In order to increase the oral bioavailability and antidiabetic effect of amentoflavone with multimechanisms, an oral micelle system was developed by using a N-vinyl pyrrolidone-maleate-guerbet alcohol monoester polymer for the first time, which was designated as P(NVP-MGAM)/AF. After oral administration, P(NVP-MGAM)/AF enhanced the oral bioavailability of amentoflavone, which was approximately 3.2 times that of amentoflavone solution. The animal study using the KKAy insulin-resistant diabetes mouse model indicated that it regulates the expression and activity of downstream signaling factors and proteins by lowering blood lipids, reducing inflammatory responses and activating the peroxisome proliferator-activated receptor (PPAR) γ signaling pathway and PI3K/Akt signaling pathway. After being made into micelles, it is more effective because of its better absorbability and bioavailability. The results from this study provide a theoretical basis for the clinical application of amentoflavone for diabetes treatment. The oral micelles of P(NVP-MGAM)/AF may become one of the most potent drugs in the treatment of diabetes mellitus, which opens up a new way for the prevention and treatment of diabetes.
In this work, we designed and synthesized a novel series of quinazoline derivatives 6-19 and then evaluated their broad-spectrum antitumor activity against MGC-803, MCF-7, PC-9, A549, and H1975, respectively. Most of them demonstrated low micromolar cytotoxicity towards five tested cell lines. In particular, compound 18 exhibited nanomolar level inhibitory activity against MGC-803 cells with an IC50 value of 0.85 μM, indicating approximately a 32-fold selectivity against GES-1 (IC50 = 26.75 μM). Further preclinical evaluation showed that compound 18 remarkably inhibited the migration of MGC-803 cells, induced cell cycle arrest at G2/M, and induced MGC-803 apoptosis, resulting in decreasing the expression of both Bcl-2 and Mcl-1, and up-regulating the expression of both Bax and cleaved PARP. No death or obvious pathological damage was observed in mice by acute toxicity assay. The in vivo antitumor evaluation suggested that compound 18 significantly decreased the average tumor volume and tumor weight without any effect on body weight, which is better than 5-Fu. Therefore, compound 18 can be used as a lead compound for the further development of antitumor drugs in the future.
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