Design, Synthesis And Antitumor Activity Of Camptothecin Sulfonyl Derivatives Modified At The 20(S)-position

The camptothecin topoisomerase I-targeting agents are new class of antitumor drugs with demonstrated clinical activity in human malignancies,such as bone cancer,liver cancer,bladder cancer and leukemia,etc.Currently,the camptothecin derivatives,irinotecan and topotecan,which were optimized from camptothecin as lead compound,and they were thus successfully utilized in the treatment of a variety of cancers.Some newer camptothecin analogs are also being clinical developed.In order to obtain better therapeutic agents with high biological activities and simultaneously circumvent,the limitations associated with camptothecin or develop a series of analogues with broader therapeutic scope.Sulfonyl compounds such as sulfonyl amidine,sulfonyl urea and sulfonamide compounds have good antitumor activities,sulfonyl derivatives of camptothecin at 20 position were designed and synthesized.This thesis mainly involves the following three aspects.1.Design,synthesis,antitumor activity and mechanism of action study of camptothecin sulfonylamidine derivatives modified at the 20-position.(1)YQL-9a,20-camptothecin sulfonyl amidine,was previously synthized in our laboratory.It showed good antitumor activity by testing the in vitro antitumor activities,and its revelant cells of KBvin IC50 value concentration of 0.026?M.Three components of reactions catalyzed by copper synthesized 20-camptothecin sulfonyl amidine and the structure-activity relationship were studied by changing the three components of camptothecin matrix,sulfonyl azide,acetylene,and amino acids.A total of 37 compounds were synthesized,and revelant in vitro of A-549,DU-145,KB,KBvin,MDA-MB-231 tumor cell lines of inhibitory activity were tested.The results showed that the 20-camptothecin sulfonyl amidine compounds have good antitumor activity.Among them,the derivative of wcpt-03 showed the best antitumor activity,and is superior to the irinotecan and camptothecn.Changing of antitumor activity and camptothecin matrix has made great influences,derived from the seven replace enhance activity,12 instead of reduce the activity.(2)Mechanism of action studies on YQL-9a.Induction of apoptosis by YQL-9a in human tumor cells.After exposure to YQL-9a,A-549 cells showed apoptotic morphological features,including cell shrinkage and membrane blebbing.Apoptosis induction was further confimed by double staining with FITC-annexin V and propidium iodide,showing that YQL-9a treatment increased the percentage of apoptotic cells.Western blot analysis showed that cleaved caspases,the executors of apoptosis,were formed in response to YQL-9a,including caspase-8,-9,and-3.The above data demonstrated that YQL-9a via induction of apoptosis to inhibit the growth of tumor cells.Activation of DNA damage response pathway by YQL-9a.Compound YQL-9a directly inhibits Topo I activity and depresses Topo I expression,which induces cellycle delay at S phase as well as activation of DNA damage-response pathway,and subsequently activates apoptosis pathway.We have enough of these data show YQL-9a is superior to the parent compound carmptothecin,showed that YQL-9a is a highly potential antitumor drug candidates.Therefore,we further study the YQL-9a in vivo antitumor activity and toxicological evaluation.Antitumor activity of YQL-9a in vivo.Xenograft model antitumor assay using human colorectal adenocarcinoma cell line HCT116.YQL-9a at 5mg/kg(P<0.01)and lOmg/kg(P<0.001)exhibited significant antitumor activity in vivo without overt signs of symptom and anaphylactic reaction.Toxicological evaluation of YQL-9a in mice.YQL-9a treated animals showed no adverse effects according to hepatic,splenic,kidney and lung parameters.Thus,the animals apparently tolerated treatment with 300 mg/kg of YQL-9a,portending an acceptable safety profile.YQL-9a is a worth to clinical antitumor medicine through the above studies of YQL-9a.2.Design,synthesis and antitumor activity of camptothecin PEG sulfonylamidine derivatives modified at the 20-position.To solve the problem of camptothecin solubility,we had introduced the polyethylene glycol to the molecular of camptothecin.Firstly,the polyethylene glycol monomethyl ether in terminal alkyne was synthesized,three components reactions catalyzed by copper synthesized 20-camptothecin PEG sulfonyl amidine.Secondly,the in vitro antitumor activities of A-549,KB,KBvin,MDA-MB-231,HCT-116 and SKOV-3 were tested.The results showed that antitumor activities of compounds WPEG-31 and WPEG-26 were better than that of the parent compound.What's more,the water solubility of camptothecin were obviously improved,while maintaining the antitumor activity.The larger the PEG molecular weight,the lower the toxicity.3.Design,synthesis and antitumor activity of camptothecin sulfonamide,sulfonylurea derivatives modified at the 20-position.Sulfonamide and sulfonylurea compounds have good antitumor activities,some of which with diversities of anti-tumor mechanism have been applied clinically.20-camptothecin sulfonamide and 20-camptothecin sulfonylurea were synthesized by introducing sulfonamide and sulfonylurea groups respectively through oriented-synthesis strategy.The antitumor test is now in progress.