Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

Abstract

Estrogen receptor ERis an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were 2 synthesised -series I containing an acrylic acid, series II with an acrylamide and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ER selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERand ER expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ER. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, whilst compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.

Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation

“…Water molecules in proximity to the ligands were retained. The preprocessed X-ray structures were previously validated by our group [ 83 ]. Compounds were drawn in ChemBioDraw Ultra 13.0.2.3021 (PerkinElmer) and converted to sd files within Pipeline Pilot [BIOVIA, Dassault Systèmes, ].…”

Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

“…The crude was purified by silica gel column chromatography (heptane:EtOAc = 2:1) to afford (S)-tertbutyl 2-((R)-(aminooxy)(phenyl)methyl)pyrrolidine-1-carboxylate 43 as a colorless oil (269 mg, 97%). 1 H NMR (400 MHz, CDCl3): δ 7.42 -7.27 (m, 5H), 5.43 (s, 2H), 5.01 (d, J = 44.7 Hz, 1H), 4.00 (d, J = 96.9 Hz, 1H), 3.61 -3.26 (m, 2H), 2.13 -1.70 (m, 3H), 1.63 (m, 1H), 1.52 -1.46 (m, 9H). 13 -butyl (2-hydroxy-3-methylbut-3-en-1-yl)carbamate (27).…”

“…Limitations in solubility, pharmacokinetics, and bioavailability of highly aromatic molecules have been well recognized; 1 the medicinal chemistry community has become increasingly aware of the requirement to create drug-like compounds containing saturated building blocks. [2][3][4] Among them, the six-membered heterocycle oxadiazines containing one oxygen and two nitrogen atoms have been considered as important skeletons because of their interesting potential in organic and medicinal chemistry. [5][6][7][8][9][10] Unlike their aromatic triazine counterparts, the bivalent character of the oxygen atom endows oxadiazines with an interesting nonaromatic and non-planar geometry which has recently been highlighted and utilized in drug discovery through the concept of "escape from flatland" developed by F. Lovering et al 11,12 Among the different types of oxadiazines classified on the basis of the positions of their heteroatoms, we focused our work on the 3-amino-1,2,4-oxadiazine (AOXD) scaffold (Figure 1).…”

Inducing Protein Degradation as a Therapeutic Strategy

“…The ability to degrade nuclear hormone receptors was the focus of two papers. In the first, O’Boyle et al developed novel selective estrogen receptor degraders (SERDs) based on the benzoxepin scaffold . Targeting another nuclear hormone receptor, Shibata et al describe the generation and characterization of an IAP-based PROTAC that can degrade the androgen receptor .…”

“…In the first, O'Boyle et al developed novel selective estrogen receptor degraders (SERDs) based on the benzoxepin scaffold. 12 Targeting another nuclear hormone receptor, Shibata et al describe the generation and characterization of an IAP-based PROTAC that can degrade the androgen receptor. 13 Two papers also explored the technology aspect of the field.…”