Design, Synthesis And Preliminary Study On Antidiabetic Activitie Of β-amino Ketone And L-tyrosine Derivatives

Diabetes (Diabetes Mellitus, DM) is a kind of endocrine and metabolic diseases characterized by hyperglycemia and endangered the health seriously. It is the third-largest noncommunicable chronic diseases worldwide. The total number of diabetic patients in China has been riseed to the second in the world, only behind India. As a serious noncommunicable chronic disease, DM has become a key public healthy problem concerned by every country in the world. Therefore, it is an urgent mission to research and develop some new antidiabetic drugs.β-amino ketones has various biological activities such as anticough antibacterial, anti-inflammatory, anticancer, antivirus, sedation, analgesia, hypotension, edema inhibition, anti-coagulation, anti-tuberculosis, anti-androgen and carbonic anhydrase inhibitory activity. It is rational to study the effects of such compounds in synthetic methods and applications. Our group studied the antidiabetic activity ofβ-amino ketone compounds for the first time. It's found that someβ-amino ketones possess many pharmacological activities such as inhibitα-glucosidase, activate the peroxi- some proliferator-activated receptor response element (PPRE), and also can use as insulin sensitizer or protein tyrosine phosphatase 1B (PTP1B) inhibitor. Based on the previous results, six kinds ofβ-amino ketones (TM-1 - TM-6) were designed and synthesized by modified the molecular structures of the active compounds according to drug design principles.Their general chemical structures as following: In this paper, sulfonamides, sulfamethoxazole and other structure units were introduced into the designedβ-amino ketone Mannich bases with three kinds of aromatic ring for the first time. Moreover, the preparation conditions ofβ-amino ketones were investigated systematically and the optimum condition and general synthetic method of this type of compounds were obtained successfully. The target compounds were synthesized directly in ethanol or ethanol/chloroform solution catalyzed by concentrated hydrochloric acid at room temperature. Eighty eight target compounds including eighty six new compounds were prepared in the yields of 30.7% -97.5%. Their chemical structures were confirmed by ¹H NMR, ¹³C NMR and ESI MS, some of them were further verified by IR and HR MS.Thiazolidinedione (TZD) drugs is one of the first-line treatment drugs for typeâ…¡diabetes. Many research results showed that only the S-configuration of the class of TZDs drugs can bind to PPARγwith high affinity. However, TZD agents only exist as racemic compounds in physiological conditions, thus it indicated that only 50% TZDs can bind to PPARγeffectively and favourablly. So far, some synthetic derivatives of L-tyrosine existed in the natural S-configuration is the PPARγagonist with the highest efficacy, which have been potential drug candidates. Based on the previous research results worldwide, we designed two types of target compounds (TM-7 - TM-12) with L-tyrosine as parent nucleus following the principle of drug design, hope to improve the lipophilicify part and investigate the correponding biological effect of esterification, saponification and dissociation of carboxylic group . A-type target molecule (2S)-methyl 2-(2-((9H-fluoren-9-yl)carbonylamino) -2-alkyl-acetamido)-3-(4-butoxyphenyl) propanoate (TM-7) were prepared in yields of 38.4%-69.2% starting from L-tyrosine via five-step reactions including the methyl esterification of carboxylic group, protection ofα-amino group, alkylation of phenolic hydroxyl group, deprotection of the amino protecting group and coupling reaction ofα-amino with the selected Fmoc-AA-OH. Then the B-type target molecule (2S) -methyl 2-alkyloxyamido-3 {4-[(alkylamino-1-yl) ethoxy]phenyl} propanoate (TM-10) were synthesized in yields of 18.9%-57.4% starting from L-tyrosine by the sequentially reaction of the methyl esterification of carboxylic group, modification ofα-amino group, bromoethylation of phenolic hydroxyl group, and then nucleophilic substitution reaction with the selected amine reagent. The hydrolysis of compounds TM-7 and TM-10 give other target compounds TM-8 and TM-11, and dissociation of carboxylic group afforded target compounds TM-9 and TM-12. On the whole, ten intermediates (including four new substances) and seventy two new target molecules were obtained. Most of the synthetic methods were by virtue of simple reaction conditions, high yields, and green chemical properties. The structures of all target compounds were confirmed by ¹H NMR, and some of the products were also verified through ¹³C NMR, ESI MS and HR MS.The biological activities ofβ-amino ketone Mannich bases were investigated preliminarily . (1) The results ofα-glucosidase inhibitor screening test revealed that theα-glucosidase inhibitory activity (50%-79.7%,10μg·mL^-1)of compounds 1e, 1g, 4b, 4h, 4k, 5d, 5e and 5n exceeds 50% of that of acarbose with concentration of 10 times(100μg/mL, 74.12%). The best compound was 5e withα-glucosidase inhibitory activity of 79.7%. (2) The results of PPRE activity displayed that PPRE agonist activity of 11 compounds (2d, 2i, 2j, 3b, 3e, 3f, 3i, 3k, 3m, 3p and 4n) reached 50% compared with that of 20-fold concentration of rosiglitazone, and the best result reached 86.7% obtained from compound 2j. The PPRE agonist activity of five compounds (2c,4d,4f,4m,4o) were more than 50% compared with that of 10-fold concentration of rosiglitazone, of compound 3m reached 135.5%. (3) The results of insulin-sensitizing activity showed that four compounds (1a,1d,1f and 1k) have insulin-sensitizing activity (241%-129%, 10μg·mL^-1) which was far more than that of 10 times concentration of rosiglitazone (100%, 100μg·mL^-1). Moreover, there were seven active compounds (5i,5l,6g,6h,6j,6l,6m) has reached more than 60% compared with that of 10 times the concentration of rosiglitazone's insulin-sensitizing activity. (4) The results of protein tyrosine phosphatase 1B inhibitory activity screening exhibited that the activity of compound 4k was 74.6%(10μg·mL^-1), and the control drug (sodium vanadate) was 93.31%(100μg·mL^-1) ; the inhibitory activity of compound 3d and 4l also reached 38.99%, 39.85%,respectively.The biological activities of target compounds (TM-7 - TM-12) with L-tyrosine as the parent structure are under way.In this paper, 9 intermediates and 160 target compounds were synthesized, among them there are 162 new compounds (including four intermediate). The antidiabetic activities ofβ-amino ketone Mannich bases were tested and the structure-activity relationships were also discussed. Some of the compounds showed good antidiabetic activity which worth further investigation. These results provided a new direction for further study on the antidiabetic drug with high efficacy and low toxicity.