Discovery of a novel inhibitor of nitric oxide production with potential therapeutic effect on acute inflammation.

Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 µM) and the activity of iNOS (IC50 = 0.082 µM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.

Design, synthesis and antitumor activity evaluation of Chrysamide B derivatives.

Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ± 1.08 µM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products.

Recent Advances in Iodine-Promoted C-S/N-S Bonds Formation.

Sulfur-containing scaffold, as a ubiquitous structural motif, has been frequently used in natural products, bioactive chemicals and pharmaceuticals, particularly C-S/N-S bonds are indispensable in many biological important compounds and pharmaceuticals. Development of mild and general methods for C-S/N-S bonds formation has great significance in modern research. Iodine and its derivatives have been recognized as inexpensive, environmentally benign and easy-handled catalysts or reagents to promote the construction of C-S/N-S bonds under mild reaction conditions, with good regioselectivities and broad substrate scope. Especially based on this, several new strategies, such as oxidation relay strategy, have been greatly developed and accelerated the advancement of this field. This review focuses on recent advances in iodine and its derivatives promoted hybridized C-S/N-S bonds formation. The features and mechanisms of corresponding reactions are summarized and the results of some cases are compared with those of previous reports. In addition, the future of this domain is discussed.

KI-catalyzed C-S bond formation via an oxidation relay strategy: efficient access to various α-thio-ß-dicarbonyl compounds.

An efficient and practical methodology to obtain α-thio-ß-dicarbonyl compounds was presented under alkaline conditions via potassium iodide (KI) catalysis; various symmetrical/unsymmetrical 1,3-dicarbonyl compounds were obtained under an aerobic atmosphere in moderate to excellent yields, with good functional group tolerance. Notably, a widely used anti-inflammatory drug butazodine could be modified with our protocol, even on a gram scale.

Melatonin derivatives combat with inflammation-related cancer by targeting the Main Culprit STAT3.

The combination between two well-studied bioactive compounds melatonin and salicylic acid with proper modifications unexpectedly creates a sharp pair of "scissors" cutting off the vicious connection between inflammation and cancer by targeting a key contributor Signal Transducers and Activators of Transcription 3 (STAT3) in the two pathological processes. A representative compound P-3 with IC50 values on each tested cell line ranging from 7.37 to 18.62 µM among the designed melatonin derivatives is equipped with the ability of curbing inflammation-promoting cancer by down-regulating the expression, activation and nuclear translocation of STAT3, breaking the feedforward loop of STAT3 activation by decreasing the expression of pro-tumorigenic cytokines, and inducing cell apoptosis through ROS triggered Cyto-c/Caspase-3 pathway. This study suggests that the melatonin derivative P-3 is likely to become a promising chemical structure for developing the novel anti-cancer agents taking effect through hindering the mutual-promoting processes between inflammation and cancer.

Hydrogen sulfide donors: Therapeutic potential in anti-atherosclerosis.

Atherosclerosis (AS), an important cause of high mortality of cardiovascular disease, involves numerous pathophysiological processes, including endothelial cell damage, oxidative stress, inflammation, lipid deposition, vascular smooth muscle proliferation and migration, macrophage-derived foam cell formation, and platelet aggregation, and seriously endangers human health and safe of life. Hydrogen sulfide (H2S) was discovered as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO), and has been proposed to exert potentially significant effects in many physiological processes, especially in atherosclerosis. Compelling evidence suggests that malfunction of CSE/H2S pathway and downregulation of endogenous H2S level contribute to the pathogenesis of atherosclerosis, whereas exogenous supplementation of H2S can ameliorate many of atherogenic processes. The current knowledge on the anti-atherogenic role of H2S comes from the use of H2S donors and CSE or CBS inhibitors, or another more accurate genetic technology, including gene knockout and gene therapy studies. Among them H2S releasing donors have vast therapeutic potential in anti-atherosclerosis and are promising as one of the clinical strategies for atherosclerosis treatment. Based on the recent studies on therapeutic effects and mechanisms of H2S donors, this review focuses on the most recent advances of therapeutic potential of H2S donors in anti-atherosclerosis, especially synthetic organic donors, because sulfide salts can release H2S rapidly and lead to various adverse effects. In addition, the future of this domain is prospected.

Novel Oxovanadium Complex VO(hntdtsc)(NPIP): Anticancer Activity and Mechanism of Action on HeLa Cells.

Oxovanadium complexes, particularly vanadyl (IV) derivatives with hybrid ligands of Schiff base and polypyridyl, have been demonstrated to possess great anticancerous therapeutic efficacy. However, most of the studies on the activity of these oxovanadium complexes have mainly focused on in vitro studies, and animal studies in vivo are extremely scarce. Based on the antitumor test results of four novel oxovanadium complexes in our previous work, this work further conducted a comprehensive antitumor activity study in vitro and in vivo on VO(hntdtsc)(NPIP), which owned the strongest inhibitory activity in vitro on multiple tumor cell proliferation. The cellular mechanism study suggested that VO(hntdtsc)(NPIP) inhibited the cell proliferation via arresting the cell cycle at G0/G1 phase through the p16-cyclin D1-CDK4-p-Rb pathway and inducing cell apoptosis through mitochondrial-dependent apoptosis pathway on HeLa cells. Inconsistent with the effects in vitro, VO(hntdtsc)(NPIP) significantly inhibited the growth of tumor and induced the apoptosis of cancer cells in mice xenograft models according to the results of nude mice in vivo image detection, H&E pathological examination, and immunohistochemical detection of p16/Ki-67 protein expression. Collectively, all the results, particularly studies in vivo, demonstrated that VO(hntdtsc)(NPIP) hold a potential to be the lead compound and further to be an anticervical cancer drug.

NaI-mediated divergent synthesis of isatins and isoindigoes: a new protocol enabled by an oxidation relay strategy.

A new approach for the synthesis of isatins and isoindigoes by an inexpensive and environmentally friendly NaI-mediated transformation is disclosed. The selectivity could be switched by simply varying the solvent, and isatins (using THF) and isoindigoes (using DMSO) could be obtained in moderate to excellent yields.

Direct access to α-sulfenylated amides/esters via sequential oxidative sulfenylation and C-C bond cleavage of 3-oxobutyric amides/esters.

An efficient, environmentally benign and unprecedented synthesis of various α-sulfenylated amides/esters has been developed under oxygen atmosphere. The reaction shows good functional group tolerance and excellent chemo/regioselectivity. All the desired products were obtained in moderate to excellent yields, even on the gram scale. Practically, the related α-thiol Weinreb amide can be readily transferred to a series of prospective compounds, and selenium atom can be introduced to the α-sites of the amides in high yields.