Protective effect of novel angiotensin receptor neprilysin inhibitor S086 on target organ injury in spontaneously hypertensive rats.

BACKGROUND: Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure associated with injury to the heart, kidney, brain, and other organs. Angiotensin receptor neprilysin inhibitors (ARNi), including angiotensin receptor blockers (ARBs) and neprilysin inhibitors (NEPi), have been shown to be safe and effective at reducing blood pressure and alleviating development of target organ injury. This study was used to develop S086 as a novel ARNi and conducted preclinical studies in animal models to evaluate the protective effects of S086 on target organs. METHODS: This study used a 14-month-old spontaneously hypertensive rat (SHR) model to evaluate the protective effects of S086 on the cardiovascular system and organs such as heart and kidney by blood pressure monitoring, urine and blood examination, pathological examination, and immunological index detection. RESULTS: After administering S086 orally to the SHR, their blood pressure and levels of renal injury indicators such as serum creatinine and urinary microalbumin were reduced, and myocardial cell necrosis and cardiac fibrosis of the heart were significantly improved. In addition, there were also significantly improvements in the histological lesions of blood vessels and the kidneys. CONCLUSIONS: The findings showed that S086 effectively reduced the blood pressure of SHR and had effects on alleviating development of heart, blood vessels and kidney.

[RhIII(Cp*)]-catalyzed arylfluorination of α-diazoketoesters for facile synthesis of α-aryl-α-fluoroketoesters.

Here we describe the Cp*Rh(iii)-catalyzed cascade arylfluorination reactions of α-diazoketoesters with arylboronic acids and N-fluorobenzenesulfonimide for one-pot C(sp3)-C(aryl) and C(sp3)-F bond formation. The arylfluorination reaction can be accomplished with remarkable chemo- and regioselectivity. Our mechanistic investigation showed that the Rh-catalyzed arylfluorination of diazoacetates occurred by (1) transmetalation of arylboronic acids to form an arylrhodium(iii) complex, (2) coupling of diazomalonates with the arylrhodium(iii) complex to form carbene-rhodium, (3) migratory carbene insertion to form a diketonato-rhodium(iii) complex - probably via rearrangement of the putative σ-alkylrhodium(iii) complex, and (4) electrophilic fluorination of the diketonato-rhodium to form the α-aryl-α-fluoromalonates.

Total syntheses of shizukaols A and E.

Shizukaols possess a common heptacyclic framework containing more than ten contiguous stereocenters and potential biological activities. Here we report that the total syntheses of shizukaols A (1) and E (2), two lindenane-type dimers from the Chloranthaceae family, are achieved via a modified biomimetic Diels-Alder reaction. The common crucial biomimetic diene 23 and ethylene species (6, 17) are obtained through either a highly Z-selective olefination of α-siloxy ketone with ynolate anions or an intramolecular Horner-Wadsworth-Emmons olefination from commercially available Wieland-Miescher ketone (7). This synthetic approach here opens up practical avenues for the total syntheses of the intriguing Chloranthaceae family members, as well as the understanding of their relevant biological action in nature.

Cp*Rh(III)-Catalyzed Cross-Coupling of Alkyltrifluoroborate with α-Diazomalonates for C(sp(3))-C(sp(3)) Bond Formation.

A Cp*Rh(III)-catalyzed cross-coupling of alkyltrifluoroborate with α-diazomalonates was developed; the C(sp(3))-C(sp(3)) bond coupled products were formed in up to 97% yields. The reaction tolerates some useful functional groups, including ketone, ester, amide, ether, sulfonyl, and thiophene. Electrospray ionization mass spectrometry (ESI-MS) analysis revealed the formation of a distinct molecular species corresponding to σ-alkylrhodium(III) complexes. The successful diazo coupling reaction may be attributed to coordination of the amide group that promotes stability of the alkylrhodium(III) complex through the formation of a five-membered metallacycle.

A concise construction of the chlorahololide heptacyclic core.

A concise and efficient strategy for the construction of the heptacyclic core of the chloranthaceae family has been developed. The key strategy comprises an S(N)2-type intramolecular nucleophilic substitution and a biomimetic endo-Diels-Alder cycloaddition.

Highly Direct alpha-Selective Glycosylations of 3,4-O-Carbonate-Protected 2-Deoxy- and 2,6-Dideoxythioglycosides by Preactivation Protocol.

A new efficient pre-activation method for the highly alpha-stereoselective glycosylation of 2-deoxysugars and 2,6-dideoxysugars has been developed using 2-deoxy- and 2,6-dideoxythioglycosides as glycosyl donors. The approach allows a wide range of glycosyl acceptors and donors to be used; the alpha-selectivity is very good to excellent.