synthetic strategies to 2'-hydroxy-4'-methylsulfonylacetophenone, a key compound for the preparation of flavonoid derivatives

International audienceDifferent strategies for the synthesis of 2′-hydroxy-4′- methylsulfonylacetophenone are reported in the present paper. This compound is considered as a key synthon for the synthesis of new flavonoid derivatives designed as potential cyclooxygenase-2 inhibitors. The retrosynthetic approach via 3′-methylsulfonylacetophenone, which included three synthetic pathways, did not allow us to obtain the expected compound. However, a synthesis from 3-mercaptophenol led to the desired acetophenone in three steps: thiophenol methylation, Friedel-Crafts acetylation and oxidation of the sulphide to the corresponding sulfone. The desired compound, 2′-hydroxy-4′- methylsulfonylacetophenone, will be used as a synthon for the preparation of novel flavonoid derivatives, such as 2′-hydroxychalcones, flavanones, flavones, and flavonols

Exploring the Use of the Suzuki Coupling Reaction in the Synthesis of 4′-Alkyl-2′-hydroxyacetophenones

International audienceA series of 4′-alkyl-2′-hydroxyacetophenones were prepared by Suzuki cross-coupling reactions of 4′-bromo-2′-hydroxyacetophenone. In these reactions, alkyl(trifluoro)borates were found to be better reactants than alkylboronic acids. 4′-Alkyl-2′-hydroxyacetophenones are key intermediates for the further synthesis of -lipoflavonoids that are more readily incorporated into lipid bilayer membranes than flavonoids and should, therefore, have superior -biological effects through increased bioavailability

Novel methylsulfonyl chalcones as potential antiproliferative drugs for human prostate cancer: Involvement of the intrinsic pathway of apoptosis

International audienceLimited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. In the present study, the apoptotic mechanism of action of RG003 (2'-hydroxy-4- methylsulfonylchalcone) and RG005 (4'-chloro-2'-hydroxy-4- methylsulfonylchalcone) in association with intracellular signalling pathways was investigated in the hormone-independent prostate carcinoma cells PC-3 and DU145. We showed that these compounds induced apoptosis through the intrinsic pathway but not through the extrinsic one. We showed that synthetic chalcones induced an activation of caspase-9 but not caspase-8 in PC-3 cells. Even if both chalcones induced apoptosis in PC-3 cells, a dominant effect of RG003 treatment was observed resulting in a disruption of δm, caspase-9 and caspase-3 activation, PARP cleavage and DNA fragmentation. Furthermore, in regard to our results, it is clear that the simultaneous inhibition of Akt and NF-κB signalling can significantly contribute to the anticancer effects of RG003 and RG005 in PC-3 prostate cancer cells. NF-κB inhibition was correlated with the reduction of COX-2 expression and induction of apoptosis. Our results clearly indicate for the first time that RG003 and RG005 exert their potent anti proliferative and pro-apoptotic effects through the modulation of Akt/NF-κB/COX-2 signal transduction pathways in PC-3 prostate cancer cells with a dominant effect for RG00

2′-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells

International audienceProstate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2′-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-?B, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-?B activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models