Triptorelin (TRP) a well-known decapeptide, is a gonadotropin-releasing hormone agonist (GnRH agonist), widely used anticancer agent for the treatment of a wide variety of hormone-responsive cancers such as prostate and breast cancer. The major limitations of cancer chemotherapy treatment are low cellular uptake, high efflux rate and the development of resistance to a certain dose of anticancer drugs, such as TRP. During the treatment of prostate cancer, TRP does cause a surge of testosterone known as a flare effect, therefore Improving of cellular uptake and duration of action of TRP is very demanding. The biological activity of TRP can potentially be enhanced by increasing and optimizing its hydrophobicity using appropriate hydrophobic linker attachment to the TRP using triphenylmethanol (TPM) which led to higher cellular uptake. In this regard, TPM-TRP prodrugs were designed to deliver and release TRP into cells. The attachment of TPM analogs along with fatty linker significantly enhanced the lipophilicity and thus the cellular uptake of these multifunctional conjugates. In this study, a number of TPM derivatives of TRP were synthesized by the reaction of 2-substituted methoxy benzenes and 1,3,5-trioxane in glacial acetic acid in 62-77% yield. The reaction of TPM derivatives with fatty linkers containing up to twelve carbons continued with conjugation to TRP afforded eight TPM-TRP conjugates with different hydrophobicity in 38-53% overall yield. Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding noncovalent physical mixtures of the TPM derivatives and TRP were performed. TPM-TRP conjugates inhibited the cell proliferation of breast carcinoma cells by 55-97% at a concentration of 5 �M after 96-120 h of incubation. These data suggest that TPM-TRP derivatives can be used as a potential prodrug for improving the cellular delivery and retention of TRP.

Triphenylmethanol derivatives of triptorelin: Design and antiproliferative evaluation

247th National Meeting (2014)

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