Dissertation > Medicine, health > Pharmacy > Pharmacology

Design, Synthesis and Preliminary Activity Evaluation of Anticancer Compounds Based on the Structure of XIAP

Author TanZuLei
Tutor NieAiHua
School PLA Military Academy of Medical Sciences
Course Medicinal Chemistry
Keywords Cancer XIAP inhibitor drug design synthesis SAR
Type Master's thesis
Year 2008
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XIAP(X-linked inhibitor of apoptosis protein)has been discovered as a new potential target for treating cancer in recent years.It has been demonstrated that XIAP is over expressed in many cancer cells such as leukemia,lung cancer cells,prostate cancer,ovarian cancer and so on,significantly higher than in normal tissue,and is also a fundamental reason for causing a variety of tumor cells resistant to chemotherapy drugs.In addition,XIAP plays an important role in cell proliferation and the transformation of normal tissue to malignant cell.And at the same time,the inhibition of XIAP plays an active role in the sensitivity of cells to chemotherapeutic drugs and blocking malignant transformation.So far,five different structures of XIAP inhibitors have been reported and demonstrated their activity of anticancer.Except for an antisense oligonucleotide inhibitor(AEG 35156)developed by Canada Aegera has entered clinical phaseⅡ,the rest of XIAP small molecular inhibitors are under preclinical way or enter clinical research in the near future.Combining the modeling method of computer-assisted drug design and the structures of XIAP inhibitors reported in literature,a basically structural pattern of small molecular XIAP inhibitor was proposed in this research.We analyzed the critical structural characteristic of interaction between caspase-9 N-terminal ATPF and XIAP BIR3.By this characteristic XIAP inhibitors can intercept the interaction. Based on this information above and reported structure-activity relationship of XIAP inhibitors,a combinatorial library containing 210 compounds,which belonged to two different structures,was designed.These compounds were screened virtually by a docking method.In this research,Two different synthetic strategies were chosen to prepare these compounds.Twenty compounds among the combinatorial library were synthesized by using this two strategies.These compounds are not reported so far in the literatures. Their structures were confirmed by 1H-NMR and MS.The reaction condition of every step including in the two synthetic strategies was investigated in detail.Especially, three different synthetic methods were used to prepare the critical intermediates secondary amines.We found that the synthesis of different structural secondary amines should use different method of reducing amides.We also found that the condition of amides containing thiazolidine acid reacting amino acids was different from acyclic amino acids reacting amino acids.A MTT method was employed to evaluate inhibitory activity of target compounds on SKOV3 ovarian cancer cells in vitro.The results showed that seven compounds,including TZL071215,TZL071125-1,TZL0429-2,TZL080428-1, MXG071223,TZL080421 and TZL08427-1,had inhibitory activity against SKOV3 ovarian cancer cells in some degree at the concentration of 100μM.The activity of two compounds,TZL071215 and TZL0429-2,was more potent than that of control compound Embelin at the concentration of 200μM.The inhibitory rate of these two compounds was 100.34%and 97.67%and the IC50value was 75.87μM and 110.41μM respectively.The inhibitory rate of Embelin was 61.50%at the at the concentration of 200μM.The SAR of the inhibitory activity of these compounds against SKOV3 ovarian cancer cells was analyzed preliminarily.The result are as follows:(1)The volume of the side chain R1 in the structureⅠandⅡshould not be small,isopropyl,isobutyl, tert-butyl and other aliphatic branched-chain with 3 to 5 carbon atoms are suitable;(2) The Removal of thiazodine acid,a non-natural amino acid,from the designed compound has little effect on the activity;(3)the benzyl or phenylethyl are still preserved as R2 substitute;(4)R3 is either the line aliphatic chain,but the length of carbon chain has specific requirements,too Short or too long is not suitable,4 to 5 is best.or the big aromatic hydrophobic groups,which is comparatively favourable for activity.This research has preliminarily proved our design ideas was feasible and laid the foundation for further research.

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