Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs

Jawzah J Alnakhli, Tennessee State University

Abstract

Triptorelin (TRP) is an anti-cancer agent used for the treatment of a wide variety of hormone-responsive cancers, such as prostate cancer. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP in a combination regiment. Improving the biological activity of TRP by increasing the cellular uptake and retention is a remedy to this end. In this study, the hydrophobicity of TRP was optimized by using an appropriate hydrophobic linker attached to tris(4-methoxyphenyl)methanol (TPM) derivatives with the expectation to improve the cellular uptake. Towards this end, a number of TRP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of 2-substituted methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene), and 1,3,5-trioxane, followed by the conjugation with TRP and decanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 5-10 µM after 24-72 h of incubation. These data suggest that TPM-TRP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP, presumably by enhancing the cellular delivery and retention of TRP. In this study, the analysis of reduced glutathione (GSH) in 3T3 cells was carried out with TPM-CH3 and TPM-TRP-CH3 drugs and observed that TPM-CH3 caused a decrease in GSH levels with increase in the concentration of doses. However, in the presence of the linkage (TPM-TRP-CH3) GSH levels remained the same which is very important and means that the triptorelin is preventing the oxidation of GSH.^

Subject Area

Chemistry|Biochemistry|Oncology

Recommended Citation

Jawzah J Alnakhli, "Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs" (2015). ETD Collection for Tennessee State University. Paper AAI1599441.
http://digitalscholarship.tnstate.edu/dissertations/AAI1599441

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