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Conformational turn triggers regio-selectivity in the bioactivation of thiophene-contained compounds mediated by cytochrome P450

  • Chun-Zhi Ai
  • Yong Liu
  • Du-Chu Chen
  • Yasmeen Saeed
  • Yi-Zhou JiangEmail author
Original Paper

Abstract

In the present work, we performed Density Functional Theory calculations to explore the bioactivation mechanism of thiophene-containing molecules mediated by P450s. For this purpose, relatively large size compounds, 2,5-diaminothiophene derivatives were selected particularly for this investigation. Here we found the successive regio-selectivity triggered by conformational turn played a significant role in the occurrence of bioactivation. 2,5-Diaminothiophene was oxidized to a 2,5-diimine thiophene-reactive intermediate by Compound I (Cpd I) through successive activations of two N–H bonds (H3–N11 and H1–N6). This reaction exhibited three special characteristics: (1) self-controlled regio-selectivity during the oxidation process. There was a large scale of conformational turn in the abstraction of the first H atom which triggers the selection of the second H for abstraction. (2) Proton-shuttle mechanism. In high spin (HS) state, proton-shuttle mechanism was observed for the abstraction of the second H atom. (3) Spin-selective manner. In protein environment, the energy barrier in HS state was much lower than that in low spin state. The novel proposed bioactivation mechanism of 2,5-diaminothiophene compounds can help us in rational design of thiophene-contained drugs avoiding the occurrence of bioactivation.

Keywords

DFT calculations Cytochrome P450 Self-controlled regio-selectivity Bioactivation mechanism Thiophene-contained compound 

Notes

Acknowledgements

This work was supported by the China Postdoctoral Science Foundation (Grant no. 2017M622784), the National Natural Science Foundation of China (Grant no. 81173124), Shenzhen Science and Technology Innovation Commission (Grant nos. JCYJ20160308104109234 and KQJSCX20170728150303243), and the National Key Research and Development Program of China (Grant no. 2017YFC1702006).

Supplementary material

775_2019_1699_MOESM1_ESM.pdf (2.8 mb)
Supplementary material 1 (PDF 2828 kb)

