Pharmacological characterization of MT-1207, a novel multitarget antihypertensive agent.

Hypertension is a serious public health problem worldwide. MT-1207, chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl) benzisothiazole hydrochloride, is a new chemical entity that has entered into clinical trial as antihypertensive agent in China. In this paper we report the pharmacological profile of MT-1207 regarding its acute, subacute, and long-term effects on hypertensive animal models, and its actions on isolated organs in vitro as well as its molecular targets. Blood pressure (BP) was measured in conscious animals; amlodipine was taken as a positive control drug. We showed that both single dose of MT-1207 (1.25-20 mg/kg, ig) in spontaneously hypertensive rats (SHR) and MT-1207 (0.25-6 mg/kg, ig) in two-kidney one-clip (2K1C) dogs dose-dependently decreased BP. MT-1207 quickly decreased BP within 5 min after administration; the hypotensive effect lasted for 8 and 12 h, respectively, in SHR and 2K1C dogs without reflex increase in heart rate. Multiple doses of MT-1207 (5 mg · kg-1 · d-1 in SHR; 2 mg · kg-1 · d-1 in 2K1C dogs, for 7 days) significantly decreased BP, slightly reduced heart rate, and both of them recovered after withdrawal. Long-term administration of MT-1207 (10 mg · kg-1 · d-1 for 4 months or more time) produced a stable BP reduction, improved baroreflex sensitivity, reduced renal and cardiovascular damage in SHR, and delayed stroke occurrence and death in stroke-prone SHR. In isolated rat aortic rings precontracted by adrenaline, KCl, noradrenaline or 5-hydroxytryptamine (5-HT), MT-1207 (10-9-10-4 M) caused concentration-dependent relaxation. In a panel of enzyme activity or radioligand binding assays of 87 molecular targets, MT-1207 potently inhibited adrenergic α1A, α1B, α1D, and 5-HT2A receptors with Ki < 1 nM. The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries. We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.

Design, Synthesis and Antibacterial Evaluation of 3-Substituted Ocotillol-Type Derivatives.

Antibiotic resistance has become a serious global problem that threatens public health. In our previous work, we found that ocotillol-type triterpenoid saponin showed good antibacterial activity. Based on preliminary structure-activity relationship, novel serious C-3 substituted ocotillol-type derivatives 7⁻26 were designed and synthesized. The in vitro antibacterial activity was tested on five bacterial strains (B. subtilis 168, S. aureus RN4220, E. coli DH5α, A. baum ATCC19606 and MRSA USA300) and compared with the tests on contrast. Among these derivatives, C-3 position free hydroxyl substituted compounds 7⁻14, showed good antibacterial activity against Gram-positive bacteria. Furthermore, compound 22 exhibited excellent antibacterial activity with minimum inhibitory concentrations (MIC) values of 2 µg/mL against MRSA USA300 and 4 µg/mL against B. subtilis. The structure-activity relationships of all current ocotillol-type derivatives our team synthesised were summarized. In addition, the prediction of absorption, distribution, metabolism, and excretion (ADME) properties and the study of pharmacophores were also conducted. These results can provide a guide to further design and synthesis works.

Synthesis and Antibacterial Evaluation of Novel 3-Substituted Ocotillol-Type Derivatives as Leads.

Due to the rapidly growing bacterial antibiotic-resistance and the scarcity of novel agents in development, bacterial infection is still a global problem. Therefore, new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, are urgently needed. In this paper, a series of antibacterial ocotillol-type C-24 epimers modified from natural 20(S)-protopanaxadiol were synthesized and evaluated for their antibacterial activity. According to the screening results of Gram-positive bacteria (B. subtilis 168 and MRSA USA300) and Gram-negative bacteria (P. aer PAO1 and A. baum ATCC19606) in vitro, the derivatives exhibited good antibacterial activity, particularly against Gram-positive bacteria with an minimum inhibitory concentrations (MIC) value of 2-16 µg/mL. The subsequent synergistic antibacterial assay showed that derivatives 5c and 6c enhanced the susceptibility of B. subtilis 168 and MRSA USA300 to chloramphenicol (CHL) and kanamycin (KAN) (FICI < 0.5). Our data showed that ocotillol-type derivatives with long-chain amino acid substituents at C-3 were good leads against antibiotic-resistant pathogens MRSA USA300, which could improve the ability of KAN and CHL to exhibit antibacterial activity at much lower concentrations with reduced toxicity.

