Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives.

In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 µM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.

Pentanuclear clusters resembling the cubane-dangler connectivity in the native oxygen-evolving center of photosystem II.

A series of pentametallic "cubane-plus-dangler" complexes have been target synthesized. Among them, the [Fe3Ni2] aggregate strongly resembled the native oxygen-evolving center by mimicking the "cubane-plus-dangler" skeleton, the aqua binding site, and the connectivity between the pendent ion and the parent cubane. Our synthetic strategy that uses tri-substituted methanol as the "cubane-generator" and carboxylate as the pendant ligand provides a feasible approach for accessing model compounds of biological catalyst systems.

Reference frame for home pulse pressure based on cardiovascular risk in 6470 subjects from 5 populations.

The absence of an outcome-driven reference frame for self-measured pulse pressure (PP) limits its clinical applicability. In an attempt to derive an operational threshold for self-measured PP, we analyzed 6470 participants (mean age 59.3 years; 56.9% women; 22.5% on antihypertensive treatment) from 5 general population cohorts included in the International Database on HOme blood pressure in relation to Cardiovascular Outcome. During 8.3 years of follow-up (median), 294 cardiovascular deaths, 393 strokes and 336 cardiac events occurred. In 3285 younger subjects (<60 years), home PP only predicted all-cause and cardiovascular mortality (P⩽0.036), whereas in 3185 older subjects (⩾60 years) PP predicted total and cardiovascular mortality (P⩽0.0067) and all cardiovascular and coronary events (P⩽0.044). However, PP did not substantially refine risk prediction based on classical risk factors including mean blood pressure (generalized R(2) statistic ⩽0.20%). In older subjects, the adjusted hazard ratios expressing the risk in the upper decile of home PP (⩾76 mm Hg) versus the average risk in whole population were 1.41 (95% confidence interval, 1.09-1.81; P=0.0081) for all-cause mortality, 1.62 (1.11-2.35; P=0.012) for cardiovascular mortality and 1.31 (1.00-1.70; P=0.047) for all fatal and nonfatal cardiovascular end points combined. The low number of events precluded an analysis by tenths of the PP distribution in younger participants. In conclusion, a home PP of ⩾76 mm Hg predicted cardiovascular outcomes in the elderly with the exception of stroke, whereas in younger subjects no threshold could be established.

Risk stratification by ambulatory blood pressure monitoring across JNC classes of conventional blood pressure.

BACKGROUND: Guidelines propose classification of conventional blood pressure (CBP) into normotension (<120/<80 mm Hg), prehypertension (120-139/80-89 mm Hg), and hypertension (≥140/≥90 mm Hg). METHODS: To assess the potential differential contribution of ambulatory blood pressure (ABP) in predicting risk across CBP strata, we analyzed outcomes in 7,826 untreated people recruited from 11 populations. RESULTS: During an 11.3-year period, 809 participants died (276 cardiovascular deaths) and 639, 383, and 225 experienced a cardiovascular, cardiac, or cerebrovascular event. Compared with normotension (n = 2,639), prehypertension (n = 3,076) carried higher risk (P ≤ 0.015) of cardiovascular (+41%) and cerebrovascular (+92%) endpoints; compared with hypertension (n = 2,111) prehypertension entailed lower risk (P ≤ 0.005) of total mortality (-14%) and cardiovascular mortality (-29%) and of cardiovascular (-34%), cardiac (-33%), or cerebrovascular (-47%) events. Multivariable-adjusted hazard ratios (HRs) for stroke associated with 24-hour and daytime diastolic ABP (+5 mm Hg) were higher (P ≤ 0.045) in normotension than in prehypertension and hypertension (1.98 vs.1.19 vs.1.28 and 1.73 vs.1.09 vs. 1.24, respectively) with similar trends (0.03 ≤ P ≤ 0.11) for systolic ABP (+10 mm Hg). However, HRs for fatal endpoints and cardiac events associated with ABP did not differ significantly (P ≥ 0.13) across CBP categories. Of normotensive and prehypertensive participants, 7.5% and 29.3% had masked hypertension (daytime ABP ≥135/≥85 mm Hg). Compared with true normotension (P ≤ 0.01), HRs for stroke were 3.02 in normotension and 2.97 in prehypertension associated with masked hypertension with no difference between the latter two conditions (P = 0.93). CONCLUSION: ABP refines risk stratification in normotension and prehypertension mainly by enabling the diagnosis of masked hypertension.

Xylomexicanins C and D, new mexicanolide-type limonoids from Xylocarpus granatum.

Two new limonoids, named xylomexicanins C and D, were isolated from a dichloromethane extract of the seeds of Xylocarpus granatum cultivated in Hainan, China, and their structures were elucidated on the basis of one- and two-dimensional NMR (including 1H, 13C-NMR, DEPT, 1H-1H COSY, HSQC, HMBC, and NOESY) and confirmed by high-resolution mass spectrometry. Xylomexicanin C exhibited antiproliferative activity against human breast carcinoma cells (KT).