Practical gram-scale synthesis of bicyclol metabolites M2 and M3.

Bicyclol, an innovative hepatoprotective drug, was approved by the Chinese National Medical Products Administration (NMPA) in 2001 to treat Hepatitis B and drug-induced liver injury. Two active metabolites of bicyclol have been identified as M2 and M3. To evaluate the impact on drug safety and efficacy of possible drug-drug interactions (DDIs) associated with these metabolites, a sufficient quantity of these metabolites is required. Herein, we report a concise novel route for the synthesis of M2 and M3 using the Suzuki-Miyaura coupling as the key step. Furthermore, we complete the gram-scale syntheses of M2 and M3.

Design, synthesis of a novel 4-O-methylsaucerneol analogue LXY7824 as potent HIF-1 inhibitor and anti-cancer agent.

Hypoxia-inducible factor-1 (HIF-1), an important transcription factor for tumor survival, is an attractive target for anti-cancer treatment. Herein, we present the design and synthesis of LXY7824, a simplified analogue of 4-O-methylsaucerneol. In addition, its significant HIF-1 inhibitory activity and potent anti-cancer activity in vivo and in vitro were also reported.

DL0805-2, a novel indazole derivative, relaxes angiotensin II-induced contractions of rat aortic rings by inhibiting Rho kinase and calcium fluxes.

AIM: DL0805-2 [N-(1H-indazol-5-yl)-1-(4-methylbenzyl) pyrrolidine-3-carboxamide] is a DL0805 derivative with more potent vasorelaxant activity and lower toxicity. This study was conducted to investigate the vasorelaxant mechanisms of DL0805-2 on angiotensin II (Ang II)-induced contractions of rat thoracic aortic rings in vitro. METHODS: Rat thoracic aortic rings and rat aortic vascular smooth muscle cells (VSMCs) were pretreated with DL0805-2, and then stimulated with Ang II. The tension of the aortic rings was measured through an isometric force transducer. Ang II-induced protein phosphorylation, ROS production and F-actin formation were assessed with Western blotting and immunofluorescence assays. Intracellular free Ca(2+) concentrations were detected with Fluo-3 AM. RESULTS: Pretreatment with DL0805-2 (1-100 µmol/L) dose-dependently inhibited the constrictions of the aortic rings induced by a single dose of Ang II (10(-7) mol/L) or accumulative addition of Ang II (10(-10)-10(-7) mol/L). The vasodilatory effect of DL0805-2 was independent of endothelium. In the aortic rings, pretreatment with DL0805-2 (1, 3, and 10 µmol/L) suppressed Ang II-induced Ca(2+) influx and intracellular Ca(2+) mobilization, and Ang II-induced phosphorylation of two substrates of Rho kinase (MLC and MYPT1). In VSMCs, pretreatment with DL0805-2 (1, 3, and 10 µmol/L) also suppressed Ang II-induced Ca(2+) fluxes and phosphorylation of MLC and MYPT1. In addition, pretreatment with DL0805-2 attenuated ROS production and F-actin formation in the cells. CONCLUSION: DL0805-2 exerts a vasodilatory action in rat aortic rings through inhibiting the Rho/ROCK pathway and calcium fluxes.

Total synthesis of xiamenmycin C and all of its stereoisomers: stereochemical revision.

Xiamenmycin C, a potent anti-fibrotic natural product, and all of its stereoisomers have been synthesized and their structures were fully characterized. Based on this study, the originally proposed structure of xiamenmycin C has been accordingly revised to be 2R,3S.

Vasodilatory effect of a novel Rho-kinase inhibitor, DL0805-2, on the rat mesenteric artery and its potential mechanisms.

PURPOSE: In the present study, we investigated the vasodilatory effect of a novel scaffold Rho-kinase inhibitor, DL0805-2, on isolated rat arterial rings including mesenteric, ventral tail, and renal arteries. We also examined the potential mechanisms of its vasodilatory action using mesenteric artery rings. METHODS: A DMT multiwire myograph system was used to test the tension of isolated small arteries. Several drugs were employed to verify the underlying mechanisms. RESULTS: DL0805-2 (10(-7)-10(-4) M) inhibited KCl (60 mM)-induced vasoconstriction in three types of small artery rings (pEC50: 5.84 ± 0.03, 5.39 ± 0.03, and 5.67 ± 0.02 for mesenteric, renal, and ventral tail artery rings, respectively). Pre-incubation with DL0805-2 (1, 3, or 10 µM) attenuated KCl (10-60 mM) and angiotensin II (AngII; 10(-6) M)-induced vasoconstriction in mesenteric artery rings. The relaxant effect on the rat mesenteric artery was partially endothelium-dependent (pEC50: 6.02 ± 0.05 for endothelium-intact and 5.72 ± 0.06 for endothelium-denuded). The influx and release of Ca(2+) were inhibited by DL0805-2. In addition, the increased phosphorylation levels of myosin light chain (MLC) and myosin-binding subunit of myosin phosphatase (MYPT1) induced by AngII were blocked by DL0805-2. However, DL0805-2 had little effect on K(+) channels. CONCLUSIONS: The present results demonstrate that DL0805-2 has a vasorelaxant effect on isolated rat small arteries and may exert its action through the endothelium, Ca(2+) channels, and the Rho/ROCK pathway.

