Design, Synthesis And Sar Study Of Novel Sulfonamide And Isoquinoline Derivatives As ARIs

Diabetes mellitus is a clinical syndrome caused by absolute or relative insulin deficiency. A lot of pathogenic factors such as genetic factors, microbial infection and their toxins, immune dysfunction and free radical toxins can lead to the dysfunction of islet or insulin resistance, resulting in metabolic disorders of sugar, protein, fat, water and electrolyte materials and causing the increased level of blood glucose. When the blood glucose level of diabetic patients is out of control, it would inevitably cause the so-called long-term complications such as retinopathy, neuropathy, renal microvascular lesion, coronary heart disease, stroke and so on. These complications not only severely affect the living standards of patients, but also put their lives in danger. Although numerous efforts have been made to treat these complications, the development of effective drugs used for these diseases is still a big challenge.In order to effectively treat diabetic complications, it is critical to understand their pathological mechanisms. However, due to the complexity of diabetic complications, fully understanding of these mechanisms is still unreachable. Until now, five possible pathological mechanisms of diabetic complications have been proposed. Among them, increased polyol pathway is reckoned as the most convincing pathogenesis as increasing proofs have revealed a link between glucose metabolism via the polyol pathway and longterm diabetic complications. It is supposed that the increased glucose in blood could lead to the abnormal enhancement of polyol pathway and the increased accumulation of sorbitol in cell, thus resulting in the occurance of diabetic complications. Aldose reductase(ALR2,EC1,1,1,21), a crucial rate-determining enzyme of polyol metabolic pathway, directly promotes the rapid accumulation of sorbitol. Therefore, aldose reductase inhibitors(ARIs), which can effectively inhibit the activity of ALR2, reveals great potential on the development of high potent therapeutic strategy for diabetic complications.Based on the latest research results of our laboratory, in this thesis, a series of sulfonyl group-containing compounds and isoquinoline derivatives as ARIs were designed and synthesized, and their biological activities was tested afterwards. Besides, I have been studied as a joint PhD student at Mc Lean hospital(a affiliated hospital to Harvard Medical School) from November 2013 to February 20115. During this period, I worked on the total systhesis of l-tetrahydropalmatine(l-THP) derivatives and this part of work is also included in this thesis.Firstly, three-dimensional quantitative structure-activity relationship studies(3DQSAR) of aromatic thiazide aldose reductase inhibitors were researched on the basis of our previous laboratory results to explore the interactions between aromatic thiazine derivatives and ALR2. The comparative molecular field analysis(CoMFA) and comparative molecular similarity index(CoMSIA) models was established under the condition of substructure superposition and molecular docking superposition, respectively. The CoMFA model crossvalidation coefficient q2=0.649 under molecular docking superposition indicates a very high predictability. The contribution of the steric field and electrostatic field were 74.4% and 25.6%, respectively, indicating that the steric field of the CoMFA model plays more important role than the electrostatic field. The CoMSIA model cross-validation coefficient q2 is 0.746 and the steric, electrostatic, hydrophobic, and acceptor fields contributed 12.3%, 24.2%, 41.9%, and 21.6%, respectively. Most of the compounds from both training set and test sets exhibit good correlation between actual and predicted values. The results of 3D contour maps revealed that C-2 and C-3 position of the benzyl ring are both steric and electronegative favored. Electronegative groups with limited steric hindrance such as NO2, CF3, CCl3 and CBr3 could be introduced to C-2 position while hydrophilic and electronegative groups like(CH2)nNO2,(CH2)nCF3, piperidine and piperazine with big steric hindrance may be favored by C-3 position. Besides, the introduction of hydrophilic and less bulky substituents(e.g. OH, F and Cl) at the C-5 positions of benzothiazine-1,1-dioxide core might be favorable for improving the biological activity. Hydrophobic and electronegative groups at the C-7 position of benzothiazine-1,1-dioxide core are suggested to be beneficial for higher aldose reductase inhibition.Secondly, rational modifications at the C-7-position of benzothiadiazine 1,1-dioxide derivatives were conducted under guidance of the three dimensional quantitative structureactivity relationship study in search of more effective aldose reductase inhibitors. Evaluation of the compounds for their inhibitory potency against aldose reductase showed that compound 2-(7-(diethylcarbamoyl)-1,1-dioxido-2-(2,4,5-trifluorobenzyl)-2H-benzo[e][1,2,4]thiadiazin-4(3H)-yl)acetic acid(73l) was the most active and has to present excellent selectivity. Structure-activity relationship analysis and molecular modeling studies highlight the importance of hydrophobic and bulky groups at the C-7-position. The substituted benzyl ring fitted well into the specificity pocket and the benzothiadiazine 1,1-dioxide core got trapped in the hydrophobic cage, which in turn led to the placement of the relatively bulky 7-diethylcarbamoyl substituent in the deep hole of the hydrophobic cage formed by Phe121, Phe122, Gln49 and Val47. The core together with the bulky 7-substituent could be accommodated by the hydrophobic cage probably due to the relatively open space of the pocket suggesting that the pocket may also play an important role in binding with ligand.In order to extend the ARIs structures of sulfonyl class, we designed and synthesized a new type of benzene sulfonyl aldose reductase inhibitors on the basis of benzothiadiazine skeleton. The aldose reductase inhibitory activities were tested and the structure-activity relationship was discussed. It is found that compound(2,4-dimethyl-6-(N-methyl-N-(3-nitrobenzyl) sulfamoyl) phenyl)glycine(81a) showed the highest biological activity(IC50 value up to 790nm), with a nitro group introduced on the benzyl ring. Molecular docking experiment results between ALR2 and compound 81 a indicated that the nitro group could hydrogen bond with residues Thr113 and Cys113. Sulfonic acid ester structure didn’t contribute as much to the biological activity as sulfonamide compounds. The substituents on the N atom type of sulfonamide compounds also have an influence on the biological activity. When methyl group was connected to the N atom, it showed the highest activity. The ranking order of the compounds displaying top levels of ALR2 inhibitory activity is methyl>ethyl>H.The systhesis research of l-tetrahydropalmatine(l-THP) derivatives during my study at McLean hospital of United States was introduced afterwards. In order to develop a useful drug for the treatment of cocaine addiction and to help explore the mechanism of alkaloids l-THP and its derivatives in treating cocaine addiction, 16 to 18 steps of reactions were conducted to totally synthesize l-THP and its derivatives, with a yield of 3%-5%. Since some alkaloid compounds showed certain aldose reductase inhibitory activity, we tested the aldose reductase inhibitory ability of l-THP and its derivatives for the first time. Structure-activity relationship shows that the phenol hydroxyl in the D ring contributed more in improving the biological activity than the A ring. Then, we studied the radical scavenging ability of l-THP and its derivatives using the free radical 1,1-diphenyl-2-trinitrobenzene hydrazine(DPPH) model, with water-soluble vitamin E(Trolox) acting as the positive control. We found that all compounds with phenolic hydroxyl groups on the benzene ring showed strong antioxidant capacity. Compound l-5 with two phenolic hydroxyls showed the strongest antioxidant activity, surpassing the positive control(vitamin E). l-THP and its derivatives can be used as lead compounds to develop double function compounds with both antioxidant activity and aldose reductase inhibitory activity.