Photocytotoxic lanthanum(III) and gadolinium(III) complexes of phenanthroline bases showing light-induced DNA cleavage activity.
Lanthanide complexes of formulation [La(B)(2)(NO(3))(3)] (1-3) and [Gd(B)(2)(NO(3))(3)] (4-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2, 5) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3, 6), have been prepared, characterized from physicochemical data, and their photoinduced DNA and protein cleavage activity studied. The photocytotoxicity of the dppz complexes 3 and 6 has been studied using HeLa cancer cells. The complexes exhibit ligand centered bands in the UV region. The dppz complexes show the lowest energy band at 380 nm in N,N-dimethylformamide (DMF). The La(III) complexes are diamagnetic. The Gd(III) complexes (4-6) have magnetic moments that correspond to seven unpaired electrons. The complexes are 1:1 electrolytic in aqueous DMF. The dpq and dppz complexes in DMF show ligand-based reductions. The complexes display moderate binding propensity to calf thymus DNA giving binding constant values in the range of 5.7 x 10(4)-5.8 x 10(5) M(-1) with a relative order: 3, 6 (dppz) > 2, 5 (dpq) > 1, 4 (phen). The binding data suggest DNA surface and/or groove binding nature of the complexes. The complexes do not show any hydrolytic cleavage of plasmid supercoiled pUC19 DNA. The dpq and dppz complexes efficiently cleave SC DNA to its nicked circular form on exposure to UV-A light of 365 nm at nanomolar complex concentration. Mechanistic studies reveal the involvement of singlet oxygen ((1)O(2)) and hydroxyl radical (HO*) as the cleavage active species. The complexes show binding propensity to bovine serum albumin (BSA) protein giving K(BSA) values of approximately 10(5) M(-1). The dppz complexes 3 and 6 show BSA protein cleavage activity in UV-A light of 365 nm. The dppz complexes 3 and 6 exhibit significant photocytotoxicity in HeLa cells giving respective IC(50) values of 341 nM and 573 nM in UV-A light of 365 nm for an exposure time of 15 min (IC(50) > 100 microM in dark for both the complexes). Control experiments show significant dark and phototoxicity of the dppz base alone (IC(50) = 413 nM in light with 4 h incubation in dark and 11.6 microM in dark with 24 h incubation). A significant decrease in the dark toxicity of the dppz base is observed on binding to the lanthanide ions while retaining similar phototoxicity.
Hussain
Akhtar
A
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
Lahiri
Debojyoti
D
Ameerunisha Begum
Mohammed S
MS
Saha
Sounik
S
Majumdar
Ritankar
R
Dighe
Rajan R
RR
Chakravarty
Akhil R
AR
D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D053837:DNA Cleavage / Q000528:radiation effects*; D005682:Gadolinium / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D007811:Lanthanum / Q000737:chemistry*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry*; D010777:Photochemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry; D014466:Ultraviolet Rays
D009942:Organometallic Compounds; D010618:Phenanthrolines; D012710:Serum Albumin, Bovine; D007811:Lanthanum; D004247:DNA; D005682:Gadolinium