2 - Acyl-five Unsaturated Heterocyclic Compounds And Their Anti-osteoporosis And Anti-diabetic Activity

By using MC3T3E1 cells transfected by recombinant plasmid PMB which targeted bone morphogenetic protein-2 and HepG2 cells transfected by expression vector pBIND-PPAR_γ-LBD,synthetic compounds and natural compounds were screened to evaluate the antiosteoporosis activities and the antidiabetic activities in vitro. 2-acetyl-benzothiophene and 2-(β-carbonylbutyryl)furan were found to have antiosteoporosis activity and antidiabetic activity respectively.With 2-acetyl-benzothiophene and 2-(β-carbonylbutyryl)furan as lead compounds, structure modification was carried out.31 compounds were synthesized.21 compounds of the synthesized compounds and 70 compounds from compound library were evaluated for their antiosteoporosis activities and antidiabetic activities in vitro and in vivo. In vitro,77compounds were found to have antiosteoporosis activities.The activities of compounds G31,G38,G28,Shy-B13,G30,Shy-B15,Shy-A39,G13,G25,G26,ShyS4, G24,G35,G32,G33 and G34 were more than 5 times of positive control Lovastatin.23 compounds were found to have antidiabetic activies.The up-regulation activities of Shy-B10,Shy-A12,Shy-A27,Shy-A38,Shy-S2 were more than 30%,the up-regulation activities of Shy-B8,Shy-A29 were more than 40%.In vivo,before the evaluation of antiosteoporosis activities of 2-acetyl-benzothiophene was carried out,the toxicity of the compound was detected.The intragastric administration LD₅0 of the compound was more than 5g/kg,the intraperitoneal injection LD₅0 was more than 1.6g/kg.Dramatic antiosteoporosis effects of 2-acetyl-benzothiophene and 2-acetyl-benzofuran were found,especially, 2-acetyl-benzothiophene at high dose had comparable effect with positive control Raloxifene.The antidiabetic effects of Shy-A12 and GHF were found.At 75mg/kg dose, Shy-A12 and GHF lowered fast blood glucose in mice,especially,Shy-A12 had comparable effect with positive control Rosiglitazone.The antiosteoporosis activities of 2-acetyl-benzothiophene and 2-acetyl-benzofuran,and the antidiabetic activity of Shy-A12 were first found.2-acetyl-benzothiophene, 2-acetyl-benzofuran and Shy-A12 had the potential to be the lead compound for antiosteoporosis drugs rsearch and antidiabetic drug research respectively.