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Design, Synthesis, and Biological Evaluation of Novel Multikinase Inhibitors

Author: LuCheng
Tutor: YuNieFang
School: Central South University
Course: Medicinal Chemistry
Keywords: multikinase inhibitors computer aided drug design synthesis
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 92
Quote: 0
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Abstract


Direct and indirect involvement of kinases in tumor growth, metastasis and apoptosis make them as most promising targets for anticancer drug discovery. However, clinical use of kinase inhibitors has led to the emergence of severe drug resistant tumors. Therefore, there is an emergent need to develop novel multikinase inhibitors.Aurora A, CDK2 and FLT3 are over expressed in many tumors, and the active sites of them were identified. In this study, we present an alignment of catalytic domainamino acid sequences of Aurora A, CDK2 and FLT3. The results has revealed that they have shared a hydrophilic surface consists of Lys162, Glu12 and Arg849 residue near the hinge. Then the binding mode of SB1317 was analyzed. On the basis of the results from molecular docking, hydrophilic groups were designed to interact with the hydrophilic surface, and aliphatic chains were designed to link these hydrophobic groups to N atom of benzyl in SB1317.In this study, we established two novel general procedure for the synthesis of macrocylic compounds of interesting, and 17 novel compounds were synthesized and the structure of them were confirmed by MS,’H-NMR and HRMS. Most of the compounds we synthesized showed potent Aurora A, CDK2 and FLT3 inhibitory activities, providing a useful guideline for the rational design of novle multikinase inhibitors.

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