DNA-binding metallo-intercalators are positively charged, planar, polycyclic, aromatic compounds that unwind the DNA double helix and insert themselves between DNA base pairs.[1] Metallo-intercalators insert themselves between two intact base pairs without expelling or replacing the original nitrogenous bases; the hydrogen bonds between the nitrogenous bases at the site of intercalation remain unbroken.[1][2][3] In addition to π-stacking between the aromatic regions of the intercalator and the nitrogenous bases of DNA, intercalation is stabilized by van der Waals, hydrophobic, electrostatic, and entropic interactions.[2] This ability to bind to specific DNA base pairs allows for potential therapeutic applications of metallo-intercalators.
Figure 1: Chemical structure of the DNA-binding metallo-intercalator complex [Ru(bpy)2(paip)]2+ with intercalative and ancillary ligands labeled.[4][5]
In the case of ruthenium intercalators, the general synthesis consists of preparing intercalative ligands followed by their coupling to a ruthenium metal complex coordinated by specific ancillary ligands.[6][7] Examples of prior ruthenium complexes used as precursors for metallo-intercalators include cis-[Ru(bpy)2Cl2] and cis-[Ru(phen)2Cl2]∙2H2O, which can be synthesized into [Ru(bpy)2(maip)]2+, [Ru(bpy)2(paip)]2+, [Ru(bpy)2(bfipH)](ClO4)2, and Ru(phen)2(bfipH)](ClO4)2.[4][5]
Mechanism of DNA-intercalationedit
Figure 2: Metallo-intercalators enter double stranded DNA via the major groove and π-stack between adjacent unbroken base pairs. Here, the phi ligand of a rhodium complex intercalates a DNA segment with the sequence 5'-G(5IU)TGCAAC-3' (PDB ID 454D).[8]
Metallo-intercalators π-stack with unbroken DNA base pairs after entering via a groove, typically the major, (in contrast to metallo-insertors, which replace expelled base pairs after entering double stranded DNA via the minor groove).[9][10] Intercalation of a metallo-intercalator creates less strain in the DNA duplex than insertion; metallo-insertors induce an untwist of the double helix and an opening of the phosphate backbone while metallo-intercalators marginally increase the rise and width of the major groove.[1][9] Intercalation of metal compounds between DNA base pairs effectively stabilizes the double helix, increasing the melting temperature of the DNA duplex.[8] Binding of metallo-intercalators to DNA is reversible and depends on the properties of the intercalating molecule. Metallo-intercalators with different metal centers, oxidation states, coordination geometries, and overall sizes will exhibit varying “depths of insertion”.[3] For example, square planar complexes penetrate deeper into the DNA base pairs than octahedral or tetrahedral complexes do.[3] Also, positive charges on the metallo-intercalator strengthen DNA-binding because of electrostatic attraction to the negatively charged sugar-phosphate backbone.[6]
Therapeutic applicationsedit
Figure 3: The wide structure of metallo-intercalators containing the ligand 5,6-chrysenequinone diimine (chrysi) can be used in anticancer therapeutics to identify mismatched DNA base pairs.[11][12]
Metallo-intercalators have a variety of potential therapeutic applications as a result of their structural diversity and universal photooxidative properties. One possible therapeutic application of metallo-intercalators is to combat cancerous tumor cells within the body by targeting specific mismatched DNA base pairs; the ability to modify the ligands bound to the metal center allows for a high degree of specificity in the binding interactions between the metallo-intercalator and the DNA sequence.[11][12][13] For example, the ligand 5,6-chrysenequinone diimine (chrysi) and its analogues are designed to be too wide to fit inside the normal span of the base pairs of B-DNA, causing it to bind instead to the wider portions of the helix at destabilized sites of mismatched bases.[11][12] After intercalation, the sample can be photoactivated by absorbing energy during irradiation with short wavelength light.[1] This activation causes the metallo-intercalator's photooxidative properties to induce a cleavage of the sugar phosphate backbone at the site of mismatch through a radical mechanism.[1][11][12] Even in the absence of irradiation, the interactions between the metallo-intercalator and DNA can substantially decrease the proliferation of cells containing DNA with mismatched base pairs.[13]
Referencesedit
^ abcdeZeglis, Brian M.; Pierre, Valerie C.; Barton, Jacqueline K. (2007). "Metallo-intercalators and Metallo-insertors" (PDF). Chemical Communications. 44 (44): 4565–79. doi:10.1039/b710949k. PMC2790054. PMID 17989802.
