Abstract
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. In this regard, 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 10-50 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. Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli. Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4807.
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