DESIGN, SYNTHESIS AND PHARMACOLOGICAL VALUATION OF γ-CARBOLINES, POTENTIAL INHIBITORS OF 5-LIPOXYGENASE AND OF CYCLOOXYGENASES.
Two key enzymatic systems in the inflammation process revealed being implicated in many cancers (colon, pancreas, breast, lung) and more particularly in prostate cancer (PCa). The 5-lipoxygenase (5-LO) monitors leucotrienes' formation which are inflammation of allergy mediators. There are two isoforms of the cyclooxygenase enzyme : COX1 and COX2. COX1 is constitutively expressed and COX2 is the inducible isoform. The cyclooxygenases monitor the formation of the prostaglandins, responsive inflammation mediators. Facing the similarities of the overexpressions of those enzymes in human cancer, a new treatment based on the disregulation of the arachidonic acid metabolism can be considered. The purpose of this study is to participate to the PCa therapeutical research particularly in its hormono-independant state by the rational design, the organic synthesis and then the pharmacological valuation of some N-benzoyltetrahydro-γ-carbolines, a new class of potential 5-LO/COX dual inhibitors. With this intention, a convergent synthetic strategy was developed starting from para substituted phenylhydrazine chlorides and 4-piperidone derivatives which further cyclise in tetrahydro-γ-carbolines by an acid catalysis (the Fischer method). In parallel, a 5-LO inhibitor, the methoxy tetrahydropyran (MTHP) part of ZD-2138, is alkylated by a polymethylenic scheme composed of three carbon atoms. The condensation reaction between the tetrahydro-γ-carboline and the alkylated MTHP in alkaline medium results in a compound which is subsequently benzoylated or benzylated. 5-LO and COX1/COX2 activities were obtained ex vivo on human whole blood. The tests measuring the inhibition of the cellular proliferation were achieved on different cellular issues (L-1210, MCF7, PC-3) in order to display the cytotoxic potential of the compounds.