Synthesis and evaluation of 2-cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13ß, 28-olide as a potent anti-inflammatory agent for intervention of LPS-induced acute lung injury.

The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13ß, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX-2, IL-6, IL-1ß, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further in vivo studies in murine model of LPS-induced acute lung injury (ALI) showed that 1 possessed more potent protective effects than the well-known anti-inflammatory drug dexamethasone by inhibiting myeloperoxidase (MPO) activity, reducing total cells and neutrophils, and suppressing inflammatory cytokines expression, and thus ameliorating the histopathological conditions of the injured lung tissue. In conclusion, compound 1 could be developed as a promising anti-inflammatory agent for intervention of LPS-induced ALI.

Proliferation of retinal pigment epithelial cells induced by (R,R)-XY-10 and (S,S)-XY-10 and their action mechanisms.

AIM: To investigate the mechanism of proliferation effect induced by (R,R)-XY-10 and (S,S)-XY-10 on retinal pigmented epithelial cells (ARPE-19). METHODS: Human retinal pigmented epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) were used to investigate the effect of (R,R)-XY-10 and (S,S)-XY-10 on cell growth, and their mechanisms of proliferative action by using ERK, AKT, PI3K, Protein kinase C (PKC) and Nitric oxide synthase (NOS) inhibitors. RESULTS: (R,R)-XY-10 and (S,S)-XY-10 dose-dependently increased ARPE-19 cell proliferation, but not on HUVECs. When treated with proliferative inhibitors, H-7 (5µmol/L), hypericin (20µmol/L), PD98059 (2µmol/L), LY294002 (50µmol/L), SH-5 (10µmol/L) and L-NAME (100µmol/L), the proliferative effect was reduced by H-7, hypericin, PD98059 and LY294002, but not by SH-5 and L-NAME. CONCLUSION: (R,R)-XY-10 and (S,S)-XY-10 can induce cell proliferation through MAPK and PI3K dependent pathway.

Synthesis and biological evaluation of nitric oxide-donating thalidomide analogues as anticancer agents.

In search of more potent anticancer agents, 15 nitric oxide (NO)-donating thalidomide analogues, 6a, 6b, 8a-8e, and 13a-13h, were designed and synthesized. Cytotoxicity of these compounds was evaluated in vitro against three human tumor cell lines (HepG2, A549, and PC-3). The results indicated that 13a-13d exhibited notable anticancer activities comparable to or stronger than that of 5-fluorouracil (5-FU). Structure-activity relationships were also discussed, based on the experimental data obtained. Generally, the cytotoxic activity of target compounds is closely related to the type of NO donors, and the length of the spacers connecting to NO donors also appears important for the bioactivities.

[Advances in the study of nitric oxide-donating drugs].

Nitric oxide (NO) as a messenger and/or effector plays important roles in vivo. The decreased availability of NO or dysfunction in NO signaling has often been implicated in the development and progression of diseases, and design and research of NO-donating drugs has become one of the important strategies in drug discovery. In connection with authors' scientific practice, this article reviews the recent advances in the research of NO-donating drugs.

Synthesis and cytotoxic evaluation of novel dimethyl [1,1'-biphenyl]-2,2'-dicarboxylates bearing 1,3,4-thiadiazole moieties.

In search of novel anticancer agents, two series of dimethyl [1,1'-biphenyl]-2,2'-dicarboxylate derivatives, 8a-8k and 9a-9k, containing both methylenedioxy and 1,3,4-thiadiazole moieties were designed and synthesized. Cytotoxicity of these compounds was evaluated in vitro against five human tumor cell lines, i.e., HepG2, KB, A549, K562, and MCF-7. The results indicated that 8h, 8j, 8k, 9d, 9g, 9h, 9j, and 9k showed notable anticancer activities comparable to or stronger than that of 5-fluorouracil, a canonical anticancer drug. Structure-activity relationships were also discussed based on the experimental data obtained.

[A novel class of anti-inflammatory and analgesic drugs--NO-donating NSAIDs].

Traditional non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors are among the most widely used drugs. However, their significant side effects in gastrointestinal and cardiovascular systems limited the use of these drugs. Recently, research and development of NO-donating NSAIDs (NO-NSAIDs) have become one of the most important strategies to reduce these side effects. NO-NSAIDs may exert a broad range of positive effects in terms of NO-mediated gastrointestinal and cardiovascular safety as well as comparable or increased anti-inflammatory, analgesic properties relative to NSAIDs. This review briefly deals with chemistry of NO-NSAIDs, more details are focused on biological significance, mechanism of action, and therapeutic potential of this novel class of drugs.

[Synthesis and antithrombotic activity of acetylsalicyl ferulic acid-coupling furoxans and nitrates].