Structural modifications of 5,6-dihydroxypyrimidines with anti-HIV activity.

A series of 5,6-dihydroxypyrimidine analogs were synthesized and evaluated for their anti-HIV activity in vitro. Among all of the analogs, several compounds exhibited significant anti-HIV activity, especially 1b and 1e, which showed the most potent anti-HIV activity with EC(50) values of 0.14 and 0.15 µM, and TI (therapeutic index) values of >300 and >900, respectively. Further docking studies revealed that the representative compounds 1e and 3a could meet the HIV-1 integrase inhibition minimal requirements of a chelating domain (two metal ions) and an aromatic domain (π-π stacking interactions).

[Results and analysis of pulmonary function examination in 76 698 cases of physical examination crowd in Henain Province].

Objective: Pulmonary function testing (PFT) and electrocardiograph (ECG) are the vital components of the cardiopulmonary exercise test (CPET). This study is to investigate clinical characteristics of abnormal PFT as pulmonary ventilation dysfunction, small airway dysfunction and gas exchange (diffusion) dysfunction. Methods: Across-sectional study was conducted The 76 698 outpatient subjects who received health examination from December 2016 to February 2019 in Henan Provincial People's Hospital were recruited. The results of the ECG, PFT were compared among different sex and age sub-groups. Then the severity of their impaired PFT were analyzed. Results: Among 76 698 subjects, 39 237 subjects were male and 37 461 subjects were female. There were total 71.04% patients with abnormal ECG. There were total 28 273 (36.86%) patients with abnormal pulmonary ventilation function. The 17 570 patients (44.78%) (17 570/39 237) were male, 10 703 patients (28.57%) (10 703/37 461) were female, both the number and percentage of abnormal pulmonary ventilation function in male was significantly more than these in female (P<0.01). The percentage detectable rates of male were significant higher than that of female in all the different age sub-groups: 20~29, 30~39, 40~49, 50~59, 60~69 and ≥70 year (P<0.01). The total detectable abnormal rate of small airway dysfunction were 43 160 and 56.26% (43 160/76 698). The 57.73% (22 661/39 237) in male was significantly higher than 54.72% (20 499/37 461) in female (x2=74.87, P<0.01). The detectable abnormal rate of small airway dysfunction in male were lower than female in 30~39 year and 40~49year sub-groups (P<0.05), but were significantly higher in 20~29, 50~59, 60~69, and ≥70 yr sub-groups (P<0.05). Abnormal gas exchange (diffusion) dysfunction were detected in 28.54% (12 940/45 107) subjects. They were 7 433 (30.55%) in male,and 5 507 (26.50%)in female with significant gender difference (P<0.05). The abnormal diffusion detectable rate in 30~39 year sub-group was significant higher in female than in male (P<0.05), and were slightly higher without significant difference in 20~29 and 40~49 year sub-groups (P>0.05), but were significant lower in female than male in 50~59, 60~69 and ≥70 year sub-groups (P<0.05). Conclusion: The abnormal detectable rates in ECG, pulmonary ventilation dysfunction, gas exchange dysfunction and small airway dysfunction were higher in male than female, and higher in elder ≥70 year subgroup than all other younger age subgroups.

Design, synthesis, and biological evaluation of 1,5-diaryl-1,2,4-triazole derivatives as selective cyclooxygenase-2 inhibitors.

A series of 1,5-diaryl-1,2,4-triazole derivatives were synthesized and evaluated as cyclooxygenase-2 (COX-2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b, 6b, 6c, 7c, 8b, 8d, 9c, and 9d have potent anti-inflammatory activity (P < 0.01), while compounds 6b, 6c, and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX-2 (COX-2 IC(50) = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX-2 IC(50) = 0.26 µM; SI = 0.015). In a rat carrageenan-induced paw edema assay, 6c exhibited moderate anti-inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX-2 in a similar mode to that of the known selective COX-2 inhibitor SC-558.

