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Drug-Biomolecule Interactions in Excited States

This study explores the photodamage to biomolecules, such as DNA and proteins, in the excited states. It discusses different types of photochemical damage and their effects, including direct photochemistry and photosensitization. The interactions between drugs and biomolecules are also examined. The research findings provide insights into the mechanisms of photodamage and potential strategies for photorepair.

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Drug-Biomolecule Interactions in Excited States

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  1. Universidad Politécnica de Valencia INSTITUTO DE TECNOLOGÍA QUIMICA, UPV-CSIC Drug-Biomolecule Interactions in the Excited States Miguel A. Miranda Israel, April 2010

  2. Outline • Introduction • Photodamage to DNA • Photorepair • Conclusions

  3. UVC: not present in ambient sunlight; it is filtered by stratosphere layer of ozone. Direct Photochemistry UVB: overlaps with the DNA and protein absorption spectra and is within the range mainly responsible for pathological effects through direct photochemical damage. UVA : photocarcinogenic and involved in photoaging, but weakly absorbed by DNA and proteins. Produces damages indirectly, through light absorption by other chromophores. Photosensitization Introduction: Photochemical damage to biomolecules Visible UVC UVB UVA IR 290 320 400 nm Photobiological spectrum

  4. Lipids (Poly)unsaturated fatty acids peroxidation Cholesterol oxidation Membrane lysis Phototoxicity • - Boscá, et al.,J. Photochem. Photobiol., B: Biol. 2000, 58, 1 • - Samadi et al., Photochem. Photobiol.2001, 73, 359 • - Miranda et al., Chem. Commun. 2002, 280 • - Boscáet al.,Chem. Commun. 2003, 1592 • Andreu et al., Org. Lett. 2006, 8, 4597 • Andreu et al.,Org. Biomol. Chem. 2008, 6, 860

  5. Proteins Drug-protein photobinding Protein-protein photocrosslinking Binding site occupancy Photoallergy Proteins Modeldyads • Miranda et al.Chem. Res. Toxicol.1998, 11, 172. • Lahoz et al.Chem. Res. Toxicol.2001, 14, 1486. • Lhiaubet-Vallet et al.J. Am. Chem. Soc. 2004, 126, 9538. • Jimenez et al.J. Am. Chem Soc. 2005, 127, 10134. • Vaya et al.ChemMedChem2006, 1, 1015. • Lhiaubet-Vallet et al.J. Phys. Chem. B 2007,111, 423. • Vaya et al. J. Phys. Chem. B2008, 112, 2694. • Vaya et al. Chem Eur. J.2008, 14, 11284. • Montanaro et al.ChemMedChem2009, 4, 1196. • Bueno et al J. Phys. Chem. B2009, 113, 6861. • Perez-Ruiz et al, J. Phys. Chem. Lett. 2010, 829. • Miranda et al.J. Am. Chem. Soc., 1999, 121, 11569. • Miranda et al.Chem. Commun., 2000, 2257. • Perez-Prieto et al.J. Org. Chem., 2004, 69, 374. • Perez-Prieto et al.J. Org. Chem., 2004, 69, 8618. • Lhiaubet-Vallet et al.J. Phys. Chem. B 2007, 111, 423. • Vaya et al.J. Phys. Chem. B 2007, 111, 9363. • Vaya et al. Chem. Phys. Lett. 2010, 486, 147.

  6. Nucleic acids Base damage Photogenotoxicity Photomutagenicity Thyminedimerization Guanineoxidation • Lhiaubet-Vallet et al.Photochem. Photobiol.2003, 77, 487. • Lhiaubet-Vallet et al.J.Phys Chem. B2004, 108, 14148. • Bosca et al.J. Am. Chem. Soc. 2006, 128, 6318. • Lhiaubet-Vallet et al.J. Phys. Chem. B2007111, 7409. • Trzcionka et al. ChemBioChem2007, 4, 367. • Lhiaubet-Vallet et al. Photochem. Photobiol. 2009, 85, 861 • Agapakis et al.Photochem. Photobiol.2000, 71,499 • Belvedere et al.Chem. Res. Toxicol.2002, 15, 1142. • Cuquerella et al.Chem. Res. Toxicol.2003, 16, 562. • Lhiaubet-Vallet et al.Toxicol. in vitro2003, 17, 651. • Chatgilialoglu et al. Chem. Res. Toxicol.2007, 20, 1820. • Paris et al. Org. Lett.2008, 10, 4409. Stereodifferentiation (chiraldrug/nucleosides) • Encinas et al.ChemPhysChem, 2004, 5, 1704. • Lhiaubet-Vallet et al.J. Am. Chem. Soc. 2005, 127, 12774. • Encinas et al.Chem. Commun. 2005, 272. • Belmadoui et al. Chem. Eur. J. 2006, 12, 553. • Jimenez et al. Org. Biomol. Chem. 2008, 6, 860.

  7. Introduction • Photodamage to DNA • Photorepair • Conclusions

  8. Benzophenone photosensitized Interaction with Thd BP Paterno-Büchi Photocycloaddition Triplet-Triplet (T-T) Energy transfer 3BP* 3Thd Oxetane formation Thymine dimer formation Encinas, Belmadoui, Climent, Gil, Miranda, Chem. Res. Toxicol.2004, 17, 857.

