Design And Synthesis 7 Small Peptide With Antihypertensive And Anti-inflammatory Activities Based On The Combination Of Traditional Chinese Medicine Molecular Chemistry

ACEI medicine like Captopril usually have side effect of dry cough,which considerably limits the clinical usage of those medicine.The side effects of dry cough are caused by the chronic use of ACEI to lead to the accumulation of bradykinin and the release of a large number of inflammatory factors.Traditional Chinese Medicine has applied the wisdom of Chinese nation for thousands of years and often recognized by the multi-target mechanism.Thus,by using of the multi-target mechanism of Chinese medicine,we could incorporate the effective structure of Western medicine and apply the notion of the Combination of Traditional Chinese Medicine Molecular Chemistry(CTMCT)to build an effective way to design “specializing on one sydrome with multi-effects" drug molecule.In the present thesis the active structure of ACE(Angiotensin converting enzyme,angiotensin converting enzyme)was induced by the structure analysis of the commonly used clinical drug molecules of ACEI,and 7 small molecular peptide were synthesized guided by the strategy of CTCMMC and the combination of drug molecular chemistry.After activity tests in vivo and in vitro,these molecules showed good activity.At the same time,the bradykinin induced mouse pneumonia model was constructed to investigate the effect of the candidate active compounds on the inflammatory factors and to indirectly explain the improvement on side effects of the dry cough.The full text is divided into the following three parts:1.Based on the stratergy of CTCMMC,7 small molecular peptide were designed and synthesized by using ACE as the target and introducing the structures of phenolic acids such as Danshensu.Themolecular structures of compounds are confirmed by MS IR and NMR spectra.2.In vitro inhibitory activity test of ACE,6a~6g compounds had inhibitory effects on ACE in a dose dependent manner.The inhibition rate of individual compounds in10μmol/L could reach 50%.In vivo studies have shown that 6a~6g compounds all could reduce the SBP of SHR.And the hypotensive amplitude of 6a~6g compounds could reach 40 mm Hg at 30 mg/kg dose.In particular,compounds 6a and 6g had advantages of prolonging the time of lowering blood pressure,decreasing the amplitude of lowering blood pressure and decreasing heart rate.The above results proves that this strategy could be used as a reference in the modification of small molecular structure of Chinese medicine.3.A nasal drip of bradykinin solution was used to induce lung inflammation in the nasal cavity of mice,and the compound was administered at the same time.The results showed that the infusion of bradykinin solution in the nasal cavity could significantly increase the content of TXA2 inflammatory factors in the lungs.Compared with the blank group,the female was more sensitive than the male.On the basis of female pneumonia Captopril had no inhibitory effect on TXA2,while synthetic compounds 221s(2,9)and 6a had inhibitory effects.The inhibition of 221s(2,9)compounds with Borneol structure was better than that of 6a compounds without borneol,which could serve as alternative compounds for ACEI’s side effect of dry cough.in the future.