William A. Maio

The classical estrogen receptor α (ERα) is a steroid hormone receptor known for its role in both health and disease. ERα, like its counterpart ERβ, acts as a receptor for its endogenous ligand 17β-estradiol (E2) and is capable of binding a diverse set of natural and synthetic small molecules. Several screening campaigns have identified various ER ligands, based on the oxabicyclo[3.3.1]-nonene scaffold, that act as ER agonists. One such campaign extensively characterized an oxabicyclic ER agonist, termed AB-1. Herein, we report the synthesis of a series of analogs based on the scaffold of AB-1 (herein termed 1 ), focusing on the enhancement of their binding to ERα and functional potencies in ER-mediated assays. We identify a new substituted compound 9 that achieves subnanomolar potencies for ERα binding (IC ₅₀ = 0.45 nM) and ER-dependent transcription (EC ₅₀ = 0.37 nM) and proliferation (EC ₅₀ = 0.03 nM), with potencies approaching those of E2 . The high potency of 9 provides a promising scaffold for the potential development of new ERα-targeted therapeutics.

The first asymmetric total synthesis of C(9)-S-(+)-taumycin A is now reported using an approach that targeted both C(9) diastereomers concurrently. To facilitate this work, we called upon the symmetrical nature of a C(5)–C(13) side-chain intermediate and exploited orthogonal protecting groups as a tactic to access both stereoisomers from a single chiral, nonracemic intermediate. In addition to our successful approach, several minor detours that helped refine our strategy and a detailed analysis of ¹H NMR data will be discussed. Select compounds included in this work were screened against the NCI60 cell line panel and displayed modest growth inhibition activity.

The sterically bulky compounds N,N′-bismesityl phenanthrene-9,10-diimine [1] and imine–nitrone [2] were synthesized. To the best of our knowledge, this is the first report of the synthesis of a bulky steric imine–nitrone accessed from the secondary ketimine using urea hydrogen peroxide over methyltrioxorhenium catalyst. Purified compounds were characterized using ¹H and ¹³C NMR, high-resolution mass spectrometry, and infrared spectrometry. We report the first crystal structure of compound 1. Detailed IR bands of compounds 1 and 2 were assigned by comparing experimentally measured spectra to individually animated modes of quantum mechanically computed spectra. We believe these compounds may be of use as bidentate ligands in the synthesis of novel organometallic compounds. The asymmetric N and O coordination sites of compound 2 might impart interesting electronic effects to organometallic compounds compared to the symmetric N,N′-coordination sites of compound 1.

The use of trimethylsilyl trifluoromethanesulfonate as a mild means to unite epoxy-carvone silyl ethers with anisole derivatives to yield products that are structurally similar to the CBD scaffold is reported. Importantly, unlike related methods, this process can utilize both epoxy-carvone diastereomers and does not require the use of air/moisture-sensitive organometallic reagents. Several examples of aryl nucleophiles as well as mechanistic insight based on in silico computational analysis are presented.

An effective late-stage large-fragment union/rearrangement exploiting the Petasis–Ferrier protocol, in conjunction with multicomponent Type I Anion Relay Chemistry (ARC) to access advanced intermediates, permits completion of a convergent, stereocontrolled total synthesis of the architecturally complex phosphomacrolide (−)-enigmazole A (1).

A small library of synthetic (−)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (−)-palmyrolide A and analogues to antagonize veratridine-stimulated Na⁺ influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (−)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (−)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required.