In order to search for new antiplatelet agents with higher potency, a series of tetramethylpyrazine ( TMP) /chalcone hybrids ( 2-26) were synthesized and evaluated based on the principle of bioisostere and hybrid-ization. They exerted inhibitory activity against adenosine diphosphate ( ADP )-induced and arachidonic acid ( AA)-induced platelet aggregation to varied extent. Among them, compound 8 was the most potent with IC50 of 0. 14 mmol/L on ADP-induced platelet aggregation ( 9. 1 folds of TMP and 10. 5 folds of chalcone ) and 0. 09 mmol/L on AA-induced platelet aggregation ( 8. 8 folds of TMP and 10. 0 folds of chalcone) , which was superior to clinically used anti-platelet drug aspirin ( ASP, IC50 =0. 15 mmol/L) .

To search for potent drugs against non-small-cell lung cancer(NSCLC),a series of hybrids(9a-9e, 10a-10e and 11a-11e﹚ from anilinopyrimidines and diazeniumdiolates were designed and synthesized.The MTT assay was employed to evaluate their antiproliferative activity against H1975 cells harboring epithelial growth factor receptor(EGFR)L858R/T790M mutation.The results showed that compounds 9a-9e displayed remarkable inhibitory activity on H1975 cells.Among these compounds, the most potent was compound 9b(IC50=0.65 μmol/L),which was superior to the positive control gefitinib.Additionally,molecular docking study indicated that 9b could bind with EGFR T790M by forming hydrogen bond, electrostatic interactions, et al, suggesting that compound 9b may be a potential anti-NSCLC agent for further investigation.

Carboxymethylcysteine (CMC) is a common drug for the clinical treatment of chronic obstructive pulmonary disease, yet its long-term use can cause severe irritation to the gastrointestinal tract.As the substrate of nitric oxide (NO) synthase (NOS), L-arginine can be converted in the body into NO beneficial to the cardiovascular system, the gastrointestinal tract and so on.As a basic amino acid, L-arginine can be salified with some compounds containing acidic groups to improve the water solubility of the parent drug and may enhance the activity and alleviate side effects due to NO release.In this study, we designed and synthesized carboxymethylcysteine L-arginate (CMCA), and tested its physico-chemical properties, and the abilities to scavenge reactive oxygen species (ROS), inhibit apoptosis and release NO in cigarette smoke-induced injury model of human bronchial epithelial cells.The results revealed that CMCA is superior to CMC or L-arginine in that it could capture ROS, release NO and suppress apoptosis, suggesting that CMCA is worthy of further research and development.

Hydrogen sulfide(H2S)is an endogenous gas messenger molecule with extremely broad biological activities including vasodilation, anti-oxidation, anti-inflammation, cardioprotection and anti-tumor. Similar to other gas messenger molecules, the biological activity of H2S is dependent on its location, concentration and duration of exposure. Therefore, the key scientific issue is how to improve the selectivity of H2S donor molecules to release appropriate concentrations of H2S at the target site(commonly pathological place), exerting therapeutic efficacy with limited side-effects. This article reviews the structures and H2S release mechanisms of two classes of H2S donors focusing on the advances in the recently developed H2S donors with controllable release potential of H2S, thus providing new ideas for future H2S-based drug research.

Protein arginine methyltransferases, which proceed the post-translational modification of both histones and non-histones, play an important role in many biological pathways. Protein arginine methyltransferase 5 (PRMT5) is a major enzyme responsible for symmetric di-methylation of arginine residues and has been suggested as a potential therapeutic target for tumors.In the past decade,the discovery and development of PRMT5 inhibitors have become one of the most important research fields.This article introduces the structure and biochemical function of PRMT5 and its correlation with cancer reviews, the binding modes and biological data of PRMT5 inhibitors under development, and discusses the clinical application potential of PRMT5 inhibitors in the treatment of cancer.