^ abGill, Martin R., and Jim A. Thomas. "Ruthenium(ii) Polypyridyl Complexes and DNA-from Structural Probes to Cellular Imaging and Therapeutics - (RSC Publishing)." Chem Soc Rev, n.d. Web. 26 Jan. 2015. <http://pubs.rsc.org/en/Content/ArticlePDF/2012/CS/c2cs15299a>.
^ abKielkopf, C. L., K. E. Erkkila, B. P. Hudson, J. K. Barton, and D. C. Rees. "INTERCALATION AND MAJOR GROOVE RECOGNITION IN THE 1.2 A RESOLUTION CRYSTAL STRUCTURE OF RH[ME2TRIEN]PHI BOUND TO 5'-G(5IU)TGCAAC-3'" RCSB Protein Data Bank. N.p., n.d. Web. 26 Jan. 2015. <http://www.rcsb.org/pdb/explore/explore.do?structureId=454D>.
^ abLauria, Antonino, Riccardo Bonsignore, and Alessio Terenzi. "Nickel(ii), Copper(ii) and Zinc(ii) Metallo-intercalators: Structural Details of the DNA-binding by a Combined Experimental and Computational Investigation - (RSC Publishing)." Royal Society of Chemistry, n.d. Web. 26 Jan. 2015. <http://pubs.rsc.org/EN/content/articlehtml/2014/dt/c3dt53066c>.
^Alessandro Biancardi, Azzurra Burgalassi, Alessio Terenzi, Angelo Spinello, Giampaolo Barone, Tarita Biver, and Benedetta Mennucci. |title="A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type ZnII Complex" |journal=Chemistry–A European Journal, |date=2015 |volume=20 |issue=24 |pages=7439-7447. |doi=10.1002/chem.201304876
^ abcdPierre, VC; Kaiser, JT; Barton, JK (2007). "Insights into finding a mismatch through the structure of a mispaired DNA bound by a rhodium intercalator". Proc. Natl. Acad. Sci. U.S.A. 104 (2): 429–34. Bibcode:2007PNAS..104..429P. doi:10.1073/pnas.0610170104. PMC1766401. PMID 17194756.
^ abcdJunicke, H.; Hart, J. R.; Kisko, J.; Glebov, O.; Kirsch, I. R.; Barton, J. K. (2003). "Bioinorganic Chemistry Special Feature: A Rhodium(III) Complex for High-affinity DNA Base-pair Mismatch Recognition". Proceedings of the National Academy of Sciences. 100 (7): 3737–42. Bibcode:2003PNAS..100.3737J. doi:10.1073/pnas.0537194100. PMC152991. PMID 12610209.
^ abHart, J. R.; Glebov, O.; Ernst, R. J.; Kirsch, I. R.; Barton, J. K. (2006). "DNA Mismatch-specific Targeting and Hypersensitivity of Mismatch-repair-deficient Cells to Bulky Rhodium(III) Intercalators". Proceedings of the National Academy of Sciences. 103 (42): 15359–5363. Bibcode:2006PNAS..10315359H. doi:10.1073/pnas.0607576103. PMC1622828. PMID 17030786.