Design and synthesis of 28-hydroxy protopanaxadiol as a novel probe template.

To explore the antitumour mechanism of 20(S)-protopanaxadiol (PPD) while maintaining its uncovered pharmacological active site 3-hydroxyl, 28-hydroxy protopanaxadiol (17), a small molecular probe template of PPD was first designed and synthesised based on the Baldwin's reaction. Thus, 28-hydroxyl of 17 was built successfully as a derivatized site of molecular probe's functional and report groups. The important intermediates and final product were confirmed by ESI-MS and nuclear magnetic resonance spectra with good yield. These studies provided a valuable basis for probe research of PPD.

Synthesis and anti-hepatocellular carcinoma activity of novel O2-vinyl diazeniumdiolate-based nitric oxide-releasing derivatives of oleanolic acid.

Considering that high levels of nitric oxide (NO) exert anti-cancer effect and the derivatives of oleanolic acid (OA) have shown potent anti-cancer activity, new O2-vinyl diazeniumdiolate-based NO releasing derivatives (5a-l, 11a-l) of OA were designed, synthesized, and biologically evaluated in the present study. These derivatives could release different amounts of NO in liver cells. Among them, 5d, 5i, 5j, 11g, 11h, and 11j released more NO in SMMC-7721 cells and displayed stronger proliferative inhibition against SMMC-7721 and HepG2 cells than OA and other tested compounds. The most active compound 5j showed almost 20-fold better solubility than OA in aqueous solution, released larger amounts of NO in liver cancer cells than that in normal ones, and exhibited potent anti-hepatocellular carcinoma activity but little effect on the normal liver cells. The inhibitory activity against the cancer cells was significantly diminished upon addition of an NO scavenger, suggesting that NO may contribute, at least in part, to the activity of 5j.

Lasiokaurin derivatives: synthesis, antimicrobial and antitumor biological evaluation, and apoptosis-inducing effects.

Herein, a series of lasiokaurin derivatives were designed and synthesized. All the derivatives together with lasiokaurin and oridonin were tested for their antimicrobial and antiproliferative activity. Compound 16 showed the most promising antimicrobial activity with MICs of 2.0 and 1.0 µg/mL against Gram-Positive bacteria S. aureus and B. subtilis, respectively. All the synthetic lasiokaurin derivatives showed better antiproliferative activity than parent compound lasiokaurin 1. Compound 10 exhibited the strongest cytotoxicity with IC50 values of 0.47 and 0.20 µM against MGC-803 and CaEs-17 cells, accordingly. Moreover, it was shown to have potent antitumor activity in vivo in a murine model of MGC-803 gastric cancer. Preliminary SARs were also concluded based on obtained data. The apoptosis-inducing effects of 10 were further investigated using CaEs-17 cells. The results showed that lasiokaurin derivative 10 could induce apoptosis via mitochondria related pathway and arrest CaEs-17 cell cycle at S phase. Compound 10 could also affect apoptosis-related proteins that was up-regulation of CDK2 and down-regulation of ATM and cyclin A1.

The Dark-Purple Tea Cultivar 'Ziyan' Accumulates a Large Amount of Delphinidin-Related Anthocyanins.

Recently, we developed a novel tea cultivar 'Ziyan' with distinct purple leaves. There was a significant correlation between leaf color and anthocyanin pigment content in the leaves. A distinct allocation of metabolic flow for B-ring trihydroxylated anthocyanins and catechins in 'Ziyan' was observed. Delphinidin, cyanidin, and pelargonidin (88.15 mg/100 g FW in total) but no other anthocyanin pigments were detected in 'Ziyan', and delphinidin (70.76 mg/100 g FW) was particularly predominant. An analysis of the catechin content in 'Ziyan' and eight other cultivars indicated that 'Ziyan' exhibits a preference for synthesizing B-ring trihydroxylated catechins (with a proportion of 74%). The full-length cDNA sequences of flavonoid pathway genes were isolated by RNA-Seq coupled with conventional TA cloning, and their expression patterns were characterized. Purple-leaved cultivars had lower amounts of total catechins, polyphenols, and water extract than ordinary non-anthocyanin cultivars but similar levels of caffeine. Because dark-purple-leaved Camellia species are rare in nature, this study provides new insights into the interplay between the accumulations of anthocyanins and other bioactive components in tea leaves.