References

  1. 1.
    Baskaran UL, Sabina EP (2017) Clinical and experimental research in antituberculosis drug-induced hepatotoxicity: a review. J Integr Med-Jim 15(1):27–36.  https://doi.org/10.1016/s2095-4964(17)60319-4 CrossRefGoogle Scholar
  2. 2.
    Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP (2017) Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut 66(6):1154–1164.  https://doi.org/10.1136/gutjnl-2016-313369 CrossRefGoogle Scholar
  3. 3.
    Fontana RJ (2014) Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 146(4):914–U437.  https://doi.org/10.1053/j.gastro.2013.12.032 CrossRefGoogle Scholar
  4. 4.
    Fang Z-Z, Zhang Y-Y, Wang X-L, Cao Y-F, Huo H, Yang L (2011) Bioactivation of herbal constituents: simple alerts in the complex system. Expert Opin Drug Metab Toxicol 7(8):989–1007.  https://doi.org/10.1517/17425255.2011.586335 CrossRefGoogle Scholar
  5. 5.
    Guengerich FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch Biochem Biophys 409(1):59–71CrossRefGoogle Scholar
  6. 6.
    Guengerich FP (2008) Cytochrome P450 and chemical toxicology. Chem Res Toxicol 21(1):70–83.  https://doi.org/10.1021/tx700079z CrossRefGoogle Scholar
  7. 7.
    Dekant W (2009) The role of biotransformation and bioactivation in toxicity. In: Luch A (eds) Molecular, clinical and environmental toxicology. Experientia Supplementum, vol 99. Springer, Basel, Boston, Berlin, GermanyGoogle Scholar
  8. 8.
    Brewer CT, Chen TS (2017) Hepatotoxicity of herbal supplements mediated by modulation of cytochrome P450. Int J Mol Sci.  https://doi.org/10.3390/ijms18112353 Google Scholar
  9. 9.
    Hollenberg PF, Kent UM, Bumpus NN (2008) Mechanism-based inactivation of human cytochromes P450s: experimental characterization, reactive intermediates, and clinical implications. Chem Res Toxicol 21(1):189–205.  https://doi.org/10.1021/tx7002504 CrossRefGoogle Scholar
  10. 10.
    Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O’Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15(3):269–299.  https://doi.org/10.1021/tx015574b CrossRefGoogle Scholar
  11. 11.
    Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, Aleo MD (2011) Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 24(9):1345–1410.  https://doi.org/10.1021/tx200168d CrossRefGoogle Scholar
  12. 12.
    Le Dang N, Hughes TB, Miller GP, Swamidass J (2017) Computational approach to structural alerts: furans, phenols, nitroaromatics, and thiophenes. Chem Res Toxicol 30(4):1046–1059.  https://doi.org/10.1021/acs.chemrestox.6b00336 CrossRefGoogle Scholar
  13. 13.
    Gramec D, Masic LP, Dolenc MS (2014) Bioactivation potential of thiophene-containing drugs. Chem Res Toxicol 27(8):1344–1358.  https://doi.org/10.1021/tx500134g CrossRefGoogle Scholar
  14. 14.
    Chan GFQ, Towers GHN, Mitchell JC (1975) Ultraviolet-mediated antibiotic activity of thiophene compounds of tagetes. Phytochemistry 14(10):2295–2296.  https://doi.org/10.1016/s0031-9422(00)91121-x CrossRefGoogle Scholar
  15. 15.
    Hudson JB, Graham EA, Miki N, Towers GHN, Hudson LL, Rossi R, Carpita A, Neri D (1989) Photoactive antiviral and cytotoxic activities of synthetic thiophenes and their acetylenic derivatives. Chemosphere 19(8–9):1329–1343.  https://doi.org/10.1016/0045-6535(89)90080-5 CrossRefGoogle Scholar
  16. 16.
    Matsuura H, Saxena G, Farmer SW, Hancock REW, Towers GHN (1996) Antibacterial and antifungal polyine compounds from Glehnia littoralis ssp leiocarpa. Planta Med 62(3):256–259.  https://doi.org/10.1055/s-2006-957872 CrossRefGoogle Scholar
  17. 17.
    Lecoeur S, Andre C, Beaune PH (1996) Tienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol Pharmacol 50(2):326–333Google Scholar
  18. 18.
    Mansuy D (1997) Molecular structure and hepatotoxicity: compared data about two closely related thiophene compounds. J Hepatol 26:22–25.  https://doi.org/10.1016/s0168-8278(97)80493-x CrossRefGoogle Scholar
  19. 19.
    Niemegeers CJE, Lenaerts FM, Awouters F, Janssen PAJ (1975) Gastrointestinal effects and acute toxicity of suprofen. Arzneimittel-Forsch/Drug Res 25(10):1537–1542Google Scholar
  20. 20.
    Castell JV, Gomezlechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P (1994) Photodynamic lipid-peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol 59(1):35–39.  https://doi.org/10.1111/j.1751-1097.1994.tb04998.x CrossRefGoogle Scholar
  21. 21.
    Priestley CC, Regan S, Park BK, Williams DP (2011) The genotoxic potential of methapyrilene using the alkaline Comet assay in vitro and in vivo. Toxicology 290(2–3):249–257.  https://doi.org/10.1016/j.tox.2011.10.002 CrossRefGoogle Scholar
  22. 22.
    Mercer AE, Regan SL, Hirst CM, Graham EE, Antoine DJ, Benson CA, Williams DP, Foster J, Kenna JG, Park BK (2009) Functional and toxicological consequences of metabolic bioactivation of methapyrilene via thiophene S-oxidation: induction of cell defence, apoptosis and hepatic necrosis. Toxicol Appl Pharmacol 239(3):297–305.  https://doi.org/10.1016/j.taap.2009.05.027 CrossRefGoogle Scholar
  23. 23.
    Hutzler JM, Balogh LM, Zientek M, Kumar V, Tracy TS (2009) Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (±)-suprofen: a comparison of kinetics and probe substrate selection. Drug Metab Dispos 37(1):59–65.  https://doi.org/10.1124/dmd.108.023358 CrossRefGoogle Scholar
  24. 24.
    Rademacher PM, Woods CM, Huang Q, Szklarz GD, Nelson SD (2012) Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9. Chem Res Toxicol 25(4):895–903.  https://doi.org/10.1021/tx200519d CrossRefGoogle Scholar
  25. 25.
    Dansette PM, Bertho G, Mansuy D (2005) First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives. Biochem Biophys Res Commun 338(1):450–455.  https://doi.org/10.1016/j.bbrc.2005.08.091 CrossRefGoogle Scholar
  26. 26.
    Mansuy D, Dansette PM (2011) Sulfenic acids as reactive intermediates in xenobiotic metabolism. Arch Biochem Biophys 507(1):174–185.  https://doi.org/10.1016/j.abb.2010.09.015 CrossRefGoogle Scholar
  27. 27.
    Dansette PM, Thang DC, Elamri H, Mansuy D (1992) Evidence for thiophene-s-oxide as a primary reactive metabolite of thiophene invivo—formation of a dihydrothiophene sulfoxide mercapturic acid. Biochem Biophys Res Commun 186(3):1624–1630.  https://doi.org/10.1016/s0006-291x(05)81594-3 CrossRefGoogle Scholar
  28. 28.
    Hu Y, Yang S, Shilliday FB, Heyde BR, Mandrell KM, Robins RH, Xie J, Reding MT, Lai Y, Thompson DC (2010) novel metabolic bioactivation mechanism for a series of anti-inflammatory agents (2,5-diaminothiophene derivatives) mediated by cytochrome P450 enzymes. Drug Metab Dispos 38(9):1522–1531.  https://doi.org/10.1124/dmd.110.032581 CrossRefGoogle Scholar
  29. 29.
    Kumar D, de Visser SP, Sharma PK, Cohen S, Shaik S (2004) Radical clock substrates, their C–H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: What does theory reveal about the clocks’ behavior? J Am Chem Soc 126(6):1907–1920.  https://doi.org/10.1021/ja039439s CrossRefGoogle Scholar
  30. 30.
    de Visser SP, Shaik S (2003) A proton-shuttle mechanism mediated by the porphyrin in benzene hydroxylation by cytochrome P450 enzymes. J Am Chem Soc 125(24):7413–7424.  https://doi.org/10.1021/ja034142f CrossRefGoogle Scholar
  31. 31.
