Syntheses and hypoglycemic activities of ethyl esters and various amides of omega-guanidino fatty acids with medium chain length.
The omega-guanidino fatty acids C6-C12 were prepared by amidination of the corresponding omega-amino acids. omega-Amino acids C7-C10 which are not available commercially, were obtained by use of Hofmann degradation of the next higher dicarboxylic monoamid monoethyl esters. For use in biological tests, the omega-guanidino fatty acids were converted into ethyl esters, dimethylamides, sometimes also into methyl- or diethylamides. In isolated fat cells these compounds inhibit glucose oxidation. The inhibition increases with increasing chain length. For example, glucose oxidation (control 100%) is diminished by the dimethylamides of 9-guanidinononanoic acid to 70%, of 10-guanidinodecanoic acid to 62%, of 11-guanidinoundecanoic acid to 17% and of 12-guanidinododecanoic acid to 12%. The same compounds -- except the ethyl esters--depress the blood glucose levels in mice after intraperitoneal injection. Blood glucose levels between 30 and 10 mg/100 ml are reached and convulsions are observed. In the mice fall test, ca. 15-30 min post inj., the mice fall down; the blood glucose values of the fallen mice are hypoglycemic. The toxicity of the compounds examined is remarkably high; lethal dose per mouse (20 g) is 3-5 mg for the dimethylamides. It is obvious that a relationship exists between the inhibition of glucose oxidation in adipocytes and the depression of blood glucose level. The stronger the inhibition, the stronger the blood glucose lowering effect.
D000273:Adipose Tissue / Q000187:drug effects; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D005227:Fatty Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology*; D007004:Hypoglycemic Agents; D066298:In Vitro Techniques; D008297:Male; D051381:Rats
D000577:Amides; D004952:Esters; D005227:Fatty Acids; D006146:Guanidines; D007004:Hypoglycemic Agents; D005947:Glucose