Jamil Kraïem

Synthesis and pharmacological profile of 6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide derivatives: non-steroidal anti-inflammatory agents with reduced ulcerogenic effects in the rat.

The new anti-inflammatory agents 6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide 6a and its analogues 6b-f were synthesized from L-valine. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 6a-f (5-20 mg/kg, i.p.) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay in albino rats, and their effects are comparable to that of piroxicam (5 mg/kg, i.p.), used as a reference drug. The nature of the substituents on the sulfonamide nitrogen and those on position three had a pronounced effect on the anti-inflammatory activity. Studies of structure-activity relationships have led to selection of compound 2,6-dimethyl-3-isopropyl-1,2-benzothiazin-3,4-diol 1,1-dioxide 6 f which exhibited the most potent activity (61.7% inhibition at 5 mg/kg, i.p. and ED(50)=4.5 mg/kg, i.p.). Comparison of the gastrointestinal safety of compounds 6a-f with that of piroxicam showed a far better tolerability for our products. This comparison was based on the ulcer index and the pH of gastric content.

Enantio- and Diastereoselective Oxidation of N-Alkylimines Using Chiral α-Bromonitriles and Hydrogen Peroxide System

Abstract Chiral α-bromonitriles were prepared with good chemical and optical yields starting from natural α-amino acids by dehydrating the corresponding α-bromoamides with thionyl chloride. The combined system α-bromonitriles/hydrogen peroxide was examined for the enantio- and diastereoselective oxidation of N-alkylimines in basic media at room temperature. The oxidation of N-tertiobutylarylimines leads to optically active oxaziridines with moderate enantiomeric excess. However, the oxidation of (S)-1-phenylethylarylimines affords the corresponding oxaziridines with good diasteromeric excess up to 97/3 as proved by gaseous-phase chromatography. GRAPHICAL ABSTRACT

Synthesis of Enantiomerically Enriched α-Bromonitriles from Amino Acids

Abstract Two methods were investigated for the preparation of six chiral α-bromonitriles with different optic purities. The nitrous deamination of amino acids gives α-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford α-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding α-bromoamids using thionyl chloride gives α-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis. GRAPHICAL ABSTRACT

Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma

Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 μM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.

Design, synthesis of new chiral fluorine-containing β-hydroxysulfonamides from natural amino acids and study of their anti-inflammatory and analgesic activities

A series of new chiral fluorine-containing β-hydroxysulfonamides were conveniently synthesized in three steps, starting from natural L-amino acids, and evaluated for their anti-inflammatory and analgesic activities. The structures of these compounds were supported by FT-IR, 1H, 13C and 19F NMR, elemental analysis and HRMS. Among the tested compounds, 4c, 4g and 4h exhibited promising anti-inflammatory activity. Moreover, compound 4h showed a significant analgesic activity. The structure–activity relationships of selected compounds were discussed.