Synthesis And Biological Evaluation Of Quinazoline Derivatives As Antitumor Agents

Quinazolines referred as privileged scaffolds in medicinal chemistry exhibit a wide variety of medicinal and biological activities, such as antiinflammatory, antimicrobial, anti-tubercular, antidiabetic, anti-HIV and anticancer activities. Quinazolines have particularly played important roles in the discovery and development of anticancer drugs. Many diverse quinazoline derivatives have been reported as novel inhibitors of several potential anticancer targets like EGFR, PARP, MPS1, JAK2, CHK2and Pinl. Furthermore, the clinical success of several4-arylaminoquinazoline-based drugs like Gefitinib, Erlotinib and Lapatinib resulted in more interests in this field. In the course of developing quinazoline-based Pinl inhibitors in our group, XLN-306was identified with potent in vitro and iv vivo antitumor activities. In order to develop novel quinazolines with increased antitumor activity and solutility, the following works have been carried out based on the scaffold of XLN-306:1. Different kinds of quinazoline-based antitumor agents which exhibit potent antitumor activities have been reviewed.2. Modifications on2-,4-and6-substituents of quinazoline scaffold of XLN-306were performed. Three series of target molecules, including6-chloro,6-nitro and6-fluoro-quinazoline derivatives, were designed and synthesized. Total45novel target compounds were obtained. All the target molecules were identified by1HNMR and ESI-HRMS.3. Biological evaluation of45compounds was carried out against several tumor cell lines by MTT assay.33compounds exhibited potent antitumor activity with IC50values at micromolar levels. Coumpounds WYK-431and WYK-417exhibited the most potent antitumor acitivties against BGC823with IC50value at10-7M level.4. Structure-activity relationships were analyzed.(1) The contribution to the antitumor activity of6-substituent on quinazoline decreased as the following order:Cl> NO2> F;(2) Small hydrophobic alkyl, flexible hydrophilic and cycloalkyl hydrophilic substituents on piperidine ring were beneficial to the inhibitory activity, while bulky hydrophilic amino acids were not tolerated.5. The in vivo antitumor activity of compound WYK-431was investigated at a dose of100mg/kg once every two days in xenograft animal model. After10days, compound WYK-431inhibited H22tumor growth with75%. Further structural optimization based on the lead structure WYK-431might provide novel antitumor agents with novel anticancer mechanisms.