Design, Synthesis And Biological Activity Of Berberine And N-(2-arylethyl) Isoquinoline Analogues

Berberine (BBR) is a natural compound with up-regulating expression on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR), and also exhibiting an ideal activity on activating AMPK. It increases low-density-lipoprotein receptor (LDLR) expression by stabilization of LDLR mRNA. In addition, We have discovered insulin receptor (InsR) to be another key target of BBR. BBR activated the promoter of InsR gene through a protein kinase C (PKC) pathway, increased the expression of InsR in liver and muscle cells, and therefore enhanced glucose consumption. So BBR shows a great potential on treating metabolic syndrome (MS). With BBR as lead,15 analogues were synthesized, the activity of up-regulation on LDLR, InsR mRNA expression and AMPK activating activity were examined. Taken the previous results together, we improved and completed the SAR based on these screening models.To disscuss the mechanism of action for BBR in vivo,4 metabolites (M1-M4) of BBR were synthesized. M1 exhibits an ideal activity on up-regulating LDLR and on activating AMPK. Therefore, the hydroxyl makes it possible to construct pro-drugs at the 9-position.During the process of BBR analogues synthesizing, we discovered another category of isoquinoline, N-(2-arylethyl) isoquinoline occasionally. The way for synthesizing them was limited, and the activity of N-(2-arylethyl) isoquinolines has not been reported. So we elucidate the mechanism of the synthesis for BBR analogues and N-arylethyl isoquinoline derivatives, and synthesize the definite derivative based on the mechanism. A novel and convient method for the synthesis of BBR derivates and N-(2-arylethyl) isoquinoline using glyoxal as the "two-carbon unit" was invented. The formation of ring C follows the orientation principle of the Friedel-Crafts reaction with regard to both kinds. The ring B of BBR analogues forms based upon the principle of the Pictet-Spengler reaction. It is an improvement to the classical methods of isoquinoline synthesis.Different substituents on ring A and D could determine the category of the final product. The ortho-para directing group at the 10-position of ring D is of assistance to the formation of the aromatic ring C. The activating group (alkoxy in this paper) at the 3-position of ring A is essential to form ring B. And then,63 derivatives were synthesized to prove these principles.After screening, SAR analysis of N-(2-arylethyl) isoquinoline derivatives for CD36 antagonists was carried out. The results suggested that introducing suitable activating groups at the ring A might increase inhibition activities for the receptor. Methoxy at the 3-position helps retain the activity, and electron donating groups at the meta position of ring D enhance the activity while electron withdrawing groups reduce it. Meanwhile, when ring D was bis-substituted the activity was much higher. When hydroxyl at the 14-position was introduced, the activity might be weakened. Compounds W9, W50 and W56 showed outstanding activities than the positive control. The IC50 of these three derivatives were 0.18,0.27 and 0.77 respectively which encouraged us to do more researches in-depth afterwards.N-(2-arylethyl) isoquinoline derivatives showed certain activities upon COX-B3 virus. W18 and W21 were screened out with 2.6 and 4.5 folds of the positive control-RBV via the selective index datas. We consider the compound W18 and W21 promising candidates for further investigation in vivo.179 compounds were synthesized, and 81 of them were target compounds. What's more,77 among them were new compounds. Their structures were confirmed by MS, 1H NMR and IR. Parts of the work were published on BMCL (2009).