| n the course of treatment of cancer patients, the phenomenon performance ofmultidrug resistance (multidrug resistance, MDR) has now become the main obstacleto cancer treatment. The mechanism of MDR is complicated, but the over-expressionof P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and breastcancer resistance protein(BCRP)is one of the important mechanisms. Overexpressionof P-glycoprotein is the earliest and most in-depth study mechanism of multidrugresistance. Searching for efficiency, low toxicity, specificity MDR reversal agents hasbecome one of the hotspots in anticancer research field.Many studies have found that the polyphenol compounds of natural low toxicityshowed significant anti-tumor and reversal activity to multidrug resistance.Preliminary study of our group found that the full methylation EGCG and fullmethylation quercetin derivatives have high MDR reversal activity. Aimed to developthe structure-activity relationship of designed flavonoids reversing multi-drug oftumors and investigate the influence of three-dimensional structure and carbonyl of C-ring, we select dihydromyricetin as the research object. Dihydromyricetin (DMY) isa polyphenol flavonols. Compared with structure of EGCG dihydromyricetin containscarbonyl in the C-4bite of C-ring, but the presence of double bond in C-ring ofquercetin makes the A ring and C ring in the same plane. Combined with thestructural characteristics and activity of EGCG and quercetin analogues, we havedesigned and synthetized14methylation dihydromyricetin analogues and test tumorMDR reversal activity. The activity test results show that the1.0μm compound of28,29,31can reverse resistance to Taxol (paclitaxel) of LCC6MDR cells, with the RF being9.5,10.5,16.2respectively, which is significantly higher activity than thepositive control sample verapamil（RF=3.3）.β-lactam antibiotics are the most widely used class of antibiotics clinically, but theemergence of bacterial β-lactamases and the abuse of antibiotics cause the resistanceof bacterium to Beta-lactam antibiotics. The New Delhi Metallo-β-lactamase (NDM-1)was first reported in2009in a Swedish patient, who travelled to New Delhi andacquired a urinary tract infection caused by Klebsiella Pneumonia. A recent studyreported that NDM-1positive strain was highly resistant to all antibiotics testedexcept tigecycline and colistin, NDM-1now becomes potentially a major globalhealth threat. So searching for the safe and effective β-lactam inhibitors is imminent.The NDM-1active site contains two zinc ions, wherein the second zinc ion playsa very important role in the process of hydrolysis of β-lactam antibiotics. Thereforecombining with zinc ion to inhibit the activity is one of the mechanisms of design ofβ-lactamase inhibitors. A large number of experiments have found that a variety ofcompounds has a certain inhibitory effect to the metal lactamase, such as biphenyltetrazole class, carbapenems, sulfhydryl compounds and derivatives of succinic acid,et al, the mercapto group, carboxyl group and phosphoric acid group of compoundshave strong binding force with zinc ions. Based on hydrolytic mechanisms we design66compounds and43hydrolysis on account of the basic nucleus of sulbactam,tazobactam and succinic acid. Subsequently, we establish a database composing of109compounds and17drug molecules and then use sulflex-dock modules ofcomputer-aided drug design software sybyl-X2.0for docking and virtual screening.Results show that the binding activity of the compound LT-3-SJ is the highest (15.38),which is higher than the binding activity of the ligand hydrolysis of ampicillin (15.10).We study the binding mode of LT-3-SJ and3Q6X, providing certain idea for furtherdesign and development of the new NDM-1inhibitors. |
PDF Full Text Request