Synthesis and Penicillin-binding Protein Inhibitory Assessment of Dipeptidic 4-Phenyl-ß-lactams from α-Amino Acid-derived Imines.

Monocyclic ß-lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six-step synthetic route was developed, providing easy access to new 3-amino-1-carboxymethyl-4-phenyl-ß-lactams, of which the penicillin-binding protein (PBP) inhibitory potency was demonstrated biochemically.

Design, synthesis and glycosidase inhibition studies of novel triazole fused iminocyclitol-δ-lactams.

Synthesis of novel triazole fused iminocyclitol-δ-lactams is described. The synthetic sequence involves the intermolecular [3 + 2] cycloaddition reaction of five-membered iminocyclitol derived azides with diethylacetylene dicarboxylate followed by intramolecular lactamisation, decarboxylation/reduction and final deprotection. Compound 3 is found to be a selective inhibitor of α-glucosidase from baker's yeast while two other compounds (2 and 4) that possess an additional hydroxymethyl group in the triazole ring are selective against ß-galactosidase from E. coli. Docking studies suggest the significance of the lactam carbonyl group for effective binding of these inhibitors with the active sites through hydrogen bonding.

A direct and general method for the reductive alkylation of tertiary lactams/amides: application to the step economical synthesis of alkaloid (-)-morusimic acid D.

Full details of the direct and general method for the reductive alkylation of tertiary lactams and amides to give tertiary sec-alkylamines are presented. This one-pot method consists of in situ activation of a lactam or an amide with Tf2O/DTBMP, addition of a Grignard reagent, and reduction of the resulting iminium intermediates. Alkyl, benzyl, and aryl Grignard reagents and several reductants or reducing conditions (LiAlH4, NaBH4, Hantzsch ester, Bu3SnH, Pd(OH)2/C, H2) could be used effectively. Reductive alkylations of substituted lactams demonstrated good to excellent 1,3-asymmetric induction to provide the corresponding di- or trisubstituted pyrrolidine/piperidine in 6:1 (LiAlH4), 11:1 (Et3SiH), and 20:1 (catalytic hydrogenation) cis/trans diastereoselectivity, respectively. The versatility of this methodology was demonstrated by its application in the concise stereoselective synthesis of piperidine alkaloid (-)-morusimic acid.

Synthesis, antiproliferative, acute toxicity and assessment of antiandrogenic activities of some newly synthesized steroidal lactams.

The 17-oxo-17a-aza-d-homo-5-androsten-3beta-yl esters (13-22) were synthesized from commercially available (25R)-5-spirosten-3beta-ol (Diosgenin) (6) as starting material. The synthesized compounds were evaluated for their antiproliferative activity, acute toxicity and effect on serum androgen level and were compared with Finasteride as positive controls. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and pharmacological screening for the synthesized compounds were reported.

Spectral properties of self-assembled squaraine-tetralactam: a theoretical assessment.

Using several theoretical approaches relying on the time-dependent density functional theory, we have computed the electronic spectrum in the visible range of a squaraine dye, either isolated or embedded into a tetralactam macrocycle. The amplitude of the bathochromic displacement induced by the complexation is well-reproduced by the most accurate models. This total shift is split into specific components, allowing us to unravel the most-important contributions (geometry modifications, polarisations...). This study constitutes a further step in the investigation of environmental effects on dyes' absorption spectra.

Structural basis of binding of high-affinity ligands to protein kinase C: prediction of the binding modes through a new molecular dynamics method and evaluation by site-directed mutagenesis.

The structural basis of protein kinase C (PKC) binding to several classes of high-affinity ligands has been investigated through complementary computational and experimental methods. Employing a recently developed q-jumping molecular dynamics (MD) simulation method, which allows us to consider the flexibility of both the ligands and the receptor in docking studies, we predicted the binding models of phorbol-13-acetate, phorbol-12,13-dibutyrate (PDBu), indolactam V (ILV), ingenol-3-benzoate, and thymeleatoxin to PKC. The "predicted" binding model for phorbol-13-acetate is virtually identical to the experimentally determined binding model for this ligand. The predicted binding model for PDBU is the same as that for phorbol-13-acetate in terms of the hydrogen-bonding network and hydrophobic contacts. The predicted binding model for ILV is the same as that obtained in a previous docking study using a Monte Carlo method and is consistent with the structure-activity relationships for this class of ligands. Together with the X-ray structure of phorbol-13-acetate in complex with PKCdelta C1b, the predicted binding models of PDBu, ILV, ingenol-3-benzoate, and thymeleatoxin in complex with PKC showed that the binding of these ligands to PKC is governed by a combination of several highly specific and optimal hydrogen bonds and hydrophobic contacts. However, the hydrogen-bonding network for each class of ligand is somewhat different and the number of hydrogen bonds formed between PKC and these ligands has no correlation with their binding affinities. To provide a direct and quantitative assessment of the contributions of several conserved residues around the binding site to PKC-ligand binding, we have made 11 mutations and measured the binding affinities of the high-affinity PKC ligands to these mutants. The results obtained through site-directed mutagenic analysis support our predicted binding models for these ligands and provide new insights into PKC-ligand binding. Although all the ligands have high affinity for the wild-type PKCdelta C1b, our site-directed mutagenic results showed that ILV is the ligand most sensitive to structural perturbations of the binding site while ingenol-3-benzoate is the least sensitive among the four classes of ligands examined here. Finally, we have employed conventional MD simulations to investigate the structural perturbations caused by each mutation to further examine the role played by each individual residue in PKC-ligand binding. MD simulations revealed that several mutations, including Pro11 --> Gly, Leu21 --> Gly, Leu24 --> Gly, and Gln27 --> Gly, cause a rather large conformational alteration to the PKC binding site and, in some cases, to the overall structure of the protein. The complete abolishment or the significant reduction in PKC-ligand binding observed for these mutants thus reflects the loss of certain direct contacts between the side chain of the mutated residue in PKC and ligands as well as the large conformational alteration to the binding site caused by the mutation.