The oxidation of isothiazolium salts 4 to stable 2‐aryl‐2,3,4,5,6,7‐hexahydro‐3‐hydroperoxy‐1,2‐benzisothiazole 1‐oxides rac‐cis‐6 (sultims) as a new class of cyclic sulfinamides is described. The formations of the oxidation products rac‐cis‐6 as well as 3‐hydroperoxy and 3‐hydroxy sultams, 8 and 9, respectively, and isothiazol‐3(2H)‐one 1,1‐dioxides 10 are presented.
The effects of a new forskolin derivative, (13R)-spiroforskolin, on the ventricular cAMP-activated chloride current (I(Cl(cAMP))) and the atrial L-type calcium current (I(Ca,L)) were measured by means of whole-cell recording from isolated guinea-pig cardiac myocytes at 30 degrees C and 20-22 degrees C, respectively. In contrast to forskolin, the derivative contains a tetrahydrofuran rather than a tetrahydropyran moiety. (13R)-spiroforskolin activated I(Cl(CAMP)) in 58% of the ventricular myocytes studied. The concentration required for the half maximal effect (EC50 value) amounted to 9.6x10(-11) M and was lower than the EC50 value for forskolin (2.4x10(-8) M). (13R)-spiroforskolin evoked a smaller maximal I(Cl(cAMP)) amplitude than forskolin. The rundown of the (13R)-spiroforskolin-activated I(Cl(cAMP)) was faster than that of the forskolin-induced current. Neither forskolin nor (13R)-spiroforskolin in maximally effective concentrations increased I(Cl(cAMP)) in cells containing high concentrations of cAMP. Furthermore, as an activator of atrial I(Ca,L) (13R)-spiroforskolin displayed a smaller activation and a lower EC50 value (5.8x10(-10) M) than forskolin (EC50 value: 3.7x10(-7) M). The effect of (13R)-spiroforskolin was observed in only 30% of the atrial cells studied. None of the drugs exerted a stimulatory effect in atrial cells containing a high [cAMP]. The washout of the drug effect was significantly faster in (13R)-spiroforskolin- than in forskolin-treated atrial myocytes. We conclude that (13R)-spiroforskolin as a forskolin derivative displays unique characteristics. It is a more potent but less efficacious activator of cardiac ionic conductances than the parent compound. The results suggest that (13R)-spiroforskolin, like forskolin, most probably exerts its effects via stimulation of the adenylyl cyclase.
The stable hydroperoxides rac-cis-2a,d and 4a,c were synthesized by oxidation of the salts 1. The 3-hydroxy sultims rac-cis-3a,b and sultams 5a,e were obtained by reduction of the corresponding hydroperoxides 2 and 4. Crystal structure analyses were performed for compounds 3b, 4a, 5a, 5e and revealed a variety of intermolecular contacts leading to cyclodimers, tetramers and polymers. In carboxylic esters 4a and 5a, cyclodimers with a 20- or 22-membered ring are formed via ‘head-to-tail’ CO⋯H-O hydrogen bonds and π/π-interactions, without participation of the SO2 group. The 1,1-dioxide 4c, which has no carbonyl substituent, forms a tetrameric unit by combining two symmetry independent molecules through strong OO-H⋯O-S-O and short nonclassical O-S-O⋯H-C hydrogen bonds. The sultam 1,1-dioxide 5e, bearing a highly substituted 2-phenyl ring, exhibits in the solid state strong intermolecular O-S-O⋯H-O hydrogen bonds and forms the first polymer chain in this cyclic sulfonamide series. In sultims 2a, 3a and 3b, but not in 2d, strong intermolecular S-O⋯H-O hydrogen bonds are observed and polymer chains originate from the c-glide plane (space group P21/c)in 2a and from two symmetry independent molecules in 3a. In the 1-oxide 2d a ‘head-to-head’ dimer was found with two strong SO⋯H-OO hydrogen bonds in a 14- or 16-membered ring. Short nonclassical C-H⋯O-C interactions connect the dimers to form polymeric chains.
Abstract3-Hydroxy- (17a - j) and 3-alkoxy-4,5,6,7-tetrahydro-benzosultams 18a-m were prepared in good yields by oxidation of the bicyclic isothiazolium salts 10 with magnesium monoperoxyphthalate (MMPP·6H2O) in acetonitrile or corresponding alcohol. A HPLC-API-MS(MS) method was used to monitor the oxidation process of 10 with MMPP. 3-Oxo-4,5,6,7-tetrahydro-benzosultams 19a - c, h, j were also obtained.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.