Abstract 2478: Novel tyrosine derivatives of temozolomide active against breast cancer cell lines.

Abstract

A series of L- and D-tyrosine derivatives of temozolomide (TMZ) was synthesized and evaluated as potentially improved anticancer agents against breast cancer cell lines. TMZ is a well tolerated, broad spectrum oral alkylating agent that crosses the blood–brain barrier. It has demonstrated activity against glioma and melanoma, as well as preclinical activity against breast cancer. Recent studies have shown the effectiveness of combining alkylating agents with the amino acid tyrosine, yielding analogs with significantly improved in vitro anticancer activity when compared with the parent compound. Following from this, we seek to improve the efficacy of TMZ by chemically modifying the C-8 position of the imidazotetrazine to include L- and D-tyrosine adducts attached either directly or via a linker of varying size. The novel TMZ derivatives were synthesized in good yields through efficient peptide synthesis methods. The anticancer efficacy of the derivatives was evaluated over several hormone-dependent and hormone-independent (ER+ and ER-) breast cancer cell lines. Preliminary results show that at a concentration of 2 x 10−5 M the novel derivatives display at least a 20% greater in vitro growth inhibitory activity when compared to TMZ, particularly in hormone-dependent MCF-7 breast cancer cell line. Structure–activity relationship (SAR) analysis suggests the influence of both the length of the linker and the stereochemistry of the tyrosine adduct on the anticancer activity of the derivatives. Further investigation will reveal if interaction with hormone-related receptors is involved in the mechanism of action of the newly synthesized derivatives. Citation Format: Jordan Kiefer O'Sullivan, Taylor R. Helphrey, Johnny Laim, Maggie C. Louie, Maria Graciela Carranza. Novel tyrosine derivatives of temozolomide active against breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2478. doi:10.1158/1538-7445.AM2013-2478