Nitric oxide (NO) as a signal transduction species and/or effector molecule plays an extremely important role in the cardiovascular, nervous, and immune systems. Insufficient production or abnormal signal transduction of NO is closely associated with onset and progression of many diseases. Studies on direct or indirect regulation of NO levels in vivo and related metabolic pathways have become a hot spot in biomedical and pharmaceutical fields. This review briefly introduces the generation of NO in vivo and its physiological and pathological functions in cardio-cerebrovascular system, with focus on the authors'' research on NO-donating cardio-cerebrovascular and related drugs, aiming to provide some reference for future development of these drugs.

Bivalent platinum drugs [Pt(II)] represented by cisplatin are the first-line drugs in clinical application, but they have defects such as severe side-effects, poor bioavailability and drug resistance.Tetravalent platinum [Pt(IV)] complexes, derivatives of Pt(II) with different substitutions in axial positions, can be reduced to Pt(II) under the action of reductants in tumor, and can therefore act as a prodrug of Pt(II).Axial substituents can improve platinum drugs'' pharmacokinetics, selectivity and bioactivity, as well as achieve anti-tumor effect by additional cytotoxic mechanisms other than DNA damage, which can overcome the drug resistance to Pt(II).This review outlines the resistance mechanisms of platinum drugs, including platinum transport, detoxification, autophagy, and DNA repair, etc.It also summarizes the structure-activity relationship, main types and advances of tetravalent platinum prodrugs, as well as possible approach to solve platinum drug resistance.

The novel oleanolic acid derivatives 2a-2e were synthesized by introducing an α, β-unsaturated ketone moiety to C-ring of oleanolic acid(OA)via a nine-step reaction sequence, yielding an active CDDO-Me analogue(1), followed by coupling of C3-OH of 1 with various aliphatic and aromatic carboxylic acids, respectively. Derivatives 3a-3e were synthesized by substituting C-1 of compounds 2a-2e with bromine. The target compounds were characterized by IR, MS and 1H NMR spectra. All the target compounds showed strong inhibitory effects against two tumor cell lines(HepG2 and A549)to a varying extent. The anti-proliferative activities of active compounds 3b and 3c(IC50=6. 13±1. 16 μmol/L and IC50=5. 49±1. 03 μmol/L, respectively)against HepG2 and A549 were more potent than compound 1 and comparable to the positive control CDDO-Me. In addition, all the target compounds displayed much weaker anti-proliferative activity against the two tumor cell lines than that against normal BEAS-2B cells. Compound 3c showed ten-fold selective inhibition against HepG2 relative to BEAS-2B cells, and is thus worthy of further study.

In order to search for new anti-inflammatory agents with strong activity and less toxicity relative to CDDO-Me, the ester prodrugs 2-8 of CDDO-Me were synthesized by treatment of oleanolic acid(OA)with DMF/K2CO3 to generate 1, followed by esterification of 1 with various aliphatic and aromatic carboxylic acids, respectively. All the target compounds showed strong inhibitory effects on LPS-induced NO production in RAW 264. 7 cells. Among them, compounds 2 and 7 possessed the most potent inhibitory effects with IC50=(2. 34±0. 67)and(3. 83±0. 97)nmol/L, respectively. Moreover, MTT assay indicated that all the target compounds(2-8)displayed much weaker anti-proliferative activity against RAW 264. 7 cell lines than CDDO-Me, suggesting that they may be less toxic than CDDO-Me.

Blood-brain barrier (BBB) damage after ischemia significantly influences stroke outcome. Compound LFHP-1c was previously discovered with neuroprotective role in stroke model, but its mechanism of action on protection of BBB disruption after stroke remains unknown. Here, we show that LFHP-1c, as a direct PGAM5 inhibitor, prevented BBB disruption after transient middle cerebral artery occlusion (tMCAO) in rats. Mechanistically, LFHP-1c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity, but also reduced the interaction of PGAM5 with NRF2, which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia. Furthermore, LFHP-1c administration by targeting PGAM5 shows a trend toward reduced infarct volume, brain edema and neurological deficits in nonhuman primate