Sodium-glucose co-transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT-2) and the proximal tubule of the nephron (SGLT-1 and SGLT-2). They contribute to renal glucose reabsorption and most of renal glucose (about 90%) is reabsorbed by SGLT-2 located in the proximal renal tubule. Selectively inhibiting activity of SGLT-2 is an innovative therapeutic strategy for treatment of type 2 diabetes by enhancing urinary glucose excretion from the body. Therefore SGLT-2 inhibitors are considered to be potential antidiabetic drugs with an unique mechanism. This review will highlight some recent advances and structure-activity relationships in the discovery and development of SGLT-2 inhibitors including O-glycoside, C-glycoside, C, O-spiro glycoside and non glycosides.

HSP90, which is the biomarker of cell stress and endogenous protective protein, functions as a molecular chaperone. Many client proteins of HSP90, including EGFR, Met, Raf-1, IKK and p53, play important roles in the occurrence and development of tumor. Binding of HSP90 inhibitors triggers the deactivation of HSP90, resulting in client protein degradation, and hence inhibits the tumor growth by blocking multiple targets involved in signaling of tumor proliferation. This review summarizes recent development of small molecule inhibitors bound to N-terminal of HSP90.

Objective To observe the apoptosis of human large cell lung cancer NCI-H661 cells induced by crotoxin,and to explore its mechanism. Methods The growth suppression of crotoxin on the NCI-H661 cells was detected by CCK-8 colorimetry,and the formation of NCI-H661 cells was observed by the plat colony experiment. This experiment included 4 groups:negative control group,crotoxin group(60 μg/ ml cro-toxin acted for 24 h),crotoxin + SB203580 group(pretreated cells using 5 μmol/ L SB203580 for 1 h,then 60 μg/ ml crotoxin acted for 24 h),SB203580 group(pretreated cells using 5 μmol/ L SB203580 for 1 h,then cultivated cells using complete culture solution). They were detected that the cell cycle and apoptosis rate of NCI-H661 cells treated with crotoxin by the flow cytometry. Additionally,they were tested that the change of the cell cycle and apoptosis rate after the NCI-H661 cells were treated with crotoxin and the activity of p38MAPK was inhibited by SB203580. Results When the concentration of crotoxin was greater than or equal to 30 μg/ ml,the inhibitory effect of crotoxin on the activity of NCI-H661 cells and colony formation,and inhibi-tion rate rose with increasing function of time and drug concentration. Flow cytometry showed that the apoptosis rate of crotoxin group and crotoxin + SB203580 group were(16. 70 ± 1. 38)% and(2. 15 ± 0. 54)% ,com-pared to the control group(1. 47 ± 0. 29)% ,and the former difference was statistically significant and the latter was not statistically significant(t = - 18. 763,P = 0. 000;t = - 1. 935,P = 0. 125). The G1 period cells of crotoxin group and crotoxin + SB203580 group were(57. 25 ± 1. 09)% and(48. 04 ± 1. 03)% ,compared to the control group(47. 46 ± 0. 69)% ,and the former difference was statistically significant and the latter was not statistically significant(t = - 13. 124,P = 0. 000;t = - 0. 809,P = 0. 464). Conclusion Crotoxin can promote the apoptosis of human large cell lung cancer NCI-H661 cells,and this effect may be related to the excitation of p38MAPK signal pathway.

To obtain higher potency and specificity, a series of 7-alkoxy analogues of illudalic acid was synthesized on the base of structure-activity relationship (SAR). All of these compounds exhibited submicromolar inhibition of the enzyme when tested against human leukocyte common antigen-related phosphatase (LAR) (for example, for 15e, IC50 = 180 nmol x L(-1)). They represent the most potent small-molecule inhibitors of LAR so far. These analogues also display excellent selectivity for LAR over other protein tyrosine phosphatases (PTPs) except for the highly homologous PTPsigma. The compound 15f is of 120-fold selectivity for LAR versus PTP-1B inhibition. The development of potent enzyme-specific inhibitors is so important that they may serve both as tools to study the role of LAR and as therapeutic agents for treatment of type II diabetes.

As an extension of the structure-based drug discovery, fragment-based drug discovery is matured increasingly, and plays an important role in drug development. Fragments in a small library, with lower molecular mass and high "ligand efficiency", are detected by SPR, MS, NMR, X-ray crystallography technologies and other biophysical methods. Then they are considered as starting points for chemical optimization with the guidance of structural biology methods to get good "drug-like" lead and candidate compounds. In this article, we reviewed the current progress of fragment-based drug discovery and detailed a number of examples to illustrate the novel strategies.

Histone acetylation is a critical process in the regulation of chromatin structure and gene expression. Histone deacetylases (HDACs) remove the acetyl group, leading to chromatin condensation and transcriptional repression. HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects. This paper describes our work on the structural determination and structure-activity relationship (SAR) optimization of tetrahydroisoquinoline compounds as HDAC inhibitors. These compounds were tested for their ability to inhibit HDAC 1, 3, 6 and for their ability to inhibit the proliferation of a panel of cancer cell lines. Among these, compound 82 showed the greatest inhibitory activity toward HDAC 1, 3, 6 and strongly inhibited growth of the cancer cell lines, with results clearly superior to those of the reference compound, vorinostat (SAHA). Compound 82 increased the acetylation of histones H3, H4 and tubulin in a concentration-dependent manner, suggesting that it is a broad inhibitor of HDACs.

Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure-activity relationship was elaborated. Together with metabolic stability tests and pharmacokinetic profiling, a representative compound () was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.