breast cancer cells. Effective inhibition derives from both nonpolar and moderately polar motifs in a multifunctional side chain of the antagonists, with the nature of the ligand core making important contributions by increasing the potency of ligands possessing similar types of side chains. Some of our new antagonists potently blocked the transcriptional activity of the three most common mutant ERs (L536R, Y537S, D538G) and inhibited mutant ER-mediated cell proliferation. Supported by our mol. modeling, these studies provide new insights into the role of specific components, involving both the ligand core and multifunctional side chain, in suppressing wild-type and mutant ER-mediated transcription and breast cancer cell proliferation. This study involved multiple reactions and reactants, such as 4-Benzyloxyphenol (cas: 103-16-2Reference of 103-16-2).
4-Benzyloxyphenol (cas: 103-16-2) belongs to ethers. Esters are widespread in nature and are widely used in industry. In nature, fats are in general triesters derived from glycerol and fatty acids. Esters are responsible for the aroma of many fruits. Many esters have the potential for conformational isomerism, but they tend to adopt an s-cis (or Z) conformation rather than the s-trans (or E) alternative, due to a combination of hyperconjugation and dipole minimization effects. The preference for the Z conformation is influenced by the nature of the substituents and solvent, if present. Lactones with small rings are restricted to the s-trans (i.e. E) conformation due to their cyclic structure.Reference of 103-16-2
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem