Identification of novel metabolites of abiraterone in human serum and their metabolic pathways.

Two novel abiraterone (Abi, 3ß-OH-Abi) metabolites in human serum were identified as 3α-OH-Abi and Δ5-Abi (D5A). Both metabolites were confirmed by their retention times on LC/MS and their product-ion mass spectra on LC-MS/MS compared to those of authentic compounds, which were chemically synthesized. The plausible metabolic pathways of these two metabolites are as follows: Abi is first oxidized to D5A by 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and then irreversibly converted to Δ4-Abi (D4A) by ∆5-∆4 isomerase. Presumably, D5A detection is difficult because of its rapid conversion to D4A and its low concentration in serum samples. In contrast, the low concentration 3α-OH-Abi was generated by reducing the remaining D5A using 3α-hydroxysteroid dehydrogenase (3α-HSD).

CuI-Catalyzed Coupling Reactions of 4-Iodopyrazoles and Alcohols: Application toward Withasomnine and Homologs.

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.

[Asymmetric Hetero-Michael Additions to α,ß-Unsaturated Carboxylic Acids by Multifunctional Boronic Acid Catalysts].

Several direct asymmetric Michael additions to α,ß-unsaturated carboxylic acids with integrated catalysts comprising chiral bifunctional thiourea and arylboronic acid were developed. First, the asymmetric aza-Michael addition of hydroxylamine derivatives efficiently afforded a variety of optically active ß-amino acid derivatives. Furthermore, upon detailed investigation of the reaction, tetrahedral borate complexes, comprising two carboxylate molecules, were found to serve as reaction intermediates. Based on this observation, a drastic improvement in product enantioselectivity was achieved upon benzoic acid addition. Second, on merely changing the solvent, the asymmetric thia-Michael addition of arylthiols afforded both enantiomers of the adducts, which are important building blocks for biologically active compounds.

A solvent-dependent chirality-switchable thia-Michael addition to α,ß-unsaturated carboxylic acids using a chiral multifunctional thiourea catalyst.

An asymmetric thia-Michael addition of arylthiols to α,ß-unsaturated carboxylic acids using a thiourea catalyst that bears arylboronic acid and tertiary amine moieties is reported. Both enantiomers of the Michael adducts can be obtained in high enantioselectivity and good yield merely by changing the solvent. The origin of the chirality switch in the products was examined in each solvent via spectroscopic analyses.

Catalytic asymmetric aza-Michael addition of fumaric monoacids with multifunctional thiourea/boronic acids.

The first chemical enantioselective synthesis of N-hydroxyaspartic acid derivatives using chiral multifunctional thiourea/boronic acid organocatalysts was developed. A series of fumaric monoacids underwent an intermolecular asymmetric aza-Michael addition of O-alkyl hydroxylamines in excellent regioselectivity. The addition of another carboxylic acid raised the enantiomeric enrichment up to 97% ee. O-Deprotection of the aza-Michael adduct provided an aspartate-derived hydroxylamine fragment applicable for KAHA (α-keto acid-hydroxylamine) ligation.

Inhibition of angiogenesis and tumor growth by a novel 1,4-naphthoquinone derivative.

Hit, Lead & Candidate Discovery Antiangiogenesis therapy is a promising way for treatment of solid cancers, and many angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) or its receptors have been developed. We explored novel antiangiogenic compounds other than anti-VEGF drugs by screening our synthetic compound library and found that 6-thiophen-3-yl-2-methoxy-1,4-naphthoquinone (6-TMNQ) had potential as a novel angiogenesis inhibitor. This paper describes the effects of 6-TMNQ on angiogenesis and tumor growth in vitro and in vivo. 6-TMNQ inhibited serum-, VEGF-, and basic fibroblast growth factor (bFGF)-stimulated proliferation of endothelial cells in a concentration-dependent manner, but had no effect on the proliferation of fibroblasts. VEGF-induced activation of VEGF receptor-2 in endothelial cells was not affected by the compound. 6-TMNQ markedly abrogated both migration and tube formation of endothelial cells. Orally administered 6-TMNQ inhibited angiogenesis in response to VEGF or bFGF in mice in a dose-dependent manner. Furthermore, when tumor-bearing mice were treated with 6-TMNQ, increase in tumor size was significantly prevented due to inhibition of angiogenesis in the tumor tissues. These results demonstrate that 6-TMNQ is an orally available compound that selectively inhibits endothelial cell proliferation and migration, and abrogates angiogenesis, resulting in the prevention of tumor growth. The mechanism of 6-TMNQ action is different from that of conventional anti-VEGF drugs.

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,ß-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas.

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,ß-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

Chiral Integrated Catalysts Composed of Bifunctional Thiourea and Arylboronic Acid: Asymmetric Aza-Michael Addition of α,ß-Unsaturated Carboxylic Acids.

The first intermolecular asymmetric Michael addition of nitrogen-nucleophiles to α,ß-unsaturated carboxylic acids was achieved through a new type of arylboronic acid equipped with chiral aminothiourea. The use of BnONH2 as a nucleophile gives a range of enantioenriched ß-(benzyloxy)amino acid derivatives in good yields and with high enantioselectivity (up to 90% yield, 97% enantiomeric excess (ee)). The obtained products are efficiently converted to optically active ß-amino acid and 1,2-diamine derivatives.

A powerful hydrogen-bond-donating organocatalyst for the enantioselective intramolecular oxa-Michael reaction of α,ß-unsaturated amides and esters.

Tuning the organocatalyst: An unprecedented enantioselective intramolecular oxa-Michael reaction of unactivated α,ß-unsaturated amides and esters catalyzed by a powerful hydrogen-bond-donating organocatalyst has been developed. Furthermore, the products obtained from this reaction have been used for the straightforward asymmetric synthesis of several natural products and biologically important compounds.

One-pot construction of multiple contiguous chiral centers using Michael addition of chiral amine.

Multiple contiguous chiral centers were constructed in one pot using three types of multistep reactions initiated with the Michael addition of N-benzyl-2(R)-methoxy-(+)-10-bornylamide to alpha,beta-unsaturated esters, i.e., asymmetric Michael-aldol reaction, double Michael addition, and double Michael-aldol reaction. The chiral 2-methoxy-10-bornyl group as well as the benzyl group on the amino group of the products in the Michael-aldol reaction could be easily cleaved by treatment with NIS (4 equiv), and beta-amino esters with multiple contiguous chiral centers were obtained in good yield. As an application, the beta-amino-beta'-hydroxy ester obtained in the asymmetric Michael-aldol reaction was converted to the beta-lactam derivative in good yield.