title: Impact of metal binding on the antitumor activity and cellular imaging of a metal chelator cationic imidazopyridine derivative.
abstract: A new water soluble cationic imidazopyridine species, viz. (1E)-1-((pyridin-2-yl)methyleneamino)-3-(3-(pyridin-2-yl)imidazo[1,5-a]pyridin-2(3H)-yl)propan-2-ol (1), as a metal chelator is prepared as its PF(6) salt and characterized. Compound 1 shows fluorescence at 438 nm on excitation at 342 nm in Tris-HCl buffer giving a fluorescence quantum yield (φ) of 0.105 and a life-time of 5.4 ns. Compound 1, as an avid DNA minor groove binder, shows pUC19 DNA cleavage activity in UV-A light of 365 nm forming singlet oxygen species in a type-II pathway. The photonuclease potential of 1 gets enhanced in the presence of Fe(2+), Cu(2+) or Zn(2+). Compound 1 itself displays anticancer activity in HeLa, HepG2 and Jurkat cells with an enhancement on addition of the metal ions. Photodynamic effect of 1 at 365 nm also gets enhanced in the presence of Fe(2+) and Zn(2+). Fluorescence-based cell cycle analysis shows a significant dead cell population in the sub-G1 phase of the cell cycle suggesting apoptosis via ROS generation. A significant change in the nuclear morphology is observed from Hoechst 33258 and an acridine orange/ethidium bromide (AO/EB) dual nuclear staining suggesting apoptosis in cells when treated with 1 alone or in the presence of the metal ions. Apoptosis is found to be caspase-dependent. Fluorescence imaging to monitor the distribution of 1 in cells shows that 1 in the presence of metal ions accumulates predominantly in the cytoplasm. Enhanced uptake of 1 into the cells within 12 h is observed in the presence of Fe(2+) and Zn(2+).
authors: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India.
authors: Mithun
authors: M
authors: Roy
authors: Balabhadrapatruni V S K
authors: BV
authors: Chakravarthi
authors: Chelliah
authors: C
authors: Jayabaskaran
authors: Anjali A
authors: AA
authors: Karande
authors: Akhil R
authors: AR
authors: Chakravarty
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D053837:DNA Cleavage; D005456:Fluorescent Dyes / Q000737:chemistry; D016193:G1 Phase; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D007501:Iron / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy; D011725:Pyridines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
chemical_list: C560104:(1E)-1-((pyridin-2-yl)methyleneamino)-3-(3-(pyridin-2-yl)imidazo(1,5-a)pyridin-2(3H)-yl)propan-2-ol; D000970:Antineoplastic Agents; D002412:Cations; D002614:Chelating Agents; D005456:Fluorescent Dyes; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D007501:Iron; D015032:Zinc; C023666:pyridine