Jean-Noel Denis

A Safe, Simple, One-Pot Preparation of N-Derivatized β-Amino Alcohols and Oxazolidinones from Amino Acids

Abstract N-tert-Butoxycarbonyl, N-benzoyl, N-benzyloxycarbonyl, and oxazolidinone derivatives of β-amino alcohols have been prepared from amino acids in 72 to 90 % yields through lithium aluminum hydride reduction followed by in situ derivatization.

The Reactions of Nitrones with Indoles

Abstract The reaction of nitrones with various indole derivatives has been studied. When the reaction was promoted by ClSiMe3, the isolated products were 3,3′-diindolylalkanes. With HCl as the activating reagent, 3-indolylhydroxylamines were isolated. The diastereoselectivity of this condensation with a nitrone derived from cysteine was investigated. A method for the introduction of an alkylhydroxylamino group onto position 2 of indole, the synthesis of three natural 3,3′-diindolylalkanes and of non-symmetric diindolylalkanes are also reported.

The reaction of nitrones with indoles. Synthesis of asymmetrical diindolylalcanes

Abstract The reaction of nitrones with indoles in the presence of HCl gives indolyl N -hydroxylamines. In the presence of Me 3 SiCl symmetrical diindolylalcanes are obtained. A synthesis of asymmetrical diindolylalcanes and the syntheses of three natural symmetrical diindolylalcanes are reported.

Taxotere® by esterification with stereochemically “wrong” (2S,3S)-phenylisoserine derivatives

Cyclically protected anti (2S, 3S) phenylisoserines on esterification with baccatin III derivatives afford Taxotere® and taxol precursors with the syn (2R, 3S) side chain.

Expanding the chemical diversity of CK2 inhibitors

None of the already described CK2 inhibitors did fulfill the requirements for successful clinical settings. In order to find innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chemical libraries. We report here the identification and characterization of several classes of new inhibitors. Whereas some share characteristics of previously known CK2 inhibitors, others are chemically unrelated and may represent new opportunities for the development of better CK2 inhibitors. By combining structure-activity relationships with a docking procedure, we were able to determine the binding mode of these inhibitors. Interestingly, beside the identification of several nanomolar ATP-competitive inhibitors, one class of chemical inhibitors displays a non-ATP competitive mode of inhibition, a feature that suggests that CK2 possess distinct druggable binding sites. For the most promising inhibitors, selectivity profiling was performed. We also provide evidence that some chemical compounds are inhibiting CK2 in living cells. Finally, the collected data allowed us to draw the rules about the chemical requirements for CK2 inhibition both inxa0vitro and in a cellular context.

Docetaxel (taxotere) derivatives: novel NbCl3-based stereoselective approach to 2′-methyldocetaxel

The C-2 methylated 2S,3R and 2R,3S side chains of docetaxel have been enantioselectively prepared and esterified with protected 10-deacetylbaccatin III to provide novel analogues of docetaxel.

Reactions of In Situ Generated N-Boc Nitrones with Aromatic and Heteroaromatic Grignard Reagents: Application to the Synthesis of Zileuton

A new class of alpha-aromatic-N-hydroxylamines has been prepared by reaction of tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates with aromatic and heteroaromatic Grignard reagents. Reactions proceed via a base-assisted elimination of the phenylsulfonyl group leading to N-Boc nitrones. This methodology has been applied to the synthesis of zileuton.

1-(1H-indol-3-yl)ethanamine derivatives as potent Staphylococcus aureus NorA efflux pump inhibitors.

The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at positionu20055 of the indole core were the most efficient inhibitors of the S.u2005aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5u2005mgu2009L−1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found.

Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents.

A collection of 3-substituted indole derivatives was prepared using nucleophilic addition of indoles to nitrones. The compounds were then tested for their antibacterial activity against almost thirty bacterial strains representative of common human pathogens. Two types of indolic molecules inhibit the growth of Staphylococcus aureus, including MRSA and VISA strains, with MIC values ranging from 8 to 16 mg/L.

Synthesis of D-Albizziine Derivatives from L-Serine

Abstract A 5 step synthesis of N-Boc-D-albizziine from Garners aldehyde, via a protected derivative of (R)-2,3-diaminopropanol, is reported. The overall yield is 30%.