Wei-Chu Xu

Novel protein kinase C inhibitors: synthesis and PKC inhibition of β-substituted polythiophene derivatives

A series of beta-substituted polythiophene derivatives was synthesized through palladium-catalyzed coupling reaction. Their structure-protein kinase C (PKC) inhibitory activity relationship was studied. The carboxaldehyde and hydroxymethyl derivatives of alpha-terthiophene were potent PKC inhibitors (IC50 = 10(-7) M).

Contrasting steric effects of the ketones and aldehydes in the reactions of the diisopinocampheyl enolborinates of methyl ketones with aldehydes

Abstract Treatment of the diisopinocampheylborinates of a representative series of methyl ketones with a representative series of aldehydes, both of differing steric requirements provides aldols whose enantiomeric purities depend on the steric requirements of both the ketones and the aldehydes. This study has shown that increasing the steric requirements of the R group in the ketones has a pernicious effect on the ee, while increasing the steric requirements of the R group in the aldehydes exerts a beneficial effect on the ee.

7-Alkyl-N2-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity

Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10μg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.

B,B-DIHALOTERPENYLBORANES AS REAGENTS FOR THE DIASTEREO- AND ENANTIOSELECTIVE SYNTHESIS OF SYN-ALDOLS

Abstract A series of known and new B,B-dihaloterpenylboranes, readily synthesized from the corresponding terpenes, were examined for the diastereo- and enantioselective synthesis of syn-aldols. Thus, IpcBCl2, EapBCl2, LgfBCl2, cis-MyrBCl2, 2-IcrBCl2, 4-IcrBCl2, and 2-IcrBBr2 in the presence of i-Pr2NEt, convert 3-pentanone to ≥99% Z-enolates, converted by aldehydes to pure syn-aldols in 7–74% enantiomeric excess (ee). The most efficient of these reagents, B,B-dibromo-2-isocaranylborane, was tested for the enolboration of 3-pentanone, followed by aldolization with a series of aldehydes.

B,B-Dihaloalkylboranes as efficient reagents for the stereoselective synthesis of syn-aldols☆

Abstract The easily synthesized B,B-dihaloalkylboranes, in the presence of either Et3N or i-Pr2NEt, converts ethyl ketones, RCOEt, to 96- ≥ 99% Z-enolates, converted by aldehydes to essentially pure syn-aldols.

A Novel Agent Effective against Clostridium difficile Infection

ABSTRACT N2-(3,4-Dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine (MorE-DCBG, 362E) is a synthetic purine that selectively inhibits the replication-specific DNA polymerase of Clostridium difficile. MorE-DCBG and its analogs strongly inhibited the growth of a wide variety of C. difficile strains. When administered orally in a hamster model of C. difficile-specific colitis, 362E was as effective as oral vancomycin, the current agent of choice for treating severe forms of the human disease.

Prodrugs of herpes simplex thymidine kinase inhibitors

Background Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model. Methods Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug. Results Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N2-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication. Conclusions Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo.