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Understanding the ancillary ligand effect on luminescent cyclometalated Ir(III) complex as a reporter for 2-acetylaminofluorene DNA(AAF-dG) adduct

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Abstract

Mutagenic agents such as aromatic amines undergo metabolic activation and produce DNA adducts at C8 position of guanine bases. N-2-acetylaminofluorene (AAF) generates different mutational outcomes when placed at G1, G2, and G3 of a NarI sequence (-G1G2CG3CC/T-). These outcomes are dictated by the conformations adopted by these adducts. Detection of such lesions is of considerable interest owing to their hazardous effects. Here, we report the synthesis of three cyclometalated [Ir(L)2dppz]+ complexes (L = 2-phenylpyridine (ppy) 1; benzo[h]quinoline (bhq) 2; 2-phenylquinoline (pq) 3; dppz = dipyrido[3,2-a:2',3'-c]phenazine) and their interaction with AAF adducted NarI DNA. Remarkably, complexes 1 and 2 displayed dominant 3LC transition characteristic of polar environment despite binding to the adducted sites. On the other hand, complex 3 binds to NarI sequences and behaves as a luminescent reporter for AAF-modified DNA. The results reported here emphasize that molecular light switching phenomenon can be stimulated by switching ancillary ligands and might act as potential probes for covalent-DNA defects.

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References

  1. Sproviero M, Verwey AM, Rankin KM, Witham AA, Soldatov DV, Manderville RA, Fekry MI, Sturla SJ, Sharma P, Wetmore SD (2014) Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity. Nucleic Acids Res 42:13405–13421. https://doi.org/10.1093/nar/gku1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lindahl T, Barnes D (2000) Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol 65:127–134. https://doi.org/10.1101/sqb.2000.65.127

    Article  CAS  PubMed  Google Scholar 

  3. Torgovnick A, Schumacher B (2015) DNA repair mechanisms in cancer developement and therapy. Front Genet 6:157. https://doi.org/10.3389/fgene.2015.00157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Boiteux S, Jinks-Robertson S (2013) DNA repair mechanisms and the bypass of DNA damage in Saccharomyces cerevisiae. Genetics 193:1025–1064. https://doi.org/10.1534/genetics.112.145219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zeglis BM, Boland JA, Barton JK (2009) Recogntion of abasic sites and single base bulges in DNA by a metalloinsertor. Biochemistry 48:839–849. https://doi.org/10.1021/bi801885w

    Article  CAS  PubMed  Google Scholar 

  6. Kingsland A, Maibaum L (2018) DNA base pair mismatches induce structural changes and alter the free-energy landscape of base flip. J Phys Chem B 122:12251–12259. https://doi.org/10.1021/acs.jpcb.8b06007

    Article  CAS  PubMed  Google Scholar 

  7. Mu H, Geacintov NE, Min JH, Zhang Y, Broyde S (2017) Nucleotide excision repair lesion-recognition protein Rad4 captures a pre-flipped partner base in a benzo[a]pyrene-derived DNA lesion: how structure impacts the binding pathway. Chemical Res Toxicol 30:1344–1354. https://doi.org/10.1021/acs.chemrestox.7b00074

    Article  CAS  Google Scholar 

  8. Sale JE, Lehmann AR, Woodgate R (2012) Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat Rev Mol Cell Biol 13:141–152. https://doi.org/10.1038/nrm3289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lehmann AR, Niimi A, Ogi T, Brown S, Sabbioneda S, Wing JF, Kannouche PL, Green CM (2007) Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair 6:891–899. https://doi.org/10.1016/j.dnarep.2007.02.003

    Article  CAS  PubMed  Google Scholar 

  10. Sarasin A (2003) A overview of the mechanisms of mutagenesis and carcinogenesis. Mutat Res - Rev Mutat Res 544:99–106. https://doi.org/10.1016/j.mrrev.2003.06.024

    Article  CAS  Google Scholar 

  11. McGregor WG, Wei D, Chen RH, Maher VM, McCormick JJ (1997) Relationship between adduct formation, rates of excision repair and the cytotoxic and mutagenic effects of structurally-related polycyclic aromatic carcinogens. Mutat Res – Fundam Mol Mech Mutagen 376:143–152. https://doi.org/10.1016/S0027-5107(97)00037-7

  12. Burnouf D, Koehl P, Fuchs R (1989) Single adduct mutagenesis: strong effect of the position of a single acetylaminofluorene adduct within a mutation hot spot. Proc Natl Acad Sci USA 86:4147–4151. https://doi.org/10.1073/pnas.86.11.4147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Belguise-Valladier P, Fuchs R (1991) Strong-sequence dependant polymorphism in adduct-induced DNA structure: analysis of single N-2-acetylaminofluorene residues bound within the NarI mutation hot spot. Biochemistry 30:10091–10100. https://doi.org/10.1021/bi00106a005

    Article  CAS  PubMed  Google Scholar 

  14. Mu H, Kropachev K, Wang L, Zhang L, Kolbanovskiy A, Kolbanovskiy M, Geacintov NE, Broyde S (2012) Nucleotide excision repair of 2-acetylaminofluorene and 2-aminofluorene-(C8)-guanine adducts: molecular dynamics simulations elucidate how lesion structure and base sequence context impact repair efficiencies. Nucleic Acids Res 40:9675–9690. https://doi.org/10.1093/nar/gks788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Patel DJ, Mao B, Gu Z, Hingerty BE, Gorin A, Basu AK, Broyde S (1998) Nuclear magnetic resonance solution structures of covalent aromatic amine-DNA adducts and their mutagenic relevance. Chemical Res Toxicol 11:391–407. https://doi.org/10.1021/tx9702143

    Article  CAS  Google Scholar 

  16. Cho BP (2004) Dynamic conformational heterogeneities of carcinogen-DNA adducts and their mutagenic relevance. J Environ Sci Health C 22:57–90. https://doi.org/10.1081/LESC-200038217

    Article  CAS  Google Scholar 

  17. Arrowsmith C, Audia J, Austin C et al (2015) The promise and peril of chemical probes. Nat Chem Biol 11:536–541. https://doi.org/10.1038/nchembio.1867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kenry CC, Liu B (2019) Enhancing the performance of pure organic room-temperature phosphorescent luminophores. Nat Commun 10:2111. https://doi.org/10.1038/s41467-019-10033-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhen X, Qu R, Chen W, Wu W, Jiang X (2021) The development of phosphorescent probes for in vitro and in vivo bioimaging. Biomater Sci 9:285–300. https://doi.org/10.1039/D0BM00819B

    Article  CAS  PubMed  Google Scholar 

  20. Ma DL, Kwan MHT, Chan DSH, Lee P, Yang H, Ma VPY, Bai LP, Jiang ZH, Leung CH (2011) Crystal violet as a fluorescent switch-on probe for i-motif: label-free DNA-based logic gate. Analyst 136:2692–2696. https://doi.org/10.1039/C1AN15091J

    Article  CAS  PubMed  Google Scholar 

  21. David Dayanidhi P, Vaidyanathan VG (2021) Structural insights into the recogniton of DNA defects by small molecules. Dalton Trans 50:5691–5712. https://doi.org/10.1039/D0DT04289G

    Article  PubMed  Google Scholar 

  22. Fung SK, Zou T, Cao B, Chen T, To WP, Yang C, Lok CN, Che CM (2016) Luminescent platinum(II) complexes with functionalized N-heterocyclic carbene or diphosphine selectively probe mismatched and abasic DNA. Nat Commun 7:1–9. https://doi.org/10.1038/ncomms10655

    Article  CAS  Google Scholar 

  23. Jackson BA, Barton JK (1997) Recognitionof DNA base mismatches by a rhodium intercalator. J Am Chem Soc 119:12986–12987. https://doi.org/10.1021/ja972489a

    Article  CAS  Google Scholar 

  24. Friedman AE, Chambron JC, Sauvage JP, Turro NJ, Barton JK (1990) Molecular “light-switch” for DNA: Ru(bpy)2(dppz)2+. J Am Chem Soc 112:4960–4962. https://doi.org/10.1021/ja00168a052

    Article  CAS  Google Scholar 

  25. David Dayanidhi P, Rosaria Pinky M, Vaidyanathan VG (2019) Selective recognition of DNA defects by cyclometalated Ir(III) complexes. Dalton Trans 48:13536–13540. https://doi.org/10.1039/D1DT90122B

    Article  PubMed  Google Scholar 

  26. Nandhini T, Anju K, Manikandamathavan V, Vaidyanathan VG, Nair BU (2015) Interactions of Ru(II) polypyridyl complexes with DNA mismatches and abasic sites. Dalton Trans 44:9044–9051. https://doi.org/10.1039/C5DT00807G

    Article  CAS  PubMed  Google Scholar 

  27. Nandhini T, Vaidyanathan VG, Nair BU (2016) Effect of conformation of the arylamine-DNA adduct on the sensitivity of [Ru(phen)2(dppz)]2+ complex. Inorg Chem Comm 73:64–68. https://doi.org/10.1016/j.inoche.2016.09.008

    Article  CAS  Google Scholar 

  28. Gillard M, Laramée-Milette B, Deraedt Q, Hanan GS, Loiseau F, Dejeu J, Defrancq E, Elias B Marcélis L (2019) Photodetection of DNA mismatches by dissymmetric Ru(II) acridine based complexes. Inorg Chem Front 6:2260-2270. https://doi.org/10.1039/C9QI00133F

  29. Deraedt Q, Marcélis L, Loiseau F, Elias B (2017) Towards mismatched DNA photoprobes and photoreagents: “elbow-shaped” Ru(II) complexes. Inorg Chem Front 4:91–103. https://doi.org/10.1039/C6QI00223D

    Article  CAS  Google Scholar 

  30. Cao Q, Li Y, Freisinger E, Qin PZ, Sigel RK, Mao ZW (2017) G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs. Inorg Chem Front 4:10–32. https://doi.org/10.1039/C6QI00300A

    Article  CAS  Google Scholar 

  31. Leung KH, He HZ, Chan DSH, Fu WC, Leung CH, Ma DL (2013) An oligonucleotide-based switch-on luminescent probe for the detection of kanamycin in aqueous solution. Sens Actuators B Chem 177:487–492. https://doi.org/10.1016/j.snb.2012.11.053

    Article  CAS  Google Scholar 

  32. Shan GG, Li HB, Sun HZ, Cao HT, Zhu DX, Su ZM (2013) Enhancing the luminescent properties and stability of cationic iridium(III) complexes based on phenylbenzoimidazole ligand: a combined experimental and theoretical study. Dalton Trans 42:11056–11065. https://doi.org/10.1039/C3DT50358E

    Article  CAS  PubMed  Google Scholar 

  33. Lin N, Ou HD, Xu D, Jin Y, Deng W, Yao ZJ (2020) An efficient probe of cyclometalated phosphorescent iridium complex for selective detection of cyanide. ACS Omega 5:4636–4645. https://doi.org/10.1021/acsomega.9b04364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lo KKW, Li SPY, Zhang KY (2011) Development of luminescent iridium(III) polypyridine complexes as chemical and biological probes. New J Chem 35:265–287. https://doi.org/10.1039/C0NJ00478B

    Article  CAS  Google Scholar 

  35. Lo KKW (2015) Luminescent rhenium(I) and iridium(III) polypyridine complexes as biological probes, imaging reagents and photocytotoxic agents. Acc Chem Res 48:2985–2995. https://doi.org/10.1021/acs.accounts.5b00211

    Article  CAS  PubMed  Google Scholar 

  36. Zhang LX, Gu YY, Wang YJ, Bai L, Du F, Zhang WY, He M, Liu YJ, Chen YZ (2019) Design, synthesis and anticancer effect studies of iridium(III) polypyridyl complexes against SGC-7901 cells. Molecules 24:3129. https://doi.org/10.3390/molecules24173129

    Article  CAS  PubMed Central  Google Scholar 

  37. Ma DL, Zhong HJ, Fu WC, Chan DSH, Kwan HY, Fong WF, Chung LH, Wong CY, Leung CH (2013) Phosphorescent imaging of living cells using a cyclometalated iridium(III) complex. PLoS ONE 8:e55751. https://doi.org/10.1371/journal.pone.0055751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lo KKW, Tso KKS (2015) Functionalization of cyclometalted iridium(III) polypyridine complexes for the design of intracellular sensors organelle-targeting imaging reagents and metallodrugs. Inorg Chem Front 2:510–524. https://doi.org/10.1039/C5QI00002E