    de Visser SP, Kumar D, Cohen S, Shacham R, Shaik S (2004) A predictive pattern of computed barriers for C–H hydroxylation by compound I of cytochrome P450. J Am Chem Soc 126(27):8362–8363.  https://doi.org/10.1021/ja04858h CrossRefGoogle Scholar
  32. 32.
    Cohen S, Kozuch S, Hazan C, Shaik S (2006) Does substrate oxidation determine the regioselectivity of cyclohexene and propene oxidation by cytochrome P450? J Am Chem Soc 128(34):11028–11029.  https://doi.org/10.1021/ja063269c CrossRefGoogle Scholar
  33. 33.
    Mallick D, Shaik S (2017) Kinetic isotope effect probes the reactive Spin state, as well as the geometric feature and constitution of the transition State during H-abstraction by heme compound II complexes. J Am Chem Soc 139(33):11451–11459.  https://doi.org/10.1021/jacs.7b04247 CrossRefGoogle Scholar
  34. 34.
    de Visser SP, Ogliaro F, Sharma PK, Shaik S (2002) What factors affect the regioselectivity of oxidation by cytochrome P450? A DFT study of allylic hydroxylation and double bond epoxidation in a model reaction. J Am Chem Soc 124(39):11809–11826.  https://doi.org/10.1021/ja026872d CrossRefGoogle Scholar
  35. 35.
    Bathelt CM, Ridder L, Mulholland AJ, Harvey JN (2003) Aromatic hydroxylation by cytochrome P450: model calculations of mechanism and substituent effects. J Am Chem Soc 125(49):15004–15005.  https://doi.org/10.1021/ja035590q CrossRefGoogle Scholar
  36. 36.
    Ai C-Z, Liu Y, Li W, Chen D-M, Zhu X-X, Yan Y-W, Chen D-C, Jiang Y-Z (2017) Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: a case of erlotinib. Plos One 12(6):1.  https://doi.org/10.1371/journal.pone.0179333 CrossRefGoogle Scholar
  37. 37.
    Shaik S, Kumar D, de Visser SP, Altun A, Thiel W (2005) Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem Rev 105(6):2279–2328.  https://doi.org/10.1021/cr030722j CrossRefGoogle Scholar
  38. 38.
    Schyman P, Lai W, Chen H, Wang Y, Shaik S (2011) The directive of the protein: how does cytochrome P450 select the mechanism of dopamine formation? J Am Chem Soc 133(20):7977–7984.  https://doi.org/10.1021/ja201665x CrossRefGoogle Scholar
  39. 39.
    Mulliken RS (1955) Electronic population analysis on LCAO-MO molecular wave functions. 3. Effects of hybridization on overlap and gross Ao populations. Journal of Chemical Physics 23(12):2338–2342.  https://doi.org/10.1063/1.1741876 CrossRefGoogle Scholar
  40. 40.
    de Visser SP, Ogliaro F, Harris N, Shaik S (2001) Multi-state epoxidation of ethene by cytochrome P450: a quantum chemical study. J Am Chem Soc 123(13):3037–3047CrossRefGoogle Scholar
  41. 41.
    Harris DL, Loew GH (1998) Theoretical investigation of the proton assisted pathway to formation of cytochrome P450 compound I. J Am Chem Soc 120(35):8941–8948.  https://doi.org/10.1021/ja981059x CrossRefGoogle Scholar
  42. 42.
    Schoneboom JC, Lin H, Reuter N, Thiel W, Cohen S, Ogliaro F, Shaik S (2002) The elusive oxidant species of cytochrome P450 enzymes: characterization by combined quantum mechanical/molecular mechanical (QM/MM) calculations. J Am Chem Soc 124(27):8142–8151.  https://doi.org/10.1021/ja026279w CrossRefGoogle Scholar
  43. 43.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision D.01. Gaussian, Inc., Wallingford CTGoogle Scholar
  44. 44.
    Hirao H, Chuanprasit P, Cheong YY, Wang X (2013) How is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine: hydrogen abstraction or nitrogen oxidation? Chemistry-a Eur J 19(23):7361–7369.  https://doi.org/10.1002/chem.201300689 CrossRefGoogle Scholar
  45. 45.
    Sevrioukova IF, Poulos TL (2017) Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4. Proc Natl Acad Sci USA 114(3):486–491.  https://doi.org/10.1073/pnas.1616198114 CrossRefGoogle Scholar
