Design, Synthesis and Antitumor Activity of FAK/PLK1 Dual Inhibitors with Quinazolinone as the Skeleton.

Febrifugine is a kind of quinazolinone compound with high biological activity from a Chinese herb called Chang Shan (Dichroa febrifuga). Febrifugine and its derivatives possess extensive biological activities, some of which exhibited anti-tumor activities as FAK inhibitors. However, they are not very effective at inhibiting tumor metastasis, perhaps because tumors gain energy through compensatory activation of other signaling pathways that promote cell migration and invasion. Therefore, seventeen novel febrifugine derivatives with quinazolinone skeleton were designed, synthesized and acted as potential FAK/PLK1 dual inhibitors. These compounds were determined by 1 H-NMR, 13 C-NMR and MS. Most of the compounds exhibited good inhibitory activity against cancer cell lines by computer-assisted screening, antitumor activity test and FAK/PLK1 inhibitory activity test, wherein compound 3b was screened as a high-efficiency lead compound.

Osteoporotic-like vertebral fracture with less than 20% height loss is associated with increased further vertebral fracture risk in older women: the MrOS and MsOS (Hong Kong) year-18 follow-up radiograph results.

Background: For osteoporotic fractures in men (MrOS) and in women (MsOS) (Hong Kong) baseline (BL) study, Chinese men and women ≥65 years were recruited during 2001 to 2003. This study presents the year-18 follow-up (FU) results. We were particularly interested in whether women with 'minimal' grade osteoporotic-like vertebral fracture (OLVF) of <20% height loss have an increased vertebral fracture (VF) risk than those without BL OLVF. Methods: At year-18 FU, spine radiography was performed on 144 males (mean: 87.4±3.1 years) and 156 females (mean: 87.0±3.2 years). OLVF classification included no OLVF (grade 0), and OLVFs with <20%, ≥20-25%, ≥25%-1/3, ≥1/3-40%, ≥40%-2/3, ≥2/3 height loss (grades 1-6). With an existing OLVF, a further height loss of ≥15% was an OLVF progression. A new incident OLVF was a change from grade 0 to ≥ grade 2 or to grade 1 with the appearance of endplate and/or cortex fracture (ECF) during FU. Both OLVF progression and incident OLVF were considered incident VF. Acquired short vertebra (aSV) was defined as with decreased vertebral anterior and middle heights, while without anterior wedging and bi-concave changes, and only those with at least two adjacent aSVs were recorded as aSV cases. Results: For subjects without BL OLVF, 12.5% of the males and 27.1% of the females had incident VF. For subjects with BL OLVF of ≥20% height loss, males' and females' incident VF rate were 20% and 66.7% respectively. Females subjects with BL minimal OLVF, while all without radiographic ECF, had an incident VF rate of 59.3% during the FU. For males with and without aSV, 11.8% and 15% have incident fracture of other vertebrae. For females with and without aSV, 35.3% and 34.5% have incident fracture of other vertebrae. Recovery from minimal or mild grades OLVF to normal shape was observed in a number of cases. Conclusions: OLVF with less than 20% height loss is associated with increased VF risk in older females, but not in older males. Acquired short vertebra (SV) is not associated with increased incident fracture risk for other vertebrae, both for females and males. OLVF among older subjects can repair and heal.

Design, Synthesis and Molecular Docking of Novel Quinazolinone Hydrazide Derivatives as EGFR Inhibitors.

A series of novel quinazolinone hydrazide derivatives were designed and synthesized as EGFR inhibitors. The results indicated that most of the aimed compounds had potential anti-tumor cell proliferation and EGFR inhibitory activities. In the comprehensive analysis of all the tested compounds, the target compound 9c showed the best anti-tumor cell proliferation activity, (IC50 =1.31 µM for MCF-7, IC50 =1.89 µM for HepG2, IC50 =2.10 µM for SGC), and IC50 =0.59 µM for the EGFR inhibitory activity. Docking results showed that compound 9c could ideally insert the active site and interact with the critical amino acid residues (Val702, Lys721, Met769, Asp831) in the active site.

Design, synthesis and bioactivity evaluation of thiazolidinedione derivatives as partial agonists targeting PPARγ.

Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPARγ) agonist with many side effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPARγ. The study of anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g, which quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay confirmed direct binding of 4 g to the LBD of PPARγ with IC50 being 1790 nM, and dose-dependently increased the transcriptional activity of PPARγ. Besides, through computer-aided drug design software simulation docking, it was found that compound 4 g showed the best binding ability to target protein PPARγ. Furthermore, because of the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced and the stability of H3 and ß-fold is increased, showing the characteristics of some PPARγ agonists, based on the docking model analysis. Together, these results suggest that 4 g is a promising PPARγ agonist that deserves further investigation.