Synthesis Of Novel Cyclen Azole Compounds And Their Researches In Chemical Biology

1,4,7,10-tetraazacyclododecane(cyclen) contains four nitrogen atoms,could coordinate with transition metal ions and lanthanide ions to form complexes,and also could be functionalized with various multifunctional groups,thus cyclen derivatives exhibit wide use as luminescent probes,DNA cleavage agents,enzyme models,Magnetic Resonance Imaging(MRI) contrast agents as well as radioimmunotherapy.In this thesis,based on the current research situation of macrocyclic polyamines,a series of novel cyclen azole compounds were designed and synthesized,their metal complexes were prepared,and their chemical biology properties including catalytic hydrolysis by mimicking carbonic anhydrase,DNA cleavage,supramoleculer recognization as well as antimicrobial activities in vitro were investigated.Cyclen as the starting material was protected by di-tert-butyl dicarbonate(Boc₂O),coupled with xylene bromide or pyridine methylene dibromide,and then reacted with a series of azole compounds to afford protected novel cyclen triazole,imidazole,pyrazole,benzimidazole derivatives. After deprotection by HBr,these novel cyclen azoles were coordinated with Zn(â…¡) or Cu(â…¡) ions to form corresponding cyclen mono-azole and di-benzimidazole complexes.Thirty nine compounds including 33 new ones were synthesized.These structures of new cyclen azoles and their Complexes were confirmed by ¹H-NMR and MS spectra as well as elemental analyses.Ten metal complexes including five cyclen mono-imidazole complexes and five cyclen mono-benzimidazole complexes were employed as carbonic anhydrase models to catalyze the hydrolysis of PNPP(p-nitrophenyl picolinate).The results showed that all these complexes could efficiently hydrolyze the PNPP on physiological conditions.The hydrolytic rates of the PNPP catalyzed by cyclen benzimidazole complexes were 14.2-43.7 fold compared with non-catalysis, and 11.5-86.9 fold by cyclen imidazole complexes. The supramolecular recognition abilities of 4 cyclen monoazole complexes and 2 cyclen dibenzimidazole complexes to bases and nucleosides were investigated.The results revealed that(1) some tested cyclen monoazole and dibenzimidazole complexes exhibit good supramocular recognition.(2) The host compounds could form 1:1 or 1:2 supramolecular complexes with the guests.(3) The cyclen mono-azole Zn(â…¡) and the cyclen di-benzimidazole Zn(â…¡) complexes with m-phenylene spacer could recognize the cytosine significantly.The DNA cleavage experiments showed that most of the cyclen monoazole and dibenzimidazole complexes could cleave efficiently DNA(pUC18) on physiological conditions,and hydrolyze the DNA to produce Form(â…¡) type in short time.The antimicrobial activities of cyclen azole complexes in vitro displayed that the cyclen mono-azole complexes had antibacterial and antifungal activities,and the cyclen dibenzimidazole complexes possessed significantly antibacterial and antifungal activities in comparison to the clinical drug fluconazole and chloromycetin.Especially the compounds 70a₁,70a₂ showed good antibacterial activities towards B.proteus with MIC₅₀=0.5-1μg·mL^-1.All cyclen azole metal complexes are promising and worthing further research and development as antibacterial and antifungal agents.