Semi-synthetic aristolactams--inhibitors of CDK2 enzyme.

Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.

New potential antitumor compounds from the plant Aristolochia manshuriensis as inhibitors of the CDK2 enzyme.

The 70% aqueous methanolic extract of the Chinese plant Aristolochia manshuriensis was found to contain two novel substituted phenanthrene compounds, SCH 546909 (1), and another phenanthrene glycoside (2). The structures of 1 and 2 were established based on NMR studies. They were identified as inhibitors of the CDK2 enzyme. Compound 1 was found to be a potent inhibitor of the CDK2 enzyme with an IC50 of 140 nM, whereas compound 2 was found to be less active with an IC50 of >10 microM.

A new antitumor compound from the plant Oryctanthus sp. as a VEGF receptor binding inhibitor.

The 70% aqueous methanolic extract of the Peruvian plant Oryctanthus sp. was found to contain a novel saccharide of a diene alpha,omega-diacid. Compound 1 was identified as an inhibitor of the VEGF receptor. The structure of this compound was established based on NMR studies. Compound 1 inhibited ligand binding to the VEGF receptor with an IC50 of 5.0 microM.

Three new compounds from the plant Lippia alva as inhibitors of chemokine receptor 5 (CCR5).

The 70% aqueous methanol extract of the Peruvian plant Lippia alva (Verbenaceae) was found to contain three novel compounds, 1, 2, and 3, which were identified as inhibitors of the chemokine receptor CCR5. The structures of 1-3 were established based on extensive NMR studies. Compounds 1-3 inhibited CCR5 receptor signaling as measured by a calcium mobilization assay with IC(50) values of 5.5, 6.0, and 7.2 microg/mL, respectively.

Two new bacterial DNA primase inhibitors from the plant Polygonum cuspidatum.

The 70% aqueous methanolic extract of the Peruvian plant Polygonum cuspidatum sp. was found to contain two novel phenolic saccharides 1 and 2, which were identified as inhibitors of the bacterial DNA primase enzyme. Structures of these two compounds were established based on high resolution NMR studies. Compound 1 and 2 inhibited the primase enzyme with an IC(50) of 4 and 5 microM, respectively.

Two antiviral compounds from the plant Stylogne cauliflora as inhibitors of HCV NS3 protease.

The 70% aq methanolic extract of the Peruvian plant Stylogne cauliflora was found to contain two novel oligophenolic compounds SCH 644343 (1) and SCH 644342 (2), which were identified as inhibitors of HCV NS3 protease. The structure of 1 and 2 was established based on high-resolution NMR studies. Compound 1 inhibited HCV NS3 protease with an IC(50) of 0.3 microM, while compound 2 showed an IC(50) of 0.8 microM.

Novel fungal metabolites as cell wall active antifungals: fermentation, isolation, physico-chemical properties, structure and biological activity.

Two novel antifungals SCH 643432 (1), and 2, were isolated from the fermentation broth of a fungus taxonomically classified as a Paecilomyces varioti. These compounds were separated from the fermentation broth filtrate by adsorption on a macroreticular resin XAD-16 (Amberlite). Purification and separation of the individual compounds were achieved by trituration of the extract with dichloromethane followed by preparative HPLC using reverse phase columns. Extensive FAB (Fast Atom Bombardment) and ESI (Electro Spray) mass spectrometric studies using fragmentation of various daughter ions, NMR experiments and degradative studies helped in elucidating the structure of compound 1. Compound 2 is an isomer of SCH 643432 (1). They were identified as straight chains peptides containing several amino acids such as alanine, aminoisobutyric acid, proline, leucine, glycine and arginine. The N-terminal is terminated in a previously identified beta-keto acid, 2-methyl 3-oxo tetradecanoic acid (MOTDA). Both compounds were active against Candida albicans, other Candidas, dermatophytes and Aspergillus (Geometric Mean MIC's 4.00, 2.59, 3.56, 11.31 and 4.49, 4.00, 5.66, 16.0 microg/ml, respectively for 1 and 2).

Condensed aromatic peptide family of microbial metabolites, inhibitors of CD28-CD80 interactions.

Three condensed aromatic peptides SCH79235 (1), SCH79236 (2), and SCH204698 (3) were isolated from the fermentation broth of a Streptomycete microorganism. The structure of SCH204698 (3) was established by extensive NMR spectral data. All these compounds exhibited good activity against CD28-CD80 binding with an IC(50) of 0.42, 0.38 and 0.22 microM, respectively.

Two selective novel triterpene glycosides from sea cucumber, Telenata Ananas: inhibitors of chemokine receptor-5.

The aqueous methanolic extract of a sea cucumber was found to contain two triterpene glycosides 1 and 2. The structures of 1 and 2 were established based on high-resolution NMR studies. Compounds 1 and 2 exhibited inhibitory activity (K(i)) of 30 and 5microM, respectively, in a chemokine receptor subtype 5 (CCR5) assay. Both compounds did not show any significant inhibition in a CXCR2 assay at 50microM, suggesting their selectivity for the CCR5 receptor.