AIM: To synthesize and study the antithrombotic activity of NO-donating aspirin derivatives. METHODS: Furoxans and nitrates were incorporated to aspirin via antioxidant ferulic acid as a linker, and the target compounds were screened for in vitro and in vivo inhibitory activities of platelet aggregation, and for inhibitory effect on A-V hypass thromhosis in rats. RESULTS: Fourteen novel compounds I(1-14), were synthesized and their structures were confirmed Iy MS, IR, 1H NMR and elemental analysis. Biological screening results demonstrated that some tested compounds exhibited potential antithrombotic activ it. CONCLUSION: Acetylsalicyl ferulic acid-coupling furoxans and nitrates might he used as a lead for further study.

Structural characterization of chlorobenzylidine.

AIM: To study the structure and crystal forms of chlorobenzylidine. METHODS: Karl Fischer titrimetry, FTIR, thermal analysis, single and powder X-ray diffraction were used for the studies of the structure of chlorobenzylidine and for the identification of two forms of chlorobenzylidine. RESULTS: Chlorobenzylidine and its diastereoisomer have been studied in this article. They can be distinguished by their different melting points. Two crystal forms of chlorobenzylidine (form A and form B) have also been detected and studied. Form A was studied by single-crystal X-ray diffraction, it crystallized in the triclinic system, space group P1(-), with two formula units per cell, is monohydrate. Karl Fischer titrimetry, FTIR, thermal analysis and powder X-ray diffraction were used for identification of the two forms. CONCLUSION: The studies of structure and crystal forms of chlorobenzylidine are very useful for the clinical research and the selection of recrystallization process.

[Studies on the chemical constituents of Cirsium japonicum DC].

AIM: In order to look for new bioactive compounds, investigation on the chemical constituents, especially on the typical polyacetylenes from the rhizomes of Cirsium japonicum DC. was carried out. METHODS: Chromatographic techniques including silica column chromatography and preparative silica thin-layer chromatography were used to separate and purify the constituents. Their structures were elucidated by physicochemical properties and spectral analyses including UV, IR, 1HNMR, 13CNMR, HMQC, HMBC and HREIMS. RESULTS: Twelve compounds were isolated from the rhizomes of Cirsium japonicum DC., and their structures were identified as cis-8, 9-epoxy-heptadeca-1-ene-11, 13-diyne-10-ol (1), ciryneol A (2), 8,9,10-triacetoxyheptadeca-1-ene-11,13-diyne (3), ciryneone F (4), cireneol G (5), ciryneol H (6), ciryneol C (7), p-coumaric acid (8), syringin (9), linarin (10), beta-sitosterol (11) and daucosterol (12). CONCLUSION: Compounds 4, 5 and 6 are new compounds, compound 3 is a new natural product and compound 8 was isolated from this plant for the first time.

Relationship between nitric oxide production and choroidal blood flow.

PURPOSE: To invent a drug which can specifically facilitate choroid blood flow via increase of nitric oxide (NO). METHOD: Cell culture was used for in vitro experiments to determine the production of NO by NO donors and colored microsphere technique was used for in vivo experiments to determine the blood flow in various tissues of rabbit eyes. RESULTS: ZX-5 and ZX-4 are two geographic isomers with ZX-5 as trans-form and ZX-4 as cis-form. (1-phenyl-3-[3-methoxy-2-propoxy-5-[4-(3,4,5-trimethoxy-phenyl)-1,3-d lane-2-yl]phenyl]thiourea). It was found that ZX-5 released significant amount of NO at 3, 10, 30 microg/ml concentrations and increased choroid blood flow at 1%, 50 microl instillation into eyes. It was not effective on the blood flow of iris or ciliary body. The corresponding ZX-4 was not effective on ocular blood flow nor it released NO. CONCLUSION: ZX-5 can specifically increase the choroidal blood flow which could be useful to suppress the choroidal neovascularization in age-related macular degeneration (AMD). It is hoped that ZX-5 type of compounds could be used for the treatment/prevention of AMD in the elderly.

[Synthesis and anti-inflammatory analgesic activities of phenylfuroxan-coupled diclofenac].

AIM: To search for new derivatives of diclofenac (DC) having higher potency than the parent drug and lacking its undesirable effects. METHODS: Coupling DC with NO donor 3-hydroxymethyl-4-phenylfuroxan and its isomer through esterification, evaluating anti-inflammatory and analgesic activities, observing side effects in the rat gastrointestinal (GI) tract and assessing NO releasing ability both in vitro and in vivo. RESULTS: Fifteen new compounds including nine target ones (II1-9) were synthesized, and their structures were determined by IR, 1HNMR, MS and elemental analysis. Compounds II3 and II9 showed anti-inflammatory activity comparable to DC. Compound II2 showed stronger anti-inflammatory and analgesic activities and less GI side effect than DC, and released NO in vivo. CONCLUSION: Compound II2 is worthy to be intensively studied.