Abstract 5114: Design, synthesis, and biological evaluation of tricyclic thieno[2,3- d]pyrimidines as microtubule targeting antitumor agents

Abstract

Abstract Microtubules are dynamic structures that, together with actin microfilaments and intermediate filaments, constitute the cellular cytoskeleton. Besides their well-known roles in cell division, their functions involve maintenance of cell shape and morphology, cellular motility, and trafficking of organelles and vesicles. Recently, we reported a compound AG 370 as a microtubule targeting agent, that circumvented the Pgp and βIII-tubulin mediated drug resistance mechanisms that limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. Molecular modeling and docking studies of the parent compound (AG 370) in the colchicine binding site (PDB: 402B) suggest that the C-5 and C-6 of parent compound are oriented towards the hydrophobic pockets with the side chain of Ala316, Val315, Leu255 and Met259. However, this binding pocket in tubulin is relatively large. To further explore the hydrophobic pocket, an additional cyclohexene ring was introduced at C-5 and C-6 of AG370. In the molecular modeling study, the resulting tricyclic scaffold showed hydrophobic interactions with the amino acids of the colchicine binding site. The 2-Me substituent of the tricyclic scaffold was replaced with a 2-H and a 2-NH2 group and 4-position of the scaffold was replaced with appropriate anilines. The 2-amino- N4-methoxyphenyl moiety (AG61) was found to be the most potent analog in the tricyclic series in both antiproliferative assay in human melanoma cancer cell line (MDA-MB-435 cell line, IC50 = 9.0 ± 0.2 nM) and in microtubule depolymerization assay in A-10 cells (EC50= 19 nM). Thus, we identified tricyclic thieno[2,3-d]pyrimidines as a novel structural scaffold with potent antiproliferative activity as well as microtubule depolymerizing activity. These analogs are selected for preclinical development. Citation Format: Farhana Islam, Aleem Gangjee, Xin Zhang, Xilin Zhou, Susan L. Mooberry. Design, synthesis, and biological evaluation of tricyclic thieno[2,3- d]pyrimidines as microtubule targeting antitumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5114. doi:10.1158/1538-7445.AM2017-5114