April 19, 2024
binding, metallo, intercalators, positively, charged, planar, polycyclic, aromatic, compounds, that, unwind, double, helix, insert, themselves, between, base, pairs, metallo, intercalators, insert, themselves, between, intact, base, pairs, without, expelling, . DNA binding metallo intercalators are positively charged planar polycyclic aromatic compounds that unwind the DNA double helix and insert themselves between DNA base pairs 1 Metallo intercalators insert themselves between two intact base pairs without expelling or replacing the original nitrogenous bases the hydrogen bonds between the nitrogenous bases at the site of intercalation remain unbroken 1 2 3 In addition to p stacking between the aromatic regions of the intercalator and the nitrogenous bases of DNA intercalation is stabilized by van der Waals hydrophobic electrostatic and entropic interactions 2 This ability to bind to specific DNA base pairs allows for potential therapeutic applications of metallo intercalators Contents 1 Synthesis of metallo intercalators 2 Mechanism of DNA intercalation 3 Therapeutic applications 4 ReferencesSynthesis of metallo intercalators edit nbsp Figure 1 Chemical structure of the DNA binding metallo intercalator complex Ru bpy 2 paip 2 with intercalative and ancillary ligands labeled 4 5 In the case of ruthenium intercalators the general synthesis consists of preparing intercalative ligands followed by their coupling to a ruthenium metal complex coordinated by specific ancillary ligands 6 7 Examples of prior ruthenium complexes used as precursors for metallo intercalators include cis Ru bpy 2Cl2 and cis Ru phen 2Cl2 2H2O which can be synthesized into Ru bpy 2 maip 2 Ru bpy 2 paip 2 Ru bpy 2 bfipH ClO4 2 and Ru phen 2 bfipH ClO4 2 4 5 Mechanism of DNA intercalation edit nbsp Figure 2 Metallo intercalators enter double stranded DNA via the major groove and p stack between adjacent unbroken base pairs Here the phi ligand of a rhodium complex intercalates a DNA segment with the sequence 5 G 5IU TGCAAC 3 PDB ID 454D 8 Metallo intercalators p stack with unbroken DNA base pairs after entering via a groove typically the major in contrast to metallo insertors which replace expelled base pairs after entering double stranded DNA via the minor groove 9 10 Intercalation of a metallo intercalator creates less strain in the DNA duplex than insertion metallo insertors induce an untwist of the double helix and an opening of the phosphate backbone while metallo intercalators marginally increase the rise and width of the major groove 1 9 Intercalation of metal compounds between DNA base pairs effectively stabilizes the double helix increasing the melting temperature of the DNA duplex 8 Binding of metallo intercalators to DNA is reversible and depends on the properties of the intercalating molecule Metallo intercalators with different metal centers oxidation states coordination geometries and overall sizes will exhibit varying depths of insertion 3 For example square planar complexes penetrate deeper into the DNA base pairs than octahedral or tetrahedral complexes do 3 Also positive charges on the metallo intercalator strengthen DNA binding because of electrostatic attraction to the negatively charged sugar phosphate backbone 6 Therapeutic applications edit nbsp Figure 3 The wide structure of metallo intercalators containing the ligand 5 6 chrysenequinone diimine chrysi can be used in anticancer therapeutics to identify mismatched DNA base pairs 11 12 Metallo intercalators have a variety of potential therapeutic applications as a result of their structural diversity and universal photooxidative properties One possible therapeutic application of metallo intercalators is to combat cancerous tumor cells within the body by targeting specific mismatched DNA base pairs the ability to modify the ligands bound to the metal center allows for a high degree of specificity in the binding interactions between the metallo intercalator and the DNA sequence 11 12 13 For example the ligand 5 6 chrysenequinone diimine chrysi and its analogues are designed to be too wide to fit inside the normal span of the base pairs of B DNA causing it to bind