Design, synthesis and antitumor evaluation of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives as potential c-Met inhibitors.

A series of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives (10a-10x) were designed, synthesized, and evaluated for their in vitro inhibitory activities against c-Met kinase and antiproliferative activities against the SH-SY5Y, MDA-MB-231, A549, and HepG2 cell lines. Most of the compounds remarkably inhibited c-Met kinase and showed moderate to good cytotoxicity and selectivity toward the four cancer cell lines. Among them, compounds 10b and 10f were the two most potent selective c-Met inhibitors with half-maximal inhibitory concentration (IC50) values of 5.17 ± 0.48 nM and 5.62 ± 0.78 nM, respectively, and suppression abilities comparable with the positive control cabozantinib. Cell proliferation assay further demonstrated that the two most promising compounds 10a and 10b also showed good cytotoxicity and selectivity toward MDA-MB-231 cells, with IC50 values of 26.67 ± 2.56 µM and 26.83 ± 2.41 µM, respectively. Compounds 10f and 10g showed cytotoxicity and selectivity toward A549 cells, with IC50 values of 20.20 ± 2.04 µM and 21.65 ± 1.58 µM, respectively. All antiproliferative activities were within the range of those of cabozantinib. Notably, these compounds presented relatively low hepatotoxicity compared with reference drugs. Moreover, the preliminary structure-activity relationship and docking studies revealed that replacement of a nitrogen-containing heterocycle on the R2 (block A) group might improve the c-Met kinase inhibitory and antiproliferative effects in MDA-MB-231 cells, whereas displacement by a substituted benzene ring, especially for the p-fluorophenyl or 4-fluoro-3-methoxyphenyl moiety, on the R2 group enhanced cytotoxicity toward A549 cells. Together, these results suggest that 10b and 10f are promising compounds and provide a basis for their development as new antitumor agents.

Study on Synthesis and Biological Evaluation of 3-Aryl Substituted Xanthone Derivatives as Novel and Potent Tyrosinase Inhibitors.

Tyrosinase plays a key role in the melanin biosynthesis since it catalyzes the transformation of tyrosine into L-dopaquinone. A large number of studies have also shown that molecules to efficiently inhibit the activity of tyrosinase would be potentially used in treating many depigmentation-related disorders. In this study, we targeted a series of structure-based 3-aryl substituted xanthone derivatives in which diverse functional groups were respectively attached on 3-aromatic ring moiety as new tyrosinase inhibitors. The results demonstrated that all obtained compounds had potent tyrosinase inhibitory activities with IC50 values at micromolar range. Especially, compound 4t was found to be the most active tyrosinase inhibitor with the IC50 value of 11.3 µM, uncovering that the introduction of the proper hydroxyl group in the 3-aromatic ring was beneficial for enhancing the inhibitory potency against tyrosinase. Moreover, the inhibition mechanism and inhibition kinetics studies revealed that compound 4t presented such inhibitory effect by acting as the reversible and competitive-uncompetitive mixed-II type inhibitor. Further molecular docking simulation showed that 3-aromatic ring of compound 4t was inserted into the narrow regions of binuclear copper-binding site at the bottom of the enzyme binding pocket, while the xanthone skeleton was positioned at the surface of tyrosinase. Taken together, these data suggested that such type of molecules might be utilized for the development of new and promising candidate for the treatment of depigmentation-related disorders.

Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease.

A series of novel ligustrazine derivatives 8a⁻r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer's disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106; for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against Aß aggregation, with IC50 values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 µM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.

Postoperative Chylous Ascites in Gynecological Malignancies: Two Case Reports and a Literature Review.

Aim: To explore the potential factors that influence the presentation and recovery of postoperative chylous ascites (CA) in gynecological malignancies. Methods: We reported two cases of postoperative CA following gynecological surgery and reviewed the clinical features of 140 patients from 16 relevant papers. Patients' clinicopathological characteristics, surgical approach, and management were summarized. The onset and resolution times of postoperative CA in different groups were analyzed separately. Results: The two patients in our report had recovery after conservative treatments. According to the literature review, the median time of onset of postoperative CA was 5 days (range, 0-75 days) after surgery. The median resolution time was 9 days (range, 2-90 days). Among patients, 87.14% of them had lymphadenectomy during gynecological surgeries, while 92.86% of the patients had resolution after conservative treatments. Conclusions: Lymphadenectomy during surgery may be relevant to the postoperative CA. Conservative management could be the initial choice for postoperative CA treatment.

[Expression of matrix metalloproteinase and tissue inhibitor of metalloproteinase in adenomyosis].

OBJECTIVE: To investigate the expressions of matrix metalloproteinase -2, -3 (MMP-2,-3) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in internal uterine endometriosis tissue and endometrium from women with and without endometriosis throughout the menstrual cycle. METHODS: Immunohistochemical staining of tissues was performed to study the expressions and locations of MMP-2, MMP-3, TIMP-2 between women with and without endometriosis. The real-time PCR technique was applied to detected the mRNA expressions of MMP-2, MMP-3 and TIMP-2. RESULTS: We found that ectopic endometrium from patients with endometriosis expressed higher levels of MMP-2 and MMP-3 and lower levers of TIMP-2 than normal controls did (P < 0.05). MMP-2 and MMP-3 were detected strongly in both stromal and epithelial cells of ectopic endometrium from patients with endometriosis, when mostly detected in the epithelial cells in the control group. All eutopic and ectopic endometrium samples from women with and without endometriosis throughout the menstrual cycle showed similar expressions of MMP-2, MMP-3 and TIMP-2. Quantitative expressions of MMP-2 mRNA, MMP-3 mRNA and TIMP-2 mRNA were significantly lower in eutopic endometrium from controls compared with ectopic endometrium from patients with endometriosis (P < 0.05). Eutopic endometrium from controls in the proliferative phase showed significantly increased expressions of MMP-2 mRNA compared with that in the secretory phase (P < 0.05). CONCLUSION: The results suggest that ectopic endometrium with adenomyosis has more invasiveness and is prone to peritoneal implantation maybe to involved in the high expressions of MMP-2 and MMP-3 and the less expressions of TIMP-2 than endometrium from women without adenomyosis does.