Synthesis of benzoylbenzamide derivatives of 17α-E-vinyl estradiol and evaluation as ligands for the estrogen receptor-α ligand binding domain.

A series consisting of substituted benzoylbenzamide derivatives of 17α-E-vinyl estradiol 6a-i and 7a-d was prepared in good overall yields from the corresponding novel iodinated benzoylbenzamide precursors using Pd(0)-catalyzed Stille coupling. Biological evaluation using competitive binding assays indicated that all compounds were effective ligands for the ERα- and ERβ-LBD (RBA = 0.5-10.

Synthesis and evaluation of 2-halogenated-1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylenes as potential estrogen receptor-targeted radiodiagnostic and radiotherapeutic agents.

A series of three 1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylene derivatives was prepared and evaluated as potential estrogen receptor imaging agents. The compounds display high binding affinity compared to estradiol, with the 2-iodo and 2-bromo-derivatives expressing higher affinity than the parent 2-nonhalogenated derivative. Evaluation in immature female rats also indicate that the compounds were all full estrogenic agonists with potencies in the same order of activity (I∼Br>H).

Targeting the estrogen receptor with metal-carbonyl derivatives of estradiol.

As part of our program to develop new probes for the estrogen receptor binding domain, we prepared and evaluated a novel 17α-(rhenium tricarbonyl bipyridyl) vinyl estradiol complex. Preparation of the final compound was achieved using the Stille coupling between the preformed brominated rhenium tricarbonyl bipyridine complex and the tributylstannyl vinyl estradiol. Competitive receptor binding assays and stimulatory assays demonstrated that the final complex retained affinity and efficacy comparable to the corresponding pyridyl vinyl estradiol analog, but lower than that of the phenyl vinyl estradiol analog.

Synthesis and evaluation of 17α-(dimethylphenyl)vinyl estradiols as probes of the estrogen receptor-α ligand binding domain.

As part of our program to explore the influence of small structural modifications on the biological response of the estrogen receptor-α (ERα), we prepared and evaluated a series of mono-and di-substituted phenyl vinyl estradiols. The target compounds were prepared in 45-80% yields using the Stille coupling reaction and evaluated using competitive binding analysis with the ERα-ligand binding domain (hERα-LBD) and estrogenic activity (induction of alkaline phosphatase in Ishikawa cells). Results indicated that the 2,4- and 2,5-dimethyl derivatives, 5b and 5c, had the highest relative binding affinity (RBA=20.

Synthesis and evaluation of 17α-E-20-(heteroaryl)norpregn-1,3,5(10),20 tetraene-3,17β-diols [17α-(heteroaryl)vinyl estradiols] as ligands for the estrogen receptor-α ligand binding domain (ERα-LBD).

A series of 17α-(heteroaryl)vinyl estradiols was prepared to evaluate the influence of heteroatom on the affinity and efficacy of estrogenic ligands for the estrogen receptor-alpha ligand binding domain (ERα-LBD). The products demonstrated reduced binding affinity compared to the parent 17α-E-phenyl vinyl estradiol, but the binding was relatively independent of the heteroatom. The greatest influence of the heteroatom was evident in the efficacy of the compounds as the thienyl derivatives 2f,g were more potent than either the pyridyl 2b-d or pyrimidinyl 2e analogs.

Synthesis and evaluation of isomeric (17alpha,20E)-11beta-methoxy-21-(trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diols as ERalpha-hormone binding domain ligands: effect of the methoxy group on receptor binding and uterotrophic growth.

In this study we have introduced the 11beta-methoxy group, a substituent known to increase in vivo potency in other steroidal estrogens, into the (17alpha,20E)-21-(trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diols: (trifluoromethylphenyl)vinyl estradiols. Receptor binding, using the ERalpha-HBD, indicated that the 11beta-methoxy group had little effect on the relative binding affinity of the target compounds compared to the corresponding 11beta-unsubstituted analogs, however, the 11beta-methoxy derivatives were significantly more potent in stimulating uterotrophic growth in immature female rats. Molecular modeling studies suggest that while the 11beta-methoxy group does not contribute significantly to the overall binding energy of the ligand-ERalpha-HBD complex, it stabilizes residues associated with the coregulator protein binding site.

Mitochondriotropic liposomes.

Mitochondrial dysfunction contributes to a large variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Increasing pharmacological efforts toward therapeutic interventions have been made leading to the emergence of "Mitochondrial Medicine" as a new field of biomedical research. The identification of molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch a multitude of new therapies for the treatment of mitochondria-related diseases, which are based either on the selective protection, repair, or eradication of cells.

Stereoselective addition of dimethyl thiophosphite to imines.

Dimethyl thiophosphite (DMTP) was synthesized from dimethyl phosphite, and the diastereoselective addition of DMTP to benzaldimines bearing chiral auxiliary groups was examined. Yields of the product alpha-aminophosphonothionates ranged from 17% to 75% after chromatography. The addition of DMTP to the benzaldimine derived from (S)-phenylglycinol afforded the highest diastereoselectivity (83:17), whereas addition of DMTP to the benzaldimine derived from threonine methyl ester and alanine methyl ester were far less diastereoselective, affording 38:62 and 61:39 ratios, respectively.

Synthesis and in vitro pharmacology of substituted quinoline-2,4-dicarboxylic acids as inhibitors of vesicular glutamate transport.

The vesicular glutamate transport (VGLUT) system selectively mediates the uptake of L-glutamate into synaptic vesicles. Uptake is linked to an H+-ATPase that provides coupling among ATP hydrolysis, an electrochemical proton gradient, and glutamate transport. Substituted quinoline-2,4-dicarboxylic acids (QDCs), prepared by condensation of dimethyl ketoglutaconate (DKG) with substituted anilines and subsequent hydrolysis, were investigated as potential VGLUT inhibitors in synaptic vesicles.