William D. Kingsbury

Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47.

Inhibitors of the cancer-related cysteine isopeptidase human ubiquitin-specific proteases 7 (USP7) and 47 (USP47) are considered to have potential as cancer therapeutics, owing to their ability to stabilize the tumor suppressor p53 and to decrease DNA polymerase β (Polβ), both of which are potential anticancer effects. A new class of dual small molecule inhibitors of these enzymes has been discovered. Compound 1, a selective inhibitor of USP7 and USP47 with moderate potency, demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines. Compound 1 has been shown to demonstrate modest activity in human xenograft multiple myeloma and B-cell leukemia in vivo models. This activity may be the result of dual inhibition of USP7 and USP47. To address issues regarding potency and developability, analogues of compound 1 have been synthesized and tested, leading to improvements in potency, solubility, and metabolic reactivity profile. Further optimization is expected to yield preclinical candidates and, ultimately, clinical candidates for the treatment of multiple myeloma, prostate cancer, and other cancers.

Determination of carboxypeptidase A using N-acetyl-phenylalanyl-3-thiaphenylalanine as substrate: Application to a direct serum assay☆

N-Acetyl-L-phenylalanyl-L-3-thiaphenylalanine has been shown to be a substrate for carboxypeptidase A. Hydrolysis of the compound obeys Michaelis-Menten kinetics with a KM of 0.22 mM and a kcat of 6720 min-1 at 22 degrees C. A colorimetric assay, employing Ellmans reagent to detect the thiophenol released upon cleavage of the peptide, has been developed. The assay can be used for the direct determination of carboxypeptidase A in serum.

The chemical rearrangement of camptothecin to mappicine ketone

Abstract Reaction of camptothecin ( 1 ) in DMF solution with sodium azide led to the formation of mappicine ketone ( 3 ). Sodium borohydride reduction of 3 gave the racemic natural product mappicine ( 4 ).

Determination of leucine aminopeptidase using phenylalanyl-3-thia-phenylalanine as substrate.

The peptide mimetic L-phenylalanyl-L-3-thiaphenylalanine has been shown to facilitate a sensitive and simple determination of leucine aminopeptidase. A colorimetric assay, employing Ellmans reagent to detect the thiophenol released upon hydrolysis of the dipeptide, has been developed. Under the experimental conditions employed the substrate has a Km of 0.054 mM and a kcat of 5800 min-1 and can distinguish sharply between leucine aminopeptidase and aminopeptidase M.

A facile synthesis of benzyl 3,7-dioxo-1-azabicyclo[3.2.0]Heptane-2-carboxylate. A potential precursor of thienamycin and clavulanic acid analogs

Abstract A novel, high yield synthesis of the 1-carbapenam ring system 3 is described in which the entire carbon framework is introduced in a single step from simple precursors.

Synthesis and antineoplastic activity of alanyl-2-glycyl peptide derivatives of nocodazole

Abstract To provide the antineoplastic agent nocodazole, 1, with improved solubility and drug-transport properties, The (S)-alanyl-2-glycyl moiety was introduced as a benzimidazole-nitrogen-substituent which would be expected to be enzymatically cleaved in vivo to regenerate 1 and achieve enhanced antineoplastic effectiveness. Synthesis produced 2 pairs of diastereo-isomers (2a–d) which were separated and purified by solubility and chromatography. Site of substitution (N1 vs. N3) and chirality were established by 1H NMR nOe difference spectra and CD spectra on 2a–d and derivatives. The compounds were evaluated in cytotoxicity, leukemia, and solid tumor models and as inhibitors of tubulin binding. These test results indicated that these compounds were not functioning as prodrugs for 1. However, the solid tumor model study showed that 2 compounds had equivalent to enhanced antitumor effectiveness over 1 itself.To provide the antineoplastic agent nocodazole, 1, with improved solubility and drug-transport properties, The (S)-alanyl-2-glycyl moiety was introduced as a benzimidazole-nitrogen-substituent which would be expected to be enzymatically cleaved in vivo to regenerate 1 and achieve enhanced antineoplastic effectiveness. Synthesis produced 2 pairs of diastereo-isomers (2a–d) which were separated and purified by solubility and chromatography. Site of substitution (N1 vs. N3) and chirality were established by 1H NMR nOe difference spectra and CD spectra on 2a–d and derivatives. The compounds were evaluated in cytotoxicity, leukemia, and solid tumor models and as inhibitors of tubulin binding. These test results indicated that these compounds were not functioning as prodrugs for 1. However, the solid tumor model study showed that 2 compounds had equivalent to enhanced antitumor effectiveness over 1 itself.

Original paperSynthesis and antineoplastic activity of alanyl-2-glycyl peptide derivatives of nocodazoleSynthèse et activité antinéoplastique de dérivés alanyl-2-glycyl peptide de nocodazole

Abstract To provide the antineoplastic agent nocodazole, 1, with improved solubility and drug-transport properties, The (S)-alanyl-2-glycyl moiety was introduced as a benzimidazole-nitrogen-substituent which would be expected to be enzymatically cleaved in vivo to regenerate 1 and achieve enhanced antineoplastic effectiveness. Synthesis produced 2 pairs of diastereo-isomers (2a–d) which were separated and purified by solubility and chromatography. Site of substitution (N1 vs. N3) and chirality were established by 1H NMR nOe difference spectra and CD spectra on 2a–d and derivatives. The compounds were evaluated in cytotoxicity, leukemia, and solid tumor models and as inhibitors of tubulin binding. These test results indicated that these compounds were not functioning as prodrugs for 1. However, the solid tumor model study showed that 2 compounds had equivalent to enhanced antitumor effectiveness over 1 itself.To provide the antineoplastic agent nocodazole, 1, with improved solubility and drug-transport properties, The (S)-alanyl-2-glycyl moiety was introduced as a benzimidazole-nitrogen-substituent which would be expected to be enzymatically cleaved in vivo to regenerate 1 and achieve enhanced antineoplastic effectiveness. Synthesis produced 2 pairs of diastereo-isomers (2a–d) which were separated and purified by solubility and chromatography. Site of substitution (N1 vs. N3) and chirality were established by 1H NMR nOe difference spectra and CD spectra on 2a–d and derivatives. The compounds were evaluated in cytotoxicity, leukemia, and solid tumor models and as inhibitors of tubulin binding. These test results indicated that these compounds were not functioning as prodrugs for 1. However, the solid tumor model study showed that 2 compounds had equivalent to enhanced antitumor effectiveness over 1 itself.