Synthesis and Evaluation of a 3,4‐dihydro‐2H‐benzoxazine Derivative as a Potent CDK9 Inhibitor for Anticancer Therapy

Abstract

Cyclin‐dependent kinase (CDK) 9 is a protein kinase that plays a major regulatory role in the process of transcription, thereby representing an attractive target in cancer therapy. A series of novel, highly potent, selective derivatives (coined compounds 8–15) were designed, synthesized, and evaluated for their inhibitory effect on CDK functions using cancer cell lines. Here, we showed that our compound 8 exhibited a potent CDK9 inhibitory activity in ICR mice, with an IC50 value of 2.3 nM as well as favorable pharmacokinetic properties. Using an MV4‐11 xenograft mouse model, compound 8 showed antitumor efficacy at a dose of 10 mg/kg; compound 8 treatment was well tolerated, with no adverse effects on body weight or animal health. Our in vitro and in vivo findings strongly suggest that compound 8 holds great promise for the development of highly potent CDK9 inhibitors in anticancer approaches.

Improvement of the metabolic stability of pan‐RAF/VEGFR2 dual inhibitors

“…The benzyl cyanide 12 was prepared by nucleophilic substitution of the benzyl bromide 11 with potassium cyanide. Methylation of the prepared compound 12 using sodium hydride and methyl iodide gave compound 13 , which underwent reduction followed by Boc protection to produce compound 15 17 . The benzoic acid 16 was efficiently prepared by hydrolysis of the compound 15 .…”

“…Methylation of the prepared compound 12 using sodium hydride and methyl iodide gave compound 13, which underwent reduction followed by Boc protection to produce compound 15. 17 The benzoic acid 16 was efficiently prepared by hydrolysis of the compound 15. After Curtius rearrangement was carried out with the compound 16 and diphenylphosphoryl azide (DPPA) at high temperature, and the addition of the obtained compound 10 to the in situ generated isocyanate produced compound 17.…”

Recent progress on radiofluorination using metals: strategies for generation of C–18F bonds

“…Carbon-fluorine bond formation is an important research topic in organic synthesis because of the widespread applications of organofluorine compounds in pharmaceuticals, agricultural applications, and materials science. [1][2][3][4][5][6][7] The insertion of a fluorine atom in a drug molecule can alter its physical, chemical, and biological properties. Furthermore, these alterations can also importantly affect drug metabolism and pharmacokinetics.…”