  9. C H O 3 Oxetanes (R)-KP-Thd C O O H Thd + Thd<>Thd Oxetanes (S)-KP-Thd Oxetanes DKP-Thd Products distribution after photolysis of Thd in the presence of KP Ketoprofen (KP) Elution Time (min) Lhiaubet-Vallet, Encinas, Miranda. J. Am. Chem. Soc.2005, 127, 12774

  10. KP/Thymidine interaction: Laser flash photolysis Triplet-Triplet transition of KP detected 3KP Quenching by Thd 3KP Enantiodifferentiation In the3KP-Thd interaction kS(Thd)= 3.6 108 M-1s-1 kR(Thd)= 5.1 108 M-1s-1 kR/kS = 1.4 Lhiaubet-Vallet, Encinas, Miranda. J. Am. Chem. Soc. 2005, 127, 12774

  11. Form II Form I Detection of thymine dimers formation in DNA Supercoiled Plasmid DNA Electrophoresis : different mobility FormI ssb dsb Form II Form III T<>T detection: T4 endo V specific of cis-syn T<>T  formation of a ssb Bosca, Lhiaubet-Vallet, Cuquerella, Castell, Miranda,J. Am. Chem. Soc., 2006, 128, 6318.

  12. DNA-photosensitization Agarose gel electrophoresis T<>T • pBR + FQ (20 mM) + UVA (355 nm) • enzymatic treatment with T4 endonuclease V ENX, NFX and PFX sensitize T<>T but ANFX does not!! No T<>T T<>T formation Form II native DNA Form I Bosca, Lhiaubet-Vallet, Cuquerella, Castell, Miranda,J. Am. Chem. Soc., 2006, 128, 6318. Lhiaubet-Vallet, Cuquerella, Castell, Bosca, Miranda,J. Phys. Chem. B, 2007, 111, 7409.

  13. Triplet state energy of thymine in DNA 275 3ENX 270 3PFX 3NFX 267 ET(kJ.mol-1) 3T (DNA) 265 3ANFX 3OFX 260 T<>T 255 3RFX Photosensitizer with ET > 267 kJ mol-1 = potential photogenotoxic agent Bosca, Lhiaubet-Vallet, Cuquerella, Castell, Miranda,J. Am. Chem. Soc., 2006, 128, 6318. Lhiaubet-Vallet, Cuquerella, Castell, Bosca, Miranda,J. Phys. Chem. B, 2007, 111, 7409.

  14. Introduction • Photodamage to biomolecules • Photorepair • Conclusions

  15. X X X R R R H N X H N H N X X H R N n h R H N O R N N H N O N O n h + ´ 5 ´ O 5 ´ N 5 ´ O O P N N P P 3 ´ 3 ´ 3 ´ X = O , N H R = M e , H ( 6 - 4 ) P h o t o p r o d u c t Formation of (6-4) pyrimidine dimers Photolyase (6-4) Photoproducts can be formed through a Paterno-Büchi photoreaction between two adjacent pyrimidines in DNA

  16. PET Cycloreversion of oxetanes in DNA repair • PET Cycloreversion of oxetanes is important for the photoenzymatic repair of • (6-4) photoproducts of the DNA dipyrimidine sites by photolyases • The mode of action involves photochemical transfer of oneelectron from a reduced and deprotonated flavin (FADH-) to an oxetane. Subsequently, the oxetane radical anion cleaves to provide one neutral pyrimidine plus one pyrimidine radical anion.

  17. Oxidative PET-cycloreversion of oxetanes Intramolecular Nucleophilic Trapping • Stepwise cycloreversion of oxetane radical cation via initial O-C2 cleavage • Spin and charge localized in the oxygen and C2, respectively • Formation of 2,3-diphenyl 4-hydroxytetrahydrofuran by intramolecular nucleophilic trapping Izquierdo, Miranda, J. Am. Chem. Soc. 2002, 124, 6532

  18. Reductive PET-cycloreversion of oxetanes Perez-Ruiz, Izquierdo, Miranda, J. Org. Chem., 2003, 68, 10103. Perez-Ruiz, Gil, Miranda, J. Org. Chem., 2005, 70, 1376.

  19. Oxidative PET-cycloreversion of thietanes: Ion-molecule complexes Argüello, Pérez-Ruiz, Miranda, Org. Lett. 2010, 12, 1756.

  20. Introduction • Photodamage to biomolecules • Photoprotection/photorepair • Conclusions

  21. Conclusions • Solar (and artificial) light may produce both desired • and undesired effects on biological systems • It is necessary to achieve a satisfactory understanding of • the chemical mechanisms involved in photobiological • effects • Based on mechanistic knowledge, it is possible to • minimize the adverse effects of light, while enhancing • its beneficial effects

  22. ACKNOWLEDGEMENTS PhD STUDENTS P. Bartovsky P. Bonancia M. Gómez M. Marin G. Nardi E. Nuin L. Piñero J. Rohacova S. Soldevila COLLABORATIONS UPV-CSIC F. Boscá S. Encinas M. J. Climent M. C. Jiménez M. L. Marin I. M. Morera R. Tormos EXTERNAL J. V. Castell J. Pérez-Prieto T. Gimisis C. Chatgilialoglu POST-DOCS R. Alonso I. Andreu M. C. Cuquerella V. Lhiaubet-Vallet R. Pérez FUNDING European Union Spanish Government Regional Government UPV and CSIC ISDIN Organon/Merck

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