Jean-Claude Gramain

Synthesis, characterization and comparative biodistribution study of a new series of p-Iodine-125 benzamides as potential melanoma imaging agents

Iodobenzamides are reported to possess some affinity for melanoma. In order to identify the compound having the most appropriate pharmacokinetic properties as a potential melanoma imaging agent, thirteen new [125I]radioiodobenzamides with a butylene amide-amine spacer and various substituents on the terminal amino group were investigated. Their synthesis, radioiodination and biodistribution in B16 melanoma bearing C57BL6 mice are described and compared to [125I] labeled N-(2-diethylaminoethyl)-4-iodobenzamide ([125I]BZA), our reference compound. Changes in the terminal amino constituents induced modifications of lipophilicity, tumor uptake and organ distribution. The dimethylaminobutyl iodobenzamide appeared to be the most promising radiopharmaceutical imaging agent for the detection of melanoma and its metastases.

Asymmetric synthesis of quinolizidine alkaloids (−)-lasubine I, (−)-lasubine II and (+)-subcosine II

Abstract The enantioselective synthesis of (−)-lasubine I 1 and the first asymmetric synthesis of (−)-lasubine II 2 and (+)-subcosine II 3 is described. The key step is the intramolecular cyclization of N-acyliminium ion 4 which is derived from (S)-aminoester 6.

Novel 4,5-Diaryl-3-hydroxy-2(5H)-furanones as Anti-Oxidants and Anti-Inflammatory Agents

In order to study the effect of phenol moieties on biological activities of ascorbic acid derivatives, we synthesized 13 novel 4,5-diaryl-3-hydroxy-2(5H)-furanones 5a-m with various substitution patterns. Compound 5 g bearing a 2,3-dihydroxy phenyl ring on the 5-position of the heterocycle appeared to be the most powerful anti-oxidant furanone with reducing activity against DPPH (IC(50)=10.3 microM), superoxide anion quenching capacity (IC(50)=0.187 mM) and lipid peroxidation inhibitory effect (IC(50)=0.129 mM). To ascertain determinant molecular features for anti-oxidant activities, structure-activity relationships were studied. Lipophilicity and molecular parameters related to electron distribution and structure (difference in heats of formation between the compound and its radical or its cation radical, energy of the highest occupied molecular orbital, HOMO) were found to correlate with the anti-oxidant action of compounds 5 in the different tests used. Oxygen-derived free radicals are known to contribute to inflammatory disorders; therefore we have investigated effects of compounds 5 in two models of inflammation: phorbol ester-induced ear edema in mice (TPA-test) and carrageenan-induced paw edema in rat. At 100 mg/kg ip in the TPA-test, the anti-inflammatory activity of compounds 5 was potent compared with that of indomethacin and ketorolac and all the results suggested a cyclooxygenase inhibition in the emergence of such properties. The combined pharmacological actions of compounds 5 associated with a favorable therapeutic index prompt with interesting perspectives for their use in heart and brain disorders as well as in inflammatory diseases.

Synthesis and anticonvulsant properties of triazolo- and imidazopyridazinyl carboxamides and carboxylic acids

Analogues of 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine PC25 containing amide or carboxylic acid function were synthesized and tested for anticonvulsant activity. The compounds having the imidazole ring substituted with an amide group have been found to be generally more active against maximal electroshock-induced seizures in mice (15.2 < or = ED50 < or = 37.5 mg kg(-1) orally). Furthermore, maximum activity was generally associated with a 2,6-dichlorobenzyl substitution pattern. 3-Amido-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine 4b was also protective in the pentylenetetrazole-induced seizures test (ED50 = 91.1 mg kg(-1) orally) and blocked strychnine-induced tonic extensor seizures (ED50 = 62.9 mg kg(-1) orally). Moreover, calculated electrostatic isopotential maps of the whole active compounds were quite similar and, consequently, could be associated to optimum anticonvulsant activity.

Enantioselective synthesis of (−)-indolizidine 167B

Abstract The enantioselective total synthesis of (−)-indolizidine 167B is described. The key step is the intramolecular cyclization of the chiral N -acyliminium ion 6 . Indolizidine 167B was obtained in 7 steps and 17% yield from ethyl ( R )-3-aminohexanoate, with an enantiomeric excess of 93%.

Diastereoselective cyclization of allylsilanes on α-acyliminium ions. A new approach to (±)-myrtine and (±)-epimyrtine

Abstract Total synthesis of (±)-myrtine and (±) epimyrtine is described using an intromolecular allylsi1ane N acyliminium ion cyclization.

ENANTIOSELECTIVE SYNTHESIS OF THE QUINOLIZIDINE ALKALOIDS (+)-MYRTINE AND (-)-EPIMYRTINE

Abstract The enantioselective synthesis of (+)-myrtine 1 and (−)-epimyrtine 2 is described starting from ( S )-2-(2-hydroxypropyl)allyltrimethylsilane 4 using an intramolecular allylsilane N -acyliminium ion cyclization.

Stereoselective preparation of tri and tetracyclic amines as potential intermediates in Aspidosperma alkaloid synthesis

Abstract The stereoselectivity of the reduction of tri and tetracyclic imines 3 and 4 , easily prepared from hexahydrocarbazolone 5 is studied.

Total synthesis of (±) aspidofractinine☆

Abstract The pentacyclic skeleton 10 of the aspidospermine group of indole alkaloids has been constructed from hexahydrocarbazol-4-one 2 with high stereoselectivity. The synthesis of (±) 19-oxo aspidofractinine 12 , a direct precursor of aspidofractinine 4 , illustrates the usefulness of this new general strategy.

A convenient allylsilane-N-acyliminium route toward 5-alkylindolizidines. Diastereoselective synthesis of (±)-indolizidine 167B

Abstract A highly diastereoselective synthesis of 5-alkylindolizidines is described via an intermolecular addition of the allylsilyl functional group of homoallylic alcohols with an N -acyliminium ion derived from pyrrolidin-2-one.