Design,Synthesis And Antitumor Activity Of Novel Quinolone-Based TopI Inhibitors

Among heterocyclic compounds,quinoline scaffold has become an important construction motif for the development of new drugs.Quinoline and its derivatives possess many types of biological activities and have been reported to show significant anticancer activity,and the Top I inhibitor based on quinolines is the research focus of current anti-tumor drugs.As the first quinolone-based alkaloid Top I inhibitor,camptothecin has a broad spectrum of anti-tumor activity,which is mainly used for the treatment of colon cancer,ovarian cancer and leukemia cancer.So far,there are a large number of camptothecin derivatives have been synthesized.As the result of research efforts,two CPT analogs,Topotecan and Irinotecan were received governmental approval for the clinical treatment and eleven additional analogs were currently under clinical evaluation.Despite excellent selectivity and specificity,camptothecins have been faced with a few clinical and pharmacological limitations as mentioned in the previous section.This has promoted the development of the Top I inhibitor of non-camptothecin to some extent.the Top I inhibitors of non-camptothecin are mainly included in two categories:indenoisoquinoline and ARC-111,and the high active molecular NSC725776 and NSC724998 have been entered into the clinical research.The indenoisoquinolines overcome many of the drawbacks associated with the camptothecins,with improvements that include:?1?greater chemical stability;?2?The antitumor spectrum is different from Camptothecin.;?3?longer residence times in the binding site;?4?diminished or abolished ejection by the ABCG2 and MDR-1 drug efflux pumps.This report details the structured-based design,synthesis and biological evaluationcamptothecin,ARC-111and indenoisoquinoline as Top I inhibitors.It involves the following four research contents:Part I:IntroductionThe present investigation details the structure-based design,synthesis,and biological evaluation of the existing quinoline Top I inhibitors.Part II:Design,synthesis,antitumor activity and action mechanism of diphosphorylat-ed camptothecin derivatives.Prodrug can effectively improve the physicochemical properties and its bioavailability in vivo,and biphosphorylation of drugs is one of important forms of prodrug.In this chapter,phosphate ester is combined with the amino acid ester of camptothecin through a multicomponent reaction.The activity test showed that the compound B-07 was superior to the cytotoxic activity of Irinotecan,and the IC₅₀ value of human lung adenocarcinoma cell?A549?was 0.391?M;Anti-tumor mechanism experiment showed that the compound B-07 could inhibit Topo I and inhibit cell growth by inducing cell cycle arrest and apoptosis.Part III:Design,synthesis,and Evaluation of fluorinated Dibenzo[c,h][1,6]naphthyridines as Topoisomerase I Inhibitors and Potential Anticancer AgentsThe role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication.The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons,the hydrogen atom,and the methyl group while also acting as a functional mimetic of the carbonyl,carbinol,and nitrile moieties.The judicious introduction of fluorine into a molecule can productively influence conformation,pKa,intrinsic potency,membrane permeability,metabolic pathways,and pharmacokinetic properties.In this study ARC-111 and their fluorinated derivatives were synthesized and assessed for their relative cytotoxicity against four human tumor cell lines.The activity test showed that the compound 4d showed superior cytotoxic activity compared with topological tikang,and its IC₅₀ value of A549 cells in human non-small cell lung cancer reached 0.00481?M.Part IV:Design,synthesis and cytotoxic activity of novel spin-labeled indenoisoquinoline derivativesStudies have shown that the introduction of a stable nitroxyl radical into pharmaceutical molecules can cut down the toxicity and potentiate the antitumor effects to a certain degree.And the introduction of nitroxyl moiety can lead to fast decomposition,higher alkylating and lower carbamoylating activity,better antimelanomic activity,lower general toxicity,and the ability to transport through cell membranes,while the nitroxyl free radicals themselves possess low toxicity and are not mutagenic or carcinogenic.In this chapter a series of novel spin-labeled indenoisoquinoline derivativeswere were synthesized and assessed for their relative cytotoxicity against four human tumor cell lines.The activity test showed that the compound X22 showed a cytotoxic activity similar to Topotecan,and its IC₅₀ value for human breast cancer cells?MCF-7?was 0.323?M.