Design and Anti-Proliferative Evaluation of Triptorelin Conjugated Tris (4-Methoxyphenyl) Methanol Derivatives
Triptorelin, a gonadotropin releasing hormone (GnRH) agonist, is being routinely used in treating patients with advanced symptoms of prostate cancer. The major limitations of triptorelin therapy include its low uptake by the cells, high efflux rate as well as resistance development, all of which significantly abrogate its bio-efficacy. Effectual strategies to increase the cellular uptake of triptorelin are therefore being contemplated to increase the potency of the drug. Modulating the hydrophobicity of the peptide by addition of hydrophobic linkers is an effective approach to this end. In this study, a number of triptorelin conjugates of tris(4-methoxyphenyl) methanol derivatives with optimized hydrophobicity were synthesized by the reaction of 2-substituted methoxy benzenes (e.g. 1-chloro-2-methoxybenzene, 1-bromo-2-methoxybenzene, 1-fluoro-2-methoxybenzene, 1-methyl-2-methylbenzene, 1-methoxy-2-nitrobenzene) and 1,3,5-trioxane followed by conjugation with triptorelin acetate in the presence of HBTU/DIPEA/DIC in moderate yields. The efficacy of synthesized triptorelin conjugates were evaluated using an in vitro lipid peroxidation assay. The derivatives effectively reduced lipid peroxidation which were measured as thiobarbituric reactive substance (TBARS) in a dose- and time-dependent manner following the Fenton's pathway. Overall, TBARS decreased between 20-30% for the treated samples of synthesized conjugates compare to their respective controls. These data establishes in vitro anti-oxidant activities of the triptorelin conjugates of tris(4-methoxyphenyl) methanol derivatives, indicating their potential biological efficacy.
Samiyah Mohammed Alhamed,
"Design and Anti-Proliferative Evaluation of Triptorelin Conjugated Tris (4-Methoxyphenyl) Methanol Derivatives"
ETD Collection for Tennessee State University.