Abstract 5515: Design and synthesis of releasable folate-drug conjugates possessing optimized carbohydrate-based spacer units

Abstract

Abstract The spacer region of releasable folate-drug conjugates may play an important role in “tailoring” the properties of the molecules for targeted therapies by: 1) modulating the affinity toward the folate receptor, 2) providing desirable hydrophilicity, and 3) changing dramatically the biological properties. Herein we describe the design and synthesis of a variety of novel carbohydrate-based spacers mimicking a peptidic backbone. After carefully optimizing the chemical structure of the carbohydrate units, we incorporated such spacers in a folate-containing molecular systems using standard solid phase synthesis (SPS). The synthetic utility of this elegant and innovative approach was exemplified by creating novel releasable folate conjugates of single cytotoxic agents, e.g. Tubulysin-Folate conjugate (currently in preclinical development) and Vinblastine-Folate conjugate, (already in clinical development). Furthermore, using the same powerful method, we synthesized several constructs containing a rational combination of two drugs (e.g. Vinblastine and Doxorubicin) attached to a single folate-targeting ligand via a dual-headed releasable Spacer-Linker system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5515.