Abstract 2512: Design and antiproliferative evaluation of cell-penetrating TPM-Dox conjugates as prodrugs

Abstract

Abstract Doxorubicin (Dox) is well-known anthracycline widely used anticancer agent for the treatment of a wide variety of cancers. 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 Dox. Improving of cellular uptake and duration of action of Dox is very demanding. This will improve its therapeutic index and decrease its side effects. The biological activity of Dox can potentially be enhanced by increasing and optimizing its hydrophobicity using appropriate hydrophobic linker attachment to the Dox using triphenylmethanol (TPM) which led to higher cellular uptake. In this regard, TPM-Dox prodrugs were designed to deliver and release Dox into cells. The attachment of TPM analogs along with fatty alcohol significantly enhanced the lipophilicity and thus the cellular uptake of these multifunctional conjugates. In this study, a number of TPM derivatives of Dox were synthesized by the reaction of 2-substituted methoxy benzenes and 1,3,5-trioxane in glacial acetic acid in 72-87% yield. The reaction of TPM derivatives with tosylated fatty diol continued with conjugation to Dox to afford eight TPM-Dox conjugates with different hydrophobicity in 44-67% overall yield. Comparative antiproliferative assays between TPM-Dox conjugates and the corresponding noncovalent physical mixtures of the TPM derivatives and Dox were performed. TPM-Dox conjugates inhibited the cell proliferation of human leukemia (CCRF- CEM), ovarian adenocarcinoma (SK-OV-3), colorectal carcinoma (HCT-116), and breast carcinoma (MDA-MB-468) cells by 63-94% at a concentration of 1 µM after 72-120 h of incubation. These data suggest that TPM-Dox derivatives can be used as a potential prodrug for improving the cellular delivery and retention of Dox. Citation Format: Yousef Beni, Andrew W. Pippas. Design and antiproliferative evaluation of cell-penetrating TPM-Dox conjugates as prodrugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2512. doi:10.1158/1538-7445.AM2014-2512