Syntheses of amino and bromo substituted cyclohexane polyols and their biological activities

Cyclitols (cyclic polyols) are an important group of medicinal natural products due to being glycosidase inhibitors and constituting structural components of other bioloactive compounds with some aminoglycoside antibiotics. Also, owing to their hydrolytic stability these compounds are considered as quite potent and promising drug candidates for treating diseases such as diabete, viral infection, and cancer. Therefore, in this study in two sections (I and II), some cyclitol derivatives were synthesized with new, stereospecific and stereoselective methods and the biological activities of the compounds synthesized were examined. In the section I, initially, 4-acetoxy enone (111) was synthesized with the base-catalyzed ring-opening and acetylation reactions applied to the endoperoxide (109) obtained from the anhydride. This compound was subjected to the 1,4-conjugate addition of azide ion. Following this, with carbonyl reduction, furan opening, the hydrolysis reaction of the acetate and acetamide groups, N-acyl (118, 119) and amino (120, 121) carbasugars was obtained in high yields. As compared with acarbose, strong α-glucosidase inhibitor activity (55-87%) of all of these compounds (118-121), moderate and weak β-glucosidase inhibitor activity (6-30%) of the three (118, 120, 121) of them, and 51% β-glucosidase activator activity of 119 from them showed. Finally it was determined to have rather weak antioxidant activity (5%) of 121 from these compounds. Further, in the section II, the methoxy tetraacetate isomers (127, 139) were synthesized with that the methoxy ketal (125), obtained from 1,4-cyclohexadiene, to be subjected to the epoxidation with m-CPBA, sulfuric acid catalyzed the trans-hydroxylation, and acetylation, respectively. For the synthesis of bromo quersitols (132-135), the methoxy group in the tetraacetate (127) was replaced with bromine by using HBr. While the ammonolysis with NH3 of the methoxy tetraacetates gave methoxy quersitols (140, 141), epi- ve muco quersitol isomers (144, 145) were afforded with the demethylation with HBr of them and then basic hydrolysis. The only two bromo quersitols from all quercitol derivatives showed strong α-glucosidase inhibition (133: 51%, 135: 36%). The formation mechanisms of products 110, 112, 118-121, 129 and 130 numbered in the study were discussed. All products were purified by crystallization and chromatographic methods and their structures were elucidated by spectroscopic techniques (1H, 13C and 2D NMR, IR). In conclusion, in this study, the new substituted cyclitol derivatives which may be formed the structural units of drug active agents were synthesized.