    Article  CAS  Google Scholar 

  39. Wang W, Vellaisamy K, Li G, Wu C, Ko CN, Leung CH, Ma DL (2017) Development of a long-lived luminescence probe for visualizing β-Galactosidase in ovarian carcinoma cells. Anal Chem 89:11679–11684. https://doi.org/10.1021/acs.analchem.7b03114

    Article  CAS  PubMed  Google Scholar 

  40. Wang W, Lu L, Wu KJ, Liu J, Leung CH, Wong CY, Ma DL (2019) Long-lived iridium(III) complexes as luminescent probes for the detection of periodate in living cells. Sens Actuators B Chem 288:392–398. https://doi.org/10.1016/j.snb.2019.03.019

    Article  CAS  Google Scholar 

  41. David Dayanidhi P, Vaidyanathan VG (2020) Switch-on effect on conformation-specific arylamine-DNA adduct by cyclometalated Ir(III) complexes. J Biol Inorg Chem 25:305–310. https://doi.org/10.1007/s00775-020-01762-7

    Article  CAS  Google Scholar 

  42. David Dayanidhi P, Vaidyanathan VG (2022) Understanding the role of ancillary ligands in the interaction of Ru(II) complexes with covalent-arylamine DNA adducts. Inorganica Chim Acta 530:120681. https://doi.org/10.1016/j.ica.2021.120681

    Article  CAS  Google Scholar 

  43. Shao F, Elias B, Lu W, Barton JK (2007) Synthesis and characterization of iridium(III) cyclometated complexes with oligonucleotides: insights into redox reactions with DNA. Inorg Chem 46:10187–10199. https://doi.org/10.1021/ic7014012

    Article  CAS  PubMed  Google Scholar 

  44. Sainuddin T, McCain J, Pinto M, Yin H, Gibson J, Hetu M, McFarland SA (2016) Organometallic Ru(II) photosensitizers derived from π-expansive cyclometalating ligands: surprising theranostic PDT effects. Inorg Chem 55:83–95. https://doi.org/10.1021/acs.inorgchem.5b01838

    Article  CAS  PubMed  Google Scholar 

  45. Smith RA, Stokes EC, Langdon-Jones EE, Platts JA, Kariuki BM, Hallett AJ, Pope SJ (2013) Cyclometalated cinchophen ligands on iridium(III): towards water-soluble complexes with visible luminescence. Dalton Trans 42:10347–10357. https://doi.org/10.1039/C3DT51098K

    Article  CAS  PubMed  Google Scholar 

  46. Lowry MS, Bernhard S (2006) Synthetically tailored excited states: phosphorescent, cyclometalated iridium(III) complexes and their applications. Chem Eur J 12:7970–7977. https://doi.org/10.1002/chem.200600618

    Article  CAS  PubMed  Google Scholar 

  47. Lo KKW, Chung CK, Zhu N (2006) Nucelic acid intercalators and avidin probes derived from luminescent cyclometalated iridium(III)-dipyridoquinoxaline and -dipyridophenazine complexes. Chem Eur J 12:1500–1512. https://doi.org/10.1002/chem.200500885

    Article  CAS  PubMed  Google Scholar 

  48. Stimpson S, Jenkinson DR, Sadler A, Latham M, Wragg DA, Meijer AJ, Thomas JA (2015) Tuning the excited state of water-soluble IrIII-based DNA intercalators that are isostructural with [RuII(NN)2(dppz)] light-switch complexes. Angew Chem 127:3043–3046. https://doi.org/10.1002/ange.201411346

    Article  Google Scholar 

  49. Lowry MS, Hudson WR, Pascal RA, Bernhard S (2004) Accelerated luminophore discovery through combinatorial synthesis. J Am Chem Soc 126:14129–14135. https://doi.org/10.1021/ja047156+

    Article  CAS  PubMed  Google Scholar 

  50. Lowry MS, Goldsmith JI, Slinker JD, Rohl R, Pascal RA, Malliaras GG, Bernhard S (2005) Single-layer electroluminescent devices and photoinduced hydrogen production from an ionic iridium(III) complex. Chem Mater 17:5712–5719. https://doi.org/10.1021/cm051312+

