Abstract 2180: Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs

Abstract

Abstract Leuprorelin (LEP) is a synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in 1985. The initial effect of administration LEP is to stimulate the pituitary secretion of FSH and LH. After a prolonged stimulation (constant concentration of LEP in the blood) pituitary becomes insensitive to the action of GnRH. This reduces the level of gonadotropin in the blood, resulting in decreased levels of sex hormones to postcastration or menopausal levels. In addition to the usual side effects of this agonist analogs of LH-RH, other reported adverse effects include transient hypertension, dry mouth, excessive salivation, paraesthesia and increased dysuria. Improving the biological activity of LEP by increasing the cellular uptake and retention is a remedy to this end. In this study, a prodrug strategy has been introduced to optimize the hydrophobicity of LEP 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, several LEP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. anisole, 2-fluoroanisole, 2-methylanisole 1,2-dimethoxybenzene or methyl 2-methoxybenzoate and 1,3,5-trioxane, followed by the conjugation with LEP and dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of LEP. Citation Format: Yousef Ahmadibeni, Kaleh Karim, William Boadi. Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2180. doi:10.1158/1538-7445.AM2017-2180