instead to the wider portions of the helix at destabilized sites of mismatched bases 11 12 After intercalation the sample can be photoactivated by absorbing energy during irradiation with short wavelength light 1 This activation causes the metallo intercalator s photooxidative properties to induce a cleavage of the sugar phosphate backbone at the site of mismatch through a radical mechanism 1 11 12 Even in the absence of irradiation the interactions between the metallo intercalator and DNA can substantially decrease the proliferation of cells containing DNA with mismatched base pairs 13 References edit a b c d e Zeglis Brian M Pierre Valerie C Barton Jacqueline K 2007 Metallo intercalators and Metallo insertors PDF Chemical Communications 44 44 4565 79 doi 10 1039 b710949k PMC 2790054 PMID 17989802 a b Gill Martin R and Jim A Thomas Ruthenium ii Polypyridyl Complexes and DNA from Structural Probes to Cellular Imaging and Therapeutics RSC Publishing Chem Soc Rev n d Web 26 Jan 2015 lt http pubs rsc org en Content ArticlePDF 2012 CS c2cs15299a gt a b c Pages Benjamin J Dale L Ang Elise P Wright and Janice R Aldrich Wright Metal Complex Interactions with DNA Royal Society of Chemistry n d Web 26 Jan 2015 lt http pubs rsc org en content articlehtml 2014 dt c4dt02700k gt a b Vargiu Attilio V and Alessandra Magistrato Detecting DNA Mismatches with Metallo Insertors A Molecular Simulation Study Inorganic Chemistry Inorganic Chemistry n d Web 26 Jan 2015 lt http pubs acs org doi pdfplus 10 1021 ic201659v gt a b Raman Natarajan Rajakumar Ramasubbu 2014 Bis amide Transition Metal Complexes Isomerism and DNA Interaction Study Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy 120 428 436 doi 10 1016 j saa 2013 10 037 PMID 24211801 a b Liu Yun Jun Liang Zhen Hua Li Zheng Zheng Yao Jun Hua Huang Hong Liang 2011 Ruthenium II Polypyridyl Complexes Synthesis and Studies of DNA Binding Photocleavage Cytotoxicity Apoptosis Cellular Uptake and Antioxidant Activity DNA and Cell Biology 30 2 829 38 doi 10 1016 j ejmech 2009 10 043 PMID 19932529 Du Ke Jie Jin Quan Wang Jun Feng Kou Guan Ying Li Li Li Wang Hui Chao and Liang a b Kielkopf C L K E Erkkila B P Hudson J K Barton and D C Rees INTERCALATION AND MAJOR GROOVE RECOGNITION IN THE 1 2 A RESOLUTION CRYSTAL STRUCTURE OF RH ME2TRIEN PHI BOUND TO 5 G 5IU TGCAAC 3 RCSB Protein Data Bank N p n d Web 26 Jan 2015 lt http www rcsb org pdb explore explore do structureId 454D gt a b Lauria Antonino Riccardo Bonsignore and Alessio Terenzi Nickel ii Copper ii and Zinc ii Metallo intercalators Structural Details of the DNA binding by a Combined Experimental and Computational Investigation RSC Publishing Royal Society of Chemistry n d Web 26 Jan 2015 lt http pubs rsc org EN content articlehtml 2014 dt c3dt53066c gt Alessandro Biancardi Azzurra Burgalassi Alessio Terenzi Angelo Spinello Giampaolo Barone Tarita Biver and Benedetta Mennucci title A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA Intercalator Salphen Type ZnII Complex journal Chemistry A European Journal date 2015 volume 20 issue 24 pages 7439 7447 doi 10 1002 chem 201304876 a b c d Pierre VC Kaiser JT Barton JK 2007 Insights into finding a mismatch through the structure of a mispaired DNA bound by a rhodium intercalator Proc Natl Acad Sci U S A 104 2 429 34 Bibcode 2007PNAS 104 429P doi 10 1073 pnas 0610170104 PMC 1766401 PMID 17194756 a b c d Junicke H Hart J R Kisko J Glebov O Kirsch I R Barton J K 2003 Bioinorganic Chemistry Special Feature A Rhodium III Complex for High affinity DNA Base pair Mismatch Recognition Proceedings of the National Academy of Sciences 100 7 3737 42 Bibcode 2003PNAS 100 3737J doi 10 1073 pnas 0537194100 PMC 152991 PMID 12610209 a b Hart J R Glebov O Ernst R J Kirsch I R Barton J K 2006 DNA Mismatch specific Targeting and Hypersensitivity of Mismatch repair deficient Cells to Bulky Rhodium III Intercalators Proceedings of the National Academy of Sciences 103 42 15359 5363 Bibcode 2006PNAS 10315359H doi 10 1073 pnas 0607576103 PMC 1622828 PMID 17030786 Retrieved from https en wikipedia org w index php title DNA binding metallo intercalators amp oldid 1163307692, wikipedia, wiki, book, books, library,
