A light- and heat-driven glycal diazidation approach to nitrogenous carbohydrate derivatives with antiviral activity.

The aminated mimetics of 2-keto-3-deoxy-sugar acids such as the anti-influenza clinical drugs oseltamivir (Tamiflu) and zanamivir (Relenza) are important bioactive molecules. Development of synthetic methodologies for accessing such compound collections is highly desirable. Herein, we describe a simple, catalyst-free glycal diazidation protocol enabled by visible light-driven conditions. This new method requires neither acid promoters nor transition-metal catalysts and takes place at ambient temperature within 1-2 hours. Notably, the desired transformations could be promoted by thermal conditions as well, albeit with lower efficacy compared to the light-induced conditions. Different sugar acid-derived glycal templates have been converted into a range of 2,3-diazido carbohydrate analogs by harnessing this mild and scalable approach, leading to the discovery of new antiviral agents.

[Research progress on molecular mechanism of Dendrobium officinale and its active components to metabolic syndrome].

Metabolic syndrome,a kind of clinical syndrome marked by the presence of symptoms such as hyperglycemia,dyslipidemia and hypertension,has an increasing incidence and comes to be present in younger people. More importantly,prolonged maintenance of this condition can significantly increase the incidence of chronic diseases such as diabetes,cardiovascular disease and cancer.However,the formation mechanism of metabolic syndrome is very complex and has not been fully studied and revealed. Dendrobium officinale is a traditional medicine and food substance with multiple physiological functions. In recent years,D. officinale has attracted much attention from the scholars both at home and abroad due to its functions such as improving blood lipid,lowering blood pressure and regulating blood sugar. However,there is no systematic review on the current studies about D. officinale in intervening metabolic syndrome and its underlying molecular mechanism. In this paper,the biological activity of the main active components,and the research or application status of D. officinale extract in the recent years were reviewed. Then,we analyzed the digestion,absorption and the safety and toxicity of D. officinale and its active components in the body. Finally,we summarized the effects of D. officinale and its active components on metabolic syndrome in animals and human bodies,and discussed its possible molecular mechanisms at the cellular level. This paper provides solid theoretical guidance and reliable molecular basis for further research and advanced development of D. officinale and its active components,especially for its oncoming clinical application.

Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates.

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes' binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.

Conjugates of salicylaldoximes and peripheral site ligands: Novel efficient nonquaternary reactivators for nerve agent-inhibited acetylcholinesterase.

A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P-S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.

Novel nonquaternary reactivators showing reactivation efficiency for soman-inhibited human acetylcholinesterase.

Soman is a highly toxic nerve agent with strong inhibition of acetylcholinesterase (AChE), but of the few reactivators showing antidotal efficiency for soman-inhibited AChE presently are all permanently charged cationic oximes with poor penetration of the blood-brain barrier. To overcome this problem, uncharged reactivators have been designed and synthesized, but few of them were efficient for treating soman poisoning. Herein, we used a dual site biding strategy to develop more efficient uncharged reactivators. The ortho-hydroxylbenzaldoximes were chosen as reactivation ligands of AChE to prevent the secondary poisoning of AChE, and simple aromatic groups were used as peripheral site ligands of AChE, which were linked to the oximes in a similar way as that found in the reactivator HI-6. The in vitro experiment demonstrated that some of the resulting conjugates have robust activity against soman-inhibited AChE, and oxime 8b was highlighted as the most efficient one. Although not good as HI-6 in vitro, these new compounds hold promise for development of more efficient centrally acting reactivators for soman poisoning due to their novel nonquaternary structures, which are predicted to be able to cross the blood-brain barrier.

New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase.

Herein, we described a new class of uncharged non-pyridinium reactivators for nerve agent-inhibited acetylcholinesterase (AChE). Based on a dual site binding strategy, we conjugated the imidazolium aldoxime to different peripheral site ligands (PSLs) of AChE through alkyl chains. Compared with the known quaternary pyridinium reactivators, two of the resulting conjugates (7g and 7h) were highlighted to be the first efficient non-pyridinium oxime conjugates exhibiting similar or superior ability to reactivate sarin-, VX- and tabun-inhibited AChE. Moreover, they were more broad-spectrum reactivators.

Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors.

We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.

