Abstract
The growing interest in anticancer hybrids in the last few years has resulted in a great number of reports on hybrid design, synthesis and bioevaluation. Many novel multi-target-directed drug candidates were synthesized, and their biological activities were evaluated. For the design of anticancer hybrid compounds, the molecules of stilbenes, aromatic quinones, and heterocycles (benzimidazole, imidazole, pyrimidine, pyridine, pyrazole, quinoline, quinazoline) were applied. A distinct group of hybrids comprises the molecules built with natural compounds: Resveratrol, curcumin, coumarin, and oleanolic acid. In this review, we present the studies on bioactive hybrid molecules of a well-known tubulin polymerization inhibitor, combretastatin A-4 and its analogs with other pharmacologically active entities. The mechanism of anticancer activity of selected hybrids is discussed considering the structure-activity relationship.
Highlights
A great number of diseases, such as cancer, cardiovascular disease, diabetes, and neurodegenerative diseases, are caused by a combination of genetic and environmental factors
To deal with mutations contributing to drug resistance, the preparation of hybrid compounds with entities of different mechanism of action seems to be more effective than using a single agent
The growing interest in anticancer hybrids in the last few years has resulted in a great number of reports on hybrid design and synthesis [4,5,6,7]
Summary
A great number of diseases, such as cancer, cardiovascular disease, diabetes, and neurodegenerative diseases, are caused by a combination of genetic and environmental factors. The design and synthesis of molecules that are hybrids of different bioactive compounds bound together by covalent bonds ensure the achievement of the multi-directional therapeutic effect. The innovative approach of hybrid design is to act with a single molecule on several biological targets with a high probability of better efficacy due to an additive or synergistic effect [1,2]. To deal with mutations contributing to drug resistance, the preparation of hybrid compounds with entities of different mechanism of action seems to be more effective than using a single agent. The search for more potent anticancer agents was focused on compounds which could overcome the drug resistance of cancer cells. The effect of 6 on tubulin polymerization in vitro and directly in SKBR3 cells was investigated Results of these tests confirmed a significant anti-microtubule activity of 6. TBhRe3lceealdlscwonasjuaglasoteinpvroevsteidgattoedb.eRaessturoltnsgofgtrhoewsethteinsthsibcoitnofirrfmorecdeall sliingnesifiscuacnht aasntRi-PmMicIr-8o2tu26bu(lleeuakcetimviitay),oNf 6C.I-MHo2r3eo(nvoenr,-flsmowallcycetollmluentrgycaannacleyrs)i,sNreCvIe-Hale4d60th(laatr,gine cceellllslutrnegatceadnwceirt)h, H6,CceTl-l1c1y6cl(ecoplroongrceassnicoenr)w, aUs2a5r1re(sCteNdSinctahneceGr2),/MMDpAha-Mse.BA-4l3l5o,f SthKe-MsixELd-e2riv(mateivlaensowmear)e, mOoVreCaAcRti-v8e, SaKgaOinVs-t3th(oevSaKrBiaRn3ccaenllcsetrh),anAaCgHaiNns,tCMACKFI--71,ceRlXlsF. 3B9o3th, SoNf t1h2eCse(creenllallinceasnccoemr),e MfroCmF-b7re(basret atustmcoarnsc, ebru),t
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