Current natural products with antihypertensive activity.

Natural products have been an important source of new drugs, which also played a dominant role in the discovery and research of new drugs for the treatment of hypertension. This review article reviews the recent progress in the research and development of natural lead compounds with antihypertensive activity, including alkaloids, diterpenes, coumarins, flavonoids, and peptides. We summarized their structures, sources, as well as the antihypertensive mechanisms. These information provides instructive reference for the following structural modifications and optimization.

Synthesis of 13-ß-elemene ester derivatives and evaluation of their antioxidant activity in human umbilical vein endothelial cells.

In the present study, a series of 13-ß-elemene ester derivatives were designed and prepared, and their antioxidant activity was investigated in the H2O2-treated human umbilical vein endothelial cells (HUVECs). Among the test compounds, the dimer compounds 5v and 5w exhibited the most potent antioxidant activity with significant ROS suppression being observed. Both compounds markedly inhibited the H2O2-induced changes in various biochemical substances, such as superoxide dismutase (SOD), malonyldialdehyde (MDA), nitric oxide (NO), and lactic dehydrogenase (LDH), which were superior to that of the positive control vitamin E. Further more, they did not produce any obvious cytotoxicity, but increased the viability of HUVECs injured by H2O2 in a dose-dependent manner. Additionally, compound 5w, designed as a prodrug-like compound, showed improved stability relative to compound 4 in vitro.

Construction of 3,6-anhydrohexosides via intramolecular cyclization of triflates and its application to the synthesis of natural product isolated from leaves of Sauropus rostratus.

A novel synthetic approach to construct various 3,6-anhydrohexosides via an intramolecular cyclization of corresponding triflates is described. The nucleophilic attack from C3 p-methoxybenzylated hydroxyl to C6 trifluoromethanesulfonate on triflate structures triggered the cyclization reaction to provide 3,6-anhydrohexosides in excellent yields, making the strategy more efficient with respect to the reported protocols. By applying this methodology, a concise first total synthesis of natural product isolated from leaves of Sauropus rostratus was accomplished.

Transformation of strictosamide to vincoside lactam by acid catalysis.

AIM: To identify the structure of the acid-catalyzed product of strictosamide and explore the reaction mechanism. METHODS: The acid-catalyzed reaction process of strictosamide was monitored by HPLC, and a macroporous resin was used to purify the reaction solution. The structure of the product was confirmed by MS, NMR, and ROESY spectra. RESULTS: The acid-catalyzed transformation yield from strictosamide to vincoside lactam was 52%. CONCLUSION: The reaction mechanism of the transformation from strictosamide to vincoside lactam may be related to the stability of the three-dimensional configuration of the compound. These results offer a new way to obtain vincoside lactam from the widely distributed indole alkaloid strictosamide by acid-catalysis.

Synthesis and ß-adrenergic blocking activity of oxime ether hybrids derived from a natural isochroman-4-one.

AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, ß1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited ß1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION: The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.

Synthesis and biological activity of 2-alkylbenzimidazoles bearing a N-phenylpyrrole moiety as novel angiotensin II AT1 receptor antagonists.

A series of 2-alkylbenzimidazoles bearing a N-phenylpyrrole moiety were synthesized and evaluated as a novel class of AT(1) receptor antagonists. Among them, compounds 10a and 10g inhibited [(125)I] AngII-binding affinity to AT(1) receptor at nanomolar level and potently inhibited the Ang II-induced pressor response by oral administration. Moreover, evaluation in spontaneously hypertensive rats showed that 10a is an orally active AT(1) receptor antagonist.