Total synthesis of (+/-)-4-demethylenglerin A.

Racemic 4-demethylenglerin A (1'), a simplified analog of the guaiane-type sesquiterpene englerin A (1), has been synthesized. The cyclic hydrocarbon core structure was built through modified Metz approach using epoxynitrile cyclization and direct Aldol reaction to prepare the precursor of RCM. The primary cytotoxicity test summarized that C4 methyl has marked impacts on the bioactivity.

Concise total synthesis of largazole.

The concise total synthesis of largazole was accomplished. The key step included the use of the Nagao thiazolidinethione auxiliary for the diastereoselective acetate aldol reaction and it acts as an acylating agent for the peptide formation.

Total synthesis of (+)-conagenin.

A new approach for the synthesis of the (+)-conagenin has been achieved based on Evans asymmetry syn-aldol reaction and the self-regeneration of stereocenters strategy.

Total synthesis of (-)-talaumidin and (-)-galbelgin.

( - )-Talaumidin (1) and ( - )-galbelgin (2) have been synthesized via 4-pentenoic acid as a starting material with the overall yield of about 17.8 and 16.9%, respectively. The key steps include Evans asymmetry anti-aldol reaction, TBS protection, hydroboration, oxidation, Friedel-Crafts arylation, etc.

A novel hypertensive crisis rat model established by excessive norepinephrine infusion and the potential therapeutic effects of Rho-kinase inhibitors on it.

Hypertension crisis is a severe disease and needs emergency treatment in clinic. It is an important task to discover novel drugs which could lower the blood pressure steadily and quickly. However, animal models for screening anti-hypertensive crisis agents are unsatisfactory. The present study aimed to establish a new hypertensive crisis rat model and then explore the therapeutic effects of three Rho-kinase inhibitors including Fasudil, DL0805-1 and DL0805-2 on such a disease model. The hypertensive crisis symptoms were developed on male Wistar rats by subcutaneously injecting small doses of norepinephrine (NE) for 10 days in the initial stage. A sudden increase in blood pressure (BP) was then induced by excessive NE infusion. Compounds to be tested were intravenously injected into the rats immediately when the rapidly increased systolic blood pressure appeared. The results have shown that after small dose administration with NE, the rats could obtain acute BP increase to a high level without sudden death when a large dose of NE was injected. Fasudil, DL0805-1 and DL0805-2 could lower the blood pressure quickly in a dose dependent manner and improve the survival rate. The compounds also prevent the animals from organ damage. In conclusion, we established a novel hypertensive crisis animal model which could evaluate agents within a short time. In this model, we found that three Rho-kinase inhibitors have potential therapeutic effects on hypertensive crisis. This work might contribute to the discovery and development of new anti-hypertensive crisis drugs.

[Synthesis and antioxiactivity of squamosamide cyclic analogs].

OBJECTIVE: To design and synthesize a series of squamosamide cyclic analogues and to test their antioxidation activity. METHODS: Eleven 3-substituted indole-2-one derivatives were designed and synthesized through 9 steps with p-hydroxyphenylacetic acid as the starting material and their structures were confirmed by nuclear magnetic resonance and mass spectrometry. RESULTS: Eleven compounds showed antioxidation activity and the activities of compounds 9 and 13 matches the positive control FLZ-52. CONCLUSION: Cyclic reconstruction with FLZ-52 as the lead compound have some antioxidation activity.

Study of stereoselective synthesis of (+/-)-neocnidilide.

Neocnidilide 1, isolated from Apium graveleues L (Umbelliferae), has shown activity to inhibit the growth of mycotoxin-producing fungi. An efficient method for the synthesis of the racemic neocnidilide by the stereoselective reaction of hemiacetal 6 with n-BuMgBr has been developed.