ABSTRACT
The significant progress made in the area of transition metal-catalyzed nitrene transfer into C-H or C[double bond, length as m-dash]C bonds mediated by iodine(iii) oxidants has been translated into many elegant synthetic applications. This feature article summarizes the main total syntheses that take advantage of such reactions, thereby highlighting that catalytic C(sp3)-H amination and alkene aziridination reactions have carved out their place in the organic chemist's toolbox.
ABSTRACT
BACKGROUND AND PURPOSE: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K(+) channels (IK(Ca)) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes. EXPERIMENTAL APPROACH: Pressure myography, western blotting, sharp microelectrode and K(+)-selective electrode recordings were used to investigate the functional expression of the CaR and IK(Ca) in rat mesenteric arteries. KEY RESULTS: Myocyte hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619-induced vessel contraction elevated the extracellular [K(+)] around the myocytes, and inhibition of this 'K(+) cloud' by iberiotoxin was needed to reveal calindol-induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IK(Ca) expression was also diminished, but IK(Ca)-generated hyperpolarizations mediated by 1-EBIO were unaffected. CONCLUSIONS AND IMPLICATIONS: The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IK(Ca) channels. Detection of CaR-mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long-term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.
Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Mesenteric Arteries/metabolism , Potassium Channels, Calcium-Activated/metabolism , Receptors, Calcium-Sensing/metabolism , Animals , Blotting, Western , Electrophysiology , Gene Expression Regulation , Male , Mesenteric Arteries/pathology , Microelectrodes , Muscle Cells/metabolism , Myography , Rats , Rats, Wistar , Rats, Zucker , Vasodilation/physiologyABSTRACT
The synthesis and calcimimetic properties of N1-arylsulfonyl-N2-(1-aryl)ethyl-3-phenylpropane-1,2-diamines are described. The most active compound of the series (3n, used at 10 microM) produced 97+/-11% of the maximal stimulation of [3H]IP production obtained by 10 mM Ca2+ in CHO cells expressing the calcium sensing receptor (CaSR). This calcimimetic activity was due to a specific interaction of this compound with the CaSR.
Subject(s)
Calcium/metabolism , Diamines/pharmacology , Receptors, Cell Surface/drug effects , Animals , CHO Cells , Cricetinae , Diamines/chemical synthesis , Inositol Phosphates/biosynthesis , Receptors, Calcium-SensingABSTRACT
Olefinic primary sulfonamides were treated with iodobenzene diacetate and potassium hydroxide in methanol to give intermediate iminoiodinanes. Catalytic copper(I) or (II) triflate then provided intramolecular nitrene delivery leading to aziridine formation except in one case where a rare copper-catalyzed C-H insertion was observed. The aziridines could be opened by various nucleophiles (methanol, thiophenol, allylmagnesium bromide, benzylamine) to give the corresponding substituted cyclic sulfonamides.
Subject(s)
Copper/chemistry , Heterocyclic Compounds, 2-Ring/chemical synthesis , Sulfonamides/chemical synthesis , Aziridines/chemical synthesis , Aziridines/chemistry , Aziridines/metabolism , Catalysis , Copper/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/metabolism , Sulfonamides/chemistry , Sulfonamides/metabolism , p-Aminoazobenzene/analogs & derivatives , p-Aminoazobenzene/chemistryABSTRACT
The first synthesis of one of the 4 possible stereoisomers of 3,4-dihydroxy-L-glutamic acid ((3S,4S)-DHGA 3), a natural product of unknown configuration, is described. The synthesis is based on the Lewis acid catalyzed reaction of benzyl alcohol with a D-ribose-derived 2,3-aziridino-gamma-lactone 4-benzyl carboxylate (6). Preliminary pharmacological studies showed that (3S,4S)-3 is an agonist of metabotropic glutamate receptors of type 1 (mGluR1) and a weak antagonist of mGluR4 but has no discernible activity with respect to mGluR2. This activity profile can be rationalized by fitting extended conformations of (3S,4S)-3 in proposed models of each of these receptor subtypes.
