Activation of EphA2 receptor kinase by an endogenous ligand Ephrin A1 promotes tumor suppression through halting cell proliferation. Glioma is a malignancy which over expresses EphA2 as it becomes deficient in the endogenous ligand Ephrin A1 which ultimately causes the ligand independent activation of EphA2 promoting cancer metastasis and invasions. Therefore, an agonist of EphA1 has great potential as a therapeutic agent. In this study, a small novel agonistic compound {1, 12 bis[4 (4 amino 6,7 dimethoxyquinazolin 2 yl) piperazin 1 yl] dodecane 1,12 dione} was used as the lead compound for the synthesis of 28 new analogs. Based on the results of the derivates a structure activity relationship was concluded. An ester linker improved activity significantly when compared to ethers or short alkane linkers. The linker activity was then further increased by the addition of an aromatic spacer. Furthermore, different monomeric compounds were tested, and the greatest activity was found in a compound having a 4 aminobenzoyl group compared to less active ortho or meta aminobenzoyl compounds. Dimeric compounds 5,6,13 and a monomeric compound 21 showed the lowest micromolar activity in the analog set. However, compounds 5 and 21 of the derivatives had the greatest selectivity for over expressed U373 cells while maintaining potency. The cell assay was performed on three cell lines by MTT to provide a novel method for selectivity towards over expressed EphA2 malignancies.

Design, synthesis, and bioactivty of EphA2 agonist towards glioblastoma

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.