Yasutsugu Ueda

Envelope Conformational Changes Induced by Human Immunodeficiency Virus Type 1 Attachment Inhibitors Prevent CD4 Binding and Downstream Entry Events

ABSTRACT BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.

Novel water soluble phosphate prodrugs of taxol® possessing in vivo antitumor activity☆

Abstract Synthesis and biological evaluation of novel taxol derivatives having a phosphonoxyphenylpropionate ester group at the 2′-position or at the 7-position of taxol are described. These were found to have much improved water solubility and both were found to generate taxol upon exposure to alkaline phosphatase. A particular derivative, 7-phosphonoxyphenylpropionate of taxol 3b exhibited antitumor activity comparable to that of taxol against the ip/ip M109 murine tumor model.

Antimicrobial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics

ABSTRACT Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-positive bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compounds against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain additional structurally related compounds. The MIC assay results of BMS-249524 and two more water-soluble derivatives, BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-positive pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Analysis of killing kinetics revealed that these compounds are bactericidal for S. aureus with at least a 3-log10 reduction of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compounds demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-positive bacterial pathogens.

In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068

ABSTRACT BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4+ T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC50) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log10, with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.

Synthesis and antitumor evaluation of 2′-oxycarbonylpaclitaxels (paclitaxel-2′-carbonates)

Abstract A number of 2′-oxycarbonylpaclitaxels (paclitaxel-2′-carbonates) 3 have been prepared and evaluated for their cytotoxicity and in vivo antitumor activity. Most of these paclitaxel-2′-carbonates were found to exhibit in vivo antitumor activity in the i.p. M109 murine tumor model system, comparable to that of the parent drug.

Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment 6. Preclinical and Human Pharmacokinetic Profiling of BMS-663749, a Phosphonooxymethyl Prodrug of the HIV-1 Attachment Inhibitor 2-(4-Benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043)

BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.

Novel, water-soluble phosphate derivatives of 2′-ethoxy carbonylpaclitaxel as potential prodrugs of paclitaxel: Synthesis and antitumor evaluation

Abstract Three new phosphate derivatives of paclitaxel-2′-ethylcarbonate 4a, 4b, and 4c, have been synthesized and evaluated for in vivo antitumor activity. All were soluble in water and two derivatives 4a and 4b were found to exhibit in vivo antitumor activity, comparable to paclitaxel in the M109 murine tumor model.

Highly regioselective formation of bromohydrins by reaction of epoxy-azetidinones with MgBr2: An alternative route to 4-bromomethylcarbonylmethyl-2-azetidinone, a key carbapenem precursor

Abstract A synthesis of 4-bromomethylcarbonylmethyl-2-azetidinone 7 , a key intermediate for carbapenem synthesis by highly regioselective ring-opening of epoxy-azetidinone 3a , followed by oxidation is described.

Cyclocondensation adducts from the lewis acid mediated reaction of 4-acetoxy-2-azetidinone with siloxydienes

Abstract A successful trapping of 1-azetin-4-one with siloxydienes as cyclocondensation adducts is described.

Synthesis and structure-activity relationship of C-3 quaternary ammonium cephalosporins exhibiting anti-MRSA activities

Abstract A series of cephalosporins bearing C-3 quaternary ammonium groups were prepared and evaluated for their anti-MRSA activity. They exhibit good to excellent in vitro activity (MICs = 1−8 μg/mL) against MRSA.