An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs.

An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs is described here, which involves introduction of a chiral group, formation and separation of diasteroisomers and final transformation of an amide to an ester. The absolute configuration of the enantiopure HAPs is confirmed by X-ray analysis of their intermediates.

Novel selective cannabinoid CB(1) receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects.

AIM: To characterize the biological profiles of MJ08, a novel selective CB(1) receptor antagonist. METHODS: Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB(1) and CB(2) receptor redistribution and intracellular Ca(2+) ([Ca(2+)](i)) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice. RESULTS: In radioligand binding assay, MJ08 selectively antagonized CB(1) receptor (IC(50)=99.9 nmol/L). In EGFP-CB(1)_U2OS cells, its IC(50) value against CB(1) receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 µmol/L) increased [Ca(2+)](i) in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB(1) cells. MJ08 (10 nmol/L-10 µmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA(2)=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB(1) cells with an EC(50) value of 78.6 nmol/L, which was lower than the EC(50) value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB(1) receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo. CONCLUSION: MJ08 is a novel, potent and selective CB(1) receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB(1) receptors.

Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5-halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides.

We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC(50)'s: 0.45-5.08 µM) are more active than Sunitinib (IC(50)'s: 1.35-6.61 µM), and the most active compound 1 h (IC(50): 0.47-3.11 µM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.

Synthesis and evaluation of novel chloropyridazine derivatives as potent human rhinovirus (HRV) capsid-binding inhibitors.

Human rhinovirus (HRV) is the most important etiologic agent causing common colds. No effective anti-HRV agents are currently available. In this paper we describe the synthesis and the evaluation of novel chloropyridazine derivatives (compounds 5a-g) as potent human rhinovirus (HRV) capsid-binding inhibitors. Results showed that compound 5e and 5f exhibited effective anti-HRV activity against HRV-2 and HRV-14. In addition, compound 5e and 5f showed lower cytotoxicity than Pirodavir.

Antitumor activities of a novel indolin-2-ketone compound, Z24: more potent inhibition on bFGF-induced angiogenesis and bcl-2 over-expressing cancer cells.

The present study was designed to select the effective dosage range of Z24 [3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one], a novel synthetic indolin-2-ketone small-molecule compound, against tumorigenesis and angiogenesis in vitro and in vivo and to investigate the primary action mechanism of Z24 on the angiogenesis by comparing with SU5416 [3-[(2,4-dimethylpyrrol-5-yl)methyllidenyl]-indolin-2-one] in the selective effects on vascular endothelial growth factor (VEGF)/basic fibroblast growth factor (bFGF) signaling and Bcl-2-related cell vitality because Z24 is a potential inhibitor of the Bcl-2 that inhibits growth of multiple tumor types in vivo in our previous study. Per os Z24 inhibited dose-dependently the mouse S180 xenograft tumor growth and angiogenesis in mouse subcutaneous (s.c.) Matrigel plugs in vivo. The maximum growth inhibitory rate was 56.1% by 80 mg/kg/day on S180 mouse sarcoma cells; however, the maximum inhibitory potency on angiogenesis in C57BL/6 mouse subcutaneous Matrigel plug model was 50 mg/kg/day. Z24 inhibited angiogenesis in chicken chorioallantoic membrane (CAM) and invasion and inhibited tube formation of endothelial cells in a dose-dependent manner. Compared with SU5416, the IC50 (50% inhibition concentration) of Z24 on the proliferation of ECV-304 carcinoma cells induced by VEGF or bFGF was 24.4 and 17.99 microM, respectively, which is higher or lower, respectively, than that of SU5416 (14.2 microM for VEGF and 22.7 microM for bFGF). Furthermore, the IC50 of Z24 on the proliferation of Bcl-2 over-expressing HeLa cells and non-Bcl-2-expressing (wild-type) HeLa cells are 11.9 and 24.8 microM, respectively. SU5416 did not exert such a selective inhibiting effect on Bcl-2 over-expressing HeLa cells. These results suggest that Z24 per os has dose-dependent antitumor and antiangiogenesis pharmacological activity. The higher selectivity of Z24 on Bcl-2 protein and on bFGF other than VEGF signaling path may contribute to its efficiency against tumor and tumor-associated angiogenesis.