title: Ferrocene-conjugated L-tryptophan copper(II) complexes of phenanthroline bases showing DNA photocleavage activity and cytotoxicity.
abstract: Ferrocene-conjugated L-tryptophan (L-Trp) reduced Schiff base (Fc-TrpH) copper(II) complexes [Cu(Fc-Trp)(L)](ClO(4)) of phenanthroline bases (L), viz. 2,2'-bipyridine (bpy in 1), 1,10-phenanthroline (phen in 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 4), were prepared and characterized and their photocytotoxicity studied. Cationic reduced Schiff base (Ph-TrpH) complexes [Cu(Ph-Trp)(L)(H(2)O)](ClO(4)) (L = phen in 5; dppz in 6) having the ferrocenyl moiety replaced by a phenyl group and the Zn(II) analogue (7) of complex 4 were prepared and used as control species. The crystal structures of 1 and 5 with respective square-planar CuN(3)O and square-pyramidal CuN(3)O(2) coordination geometry show significantly different core structures. Complexes 1-4 exhibit a Cu(II)-Cu(I) redox couple near -0.1 V and the Fc(+)-Fc couple at ~0.5 V vs SCE in DMF-0.1 M [Bu(n)(4)N](ClO(4)) (Fc = ferrocenyl moiety). The complexes display a copper(II)-based d-d band near 600 nm and a Fc-centered band at ~450 nm in DMF-Tris-HCl buffer. The complexes are efficient binders to calf thymus DNA. They are synthetic chemical nucleases in the presence of thiol or H(2)O(2), forming hydroxyl radicals. The photoactive complexes are cleavers of pUC19 DNA in visible light, forming hydroxyl radicals. Complexes 2-6 show photocytotoxicity in HeLa cancer cells, giving IC(50) values of 4.7, 10.2, 1.3, 4.8, and 4.3 μM, respectively, in visible light with the appearance of apoptotic bodies. The complexes also show photocytotoxicity in MCF-7 cancer cells. Nuclear chromatin cleavage has been observed with acridine orange/ethidium bromide (AO/EB) dual staining with complex 4 in visible light. The complexes induce caspase-independent apoptosis in the HeLa cells.
authors.affiliation: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Tridib K
authors.initials: TK
authors.lastname: Goswami
authors.forename: Balabhadrapatruni V S K
authors.initials: BV
authors.lastname: Chakravarthi
authors.forename: Mithun
authors.initials: M
authors.lastname: Roy
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Karande
authors.forename: Akhil R
authors.initials: AR
authors.lastname: Chakravarty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects*; D053837:DNA Cleavage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005296:Ferrous Compounds / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D000075163:Metallocenes; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry; D012545:Schiff Bases / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; D009942:Organometallic Compounds; D010618:Phenanthrolines; D012545:Schiff Bases; D003300:Copper; D014364:Tryptophan; D004247:DNA; C427203:calf thymus DNA; C004998:ferrocene