  46. 46.
    Ogliaro F, Cohen S, Filatov M, Harris N, Shaik S (2000) The high-valent compound of cytochrome P450: The nature of the Fe-S bond and the role of the thiolate ligand as an internal electron donor. Angew Chemie-Int Edit 39(21):3851.  https://doi.org/10.1002/1521-3773(20001103)39:21%3c3851:aid-anie3851%3e3.0.co;2-9 CrossRefGoogle Scholar
  47. 47.
    Kumar D, de Visser SP, Shaik S (2003) How does product isotope effect prove the operation of a two-state “rebound” mechanism in C–H hydroxylation by cytochrome P450? J Am Chem Soc 125(43):13024–13025.  https://doi.org/10.1021/ja036906x CrossRefGoogle Scholar
  48. 48.
    Ji L, Schueuermann G (2013) Model and mechanism: N-hydroxylation of primary aromatic amines by cytochrome P450. Angew Chemie-Int Edit 52(2):744–748.  https://doi.org/10.1002/anie.201204116 CrossRefGoogle Scholar
  49. 49.
    Ravula T, Barnaba C, Mahajan M, Anantharamaiah GM, Im S-C, Waskell L, Ramamoorthy A (2017) Membrane environment drives cytochrome P450’s spin transition and its interaction with cytochrome b(5). Chem Commun 53(95):12798–12801.  https://doi.org/10.1039/c7cc07520k CrossRefGoogle Scholar
  50. 50.
    Ahuja S, Jahr N, Im SC, Vivekanandan S, Popovych N, Le Clair SV, Huang R, Soong R, Xu JD, Yamamoto K, Nanga RP, Bridges A, Waskell L, Ramamoorthy A (2013) A model of the membrane-bound cytochrome b(5)-Cytochrome P450 complex from NMR and mutagenesis data. J Biol Chem 288(30):22080–22095.  https://doi.org/10.1074/jbc.M112.448225 CrossRefGoogle Scholar
  51. 51.
    Zhang M, Huang R, Im SC, Waskell L, Ramamoorthy A (2015) Effects of membrane mimetics on cytochrome P450-Cytochrome b(5) interactions characterized by NMR spectroscopy. J Biol Chem 290(20):12705–12718.  https://doi.org/10.1074/jbc.M114.597096 CrossRefGoogle Scholar
  52. 52.
    Prade E, Mahajan M, Im SC, Zhang M, Gentry KA, Anantharamaiah GM, Waskell L, Ramamoorthy A (2018) A minimal functional complex of cytochrome P450 and FBD of cytochrome P450 reductase in nanodiscs. Angew Chemie-Int Edit 57(28):8458–8462.  https://doi.org/10.1002/anie.201802210 CrossRefGoogle Scholar
  53. 53.
    Denisov IG, Sligar SG (2016) Nanodiscs for structural and functional studies of membrane proteins. Nat Struct Mol Biol 23(6):481–486.  https://doi.org/10.1038/nsmb.3195 CrossRefGoogle Scholar
  54. 54.
    Mahajan M, Ravula T, Prade E, Anantharamaiah GM, Ramamoorthy A (2019) Probing membrane enhanced protein-protein interactions in a minimal redox complex of cytochrome-P450 and P450-reductase. Chem Commun (Camb, Engl) 55(41):1.  https://doi.org/10.1039/c9cc01630a Google Scholar
  55. 55.
    Barnaba C, Ramamoorthy A (2018) Picturing the membrane-assisted choreography of cytochrome P450 with lipid nanodiscs. Chem Phys Chem 19(20):2603–2613.  https://doi.org/10.1002/cphc.201800444 CrossRefGoogle Scholar
  56. 56.
    Hollingsworth SA, Batabyal D, Nguyen BD, Poulos TL (2016) Conformational selectivity in cytochrome P450 redox partner interactions. Proc Natl Acad Sci USA 113(31):8723–8728.  https://doi.org/10.1073/pnas.1606474113 CrossRefGoogle Scholar

Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  • Chun-Zhi Ai
    • 1
    • 2
  • Yong Liu
    • 3
  • Du-Chu Chen
    • 1
    • 2
  • Yasmeen Saeed
    • 1
    • 2
  • Yi-Zhou Jiang
    • 1
    Email author
  1. 1.Institute for Advanced StudyShenzhen UniversityShenzhenChina
  2. 2.Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic EngineeringShenzhen UniversityShenzhenChina
  3. 3.School of Life Science and MedicineDalian University of TechnologyPanjinChina

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