    Article  CAS  Google Scholar 

  51. Olson E, Hu D, Hörmann A, Jonkman A, Arkin M, Stemp E, Barton JK, Barbara P (1997) First observation of the key intermediate in the “light-switch” mechanism of [Ru(phen)2(dppz)]2+. J Am Chem Soc 119:11458–11467. https://doi.org/10.1021/ja971151d

    Article  CAS  Google Scholar 

  52. Liu C, Zhou J, Xu H (1998) Interaction of the copper(II) macrocyclic complexes with DNA studied by fluorescence quenching of ethidium. J Inorg Biochem 71:1–6. https://doi.org/10.1016/S0162-0134(98)10025-9

    Article  CAS  PubMed  Google Scholar 

  53. Galindo-Murillo R, Cheatham TE III (2021) Ethidium bromide interactions with DNA: an exploration of a classic DNA-ligand complex with unbiased molecular dynamics simulations. Nucleic Acids Res 49:3735–3747. https://doi.org/10.1093/nar/gkab143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cullen A, Long C, Pryce MT (2021) Explaning the role of water in the “light-switch” probe for DNA intercalation: modelling water loss from [Ru(phen)2(dppz)]2+.2H2O using DFT and TD-DFT methods. J Photochem Photobiol A: Chem 410:113169. https://doi.org/10.1016/j.jphotochem.2021.113169

  55. Wilson T, Williamson MP, Thomas JA (2010) Differentiating quadruplexes: binding preferences of a luminescent dinuclear ruthenium(II) complex with 4-stranded DNA structures. Org Biomol Chem 8:2617–2621. https://doi.org/10.1039/B924263E

    Article  CAS  PubMed  Google Scholar 

  56. Jain V, Hilton B, Patnaik S, Zou Y, Chiarelli MP, Cho BP (2012) Conformational and thermodynamic properties modulate the nucleotide excision repair of 2-aminofluorene and 2-acetylaminofluorene dG adducts in NarI sequence. Nucleic Acids Res 40:3939–3951. https://doi.org/10.1093/nar/gkr1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Xu L, Cho BP (2016) Conformational insights into the mechanism of acetylaminofluorene-dG-induced frameshift mutations in the NarI mutational hotspot. Chemical Res Toxicol 29:213–226. https://doi.org/10.1021/acs.chemrestox.5b00484

    Article  CAS  Google Scholar 

  58. Jain V, Hilton B, Lin B, Patnaik S, Liang F, Darian E, Zou Y, MacKerell AD Jr, Cho BP (2013) Unusual sequence effects on nucleotide excision repair of arylamine lesions: DNA binding/distortion as a primary recognition factor. Nucleic Acids Res 41:869–880. https://doi.org/10.1093/nar/gks1077

    Article  CAS  PubMed  Google Scholar 

  59. Lim MH, Song H, Olmon ED, Dervan EE, Barton JK (2009) Sensitivity of Ru(bpy)2(dppz)2+ luminescence to DNA defects. Inorg Chem 48:5392–5397. https://doi.org/10.1021/ic900407n

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cordier C, Pierre VC, Barton JK (2007) Insertion of bulky rhodium complex into a DNA cytosine-cytosine mismatch: an NMR solution study. J Am Chem Soc 129:12287–12295. https://doi.org/10.1021/ja0739436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pierre VC, Kaiser JT, Barton JK (2007) Insights into finding a mismatch throught the structure of a mispaired DNA bound by a rhodium intercalator. Proc Natl Acad Sci USA 104:429–434. https://doi.org/10.1073/pnas.0610170104

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research work was supported by SERB (SERB/EMR/006068).

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Science and Engineering Research Board, SERB/EMR/006068

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  1. Advanced Materials Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai, 600020, India

    P. David Dayanidhi & V. G. Vaidyanathan

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    P. David Dayanidhi & V. G. Vaidyanathan

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Dayanidhi, P.D., Vaidyanathan, V.G. Understanding the ancillary ligand effect on luminescent cyclometalated Ir(III) complex as a reporter for 2-acetylaminofluorene DNA(AAF-dG) adduct. J Biol Inorg Chem 27, 189–199 (2022). https://doi.org/10.1007/s00775-021-01920-5

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