Abstract 1865: Buserelin trisphenylmethanol derivatives as anti-cancer prodrugs

Buserelin (BUS) is a synthetic nonapeptide agonist analog of LH-RH, first reported by Hoechst in 1976. It is used for the treatment of advanced prostate cancer. Side effects of buserelin include musculoskeletal pain, hearing disorders, increased thirst, worsening hypertension, anxiety, memory and concentration disturbances, fatigue, nervousness, palpitations, leukopenia, thrombocytopenia, altered blood lipids, and glucose intolerance. Therefore, improving of the biological activity of BUS by increasing the cellular uptake and retention is a remedy to this end. In this research, tris(4-methoxyphenyl)methanol (TPM) derivatives were synthesized and linked to BUS through hydrophobic linkers to enhance and optimize the hydrophobicity of this drug with the expectation to improve the cellular uptake. In this regard, several BUS conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. anisole, 2-fluoroanisole, 2-trifluoromethylanisole, 2-methylanisole, or 1,2-dimethoxybenzene, and 1,3,5-trioxane, followed by the conjugation with BUS and lauric acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-BUS conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and BUS were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-BUS conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 48-86%, 32-77%, 42-67%, respectively, at a concentration of 1-25 µM after 24-72 h of incubation. These data suggest that TPM-BUS derivatives with optimized hydrophobicity can be used to improve the biological activity of BUS. Note: This abstract was not presented at the meeting. Citation Format: Ryan Beni, William Boadi, Renner Antwi. Buserelin trisphenylmethanol derivatives as anti-cancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1865.