Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2009 NONCOVALENT INTERACTION OF PLATINUM PLANAR AMINE COMPOUNDS WITH TRYPTOPHAN: A STRATEGY TO INTERFERE WITH P53-MDM2 INTERACTIONS AND TARGETING RETROVIRAL ZN FINGER-DNA INTERACTION (HIV NCP7) Aaron Bate Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Chemistry Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/29 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass For more information, please contact libcompass@vcu.edu 1 © Aaron Bate 2009 All Rights Reserved 2 NONCOVALENT INTERACTION OF PLATINUM PLANAR AMINE COMPOUNDS WITH TRYPTOPHAN: A STRATEGY TO INTERFERE WITH P53-MDM2 INTERACTIONS AND TARGETING RETROVIRAL ZN FINGER-DNA INTERACTION (HIV NCP7) A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University By Aaron B Bate B Sc In Chemistry, Salisbury Univeristy-2007 Director: Dr Nicholas Farrell PROFESSOR, DEPARTMENT OF CHEMISTRY, COLLEGE OF HUMANITIES AND SCIENCES, VIRGINIA COMMONWEALTH UNIVERSITY Virginia Commonwealth University Richmond, Virginia December, 2009 3 Acknowledgements This thesis and research for the past two years is a result of a joint effort from several individuals First I would like to thank my wife for giving me the love and support to get through my graduate work; my advisor Dr Nicholas Farrell for giving me the opportunity to work on this project and for providing me with the resources and tools to make a contribution towards this project; Dr Yun Qu for assisting me and teaching me the spectroscopic techniques of NMR; my committee for providing advice on my research project; past and present group members: Dr Ibrahim Zgani, Brad Benedetti, Ralph Kipping, Dr Michael Vadala, Chris Lopez, and Dr Quiete De Paula for their support, patience and guidance I would also like to thank God for providing the opportunities that lead me to where I am now 4 Table of Contents Acknowledgements………………………………………………………………………………………2 List of Figures… List of Schemes………………………………………………………………………………………… List of Tables…………………………………………………………………………………………… List of Abbreviations…………………………………………………………………………………… Chapter N0 Introduction…………………………………………………………………………… 10 1.1 π stacking……………………………………………………………………… 10 1.2 π-π stacking in biological processes……………………………………….13 1.3 Nucleobase Modification………………………………………………….21 1.4 References…………………………………………………………………26 Platination of Nucleobases………………………………………………………27 2.1 Abstract………………………………………………………………… 27 2.2 Introduction……………………………………………………………….27 2.3 Results and Discussion…………………………………………………….30 2.4 Stacking interaction by fluorescence spectroscopy……………………… 37 2.5 Experimental section………………………………………………………48 2.6 Conclusion…………………………………………………………………54 2.7 References…………………………………………………………………55 VITA…………………………………………………………………………………….57 Supplemental Information……………………………………………………………….59 5 List of Figures Page Figure 1.1: Principal orientations of aromatic-aromatic interactions……………………………10 Figure 1.2: Pictorial representation of the electrostatic interactions…………………………….11 Figure 1.3: π-π repulsion in benzene-benzene interaction if in face-to-face alignment…………12 Figure 1.4: Decrease in π-electron density for aromatic rings containing a nitrogen heteroatom within the ring……………………………………………………………………………………13 Figure 1.5: Unpaired T in the MutS co-crystal partially stacked in the DNA duplex………… 15 Figure 1.6: Stacking of Phe 39 of the MutS to the unpaired T of the DNA…………………….15 Figure 1.7: Three dimensional structure of the 82-nucleotide RNA-DNA complex……………17 Figure 1.8: View of complex perpendicular to the principal axis, showing stacking interactions………………………………………………………………………………………18 Figure 1.9: Crystal structure of p53 (green)/MDM2 (yellow and white) binding pocket Three amino acids of p53 shown inside binding pocket, leucine, tryptophan and phenylalanine; which are essential for the binding of MDM2………………………………………………………….20 Figure 1.10 Sequence of NCp7 showing coordinating residues in red…………………………20 Figure 1.11 Amino acids capable of π-π stacking interactions………………………………….21 Figure 1.12 Nucleobases adenine (A), guanine (G), thymine (T), and cytosine (C)……………21 6 Figure 1.13: Protonation, alkylation or coordination of a metal ion such as Pd(II) or Pt(II) to a nucleobases strengthens the interaction by lowering the energy of the lowest unoccupied molecular orbital of the modified nucleobases (LUMO) and improving overlap with the highest occupies molecular orbital (HOMO) in N-acetyl tryptophan………………………………… 22 Figure 1.14: HOMO/LUMO energies for nulceobases, methylated nucleobases and metal coordinated nucleobases Dash line is the HOMO of N-AcTrp [Pd(dien)(1-MethylCytosiene)]2+ (1); [Pt(dien)(1-MethylCytosiene)]2+ (2); [Pd(dien)(9-EthylGuanine)]2+ (3); [Pt(dien)(9EthylGuanine)]2+ (4)…………………………………………………………………………….23 Figure 1.15: Platination, Pt(II), of a nucleobase enhances the interaction by lowering the energy of the LUMO of the nucleobase and improving the overlap with the HOMO of the N-acetyl tryptophan……………………………………………………………………………………….24 Figure 1.16: Correlation between association constants, determined for free 1-MeCyt and Pd/Pt1MeCyt complexes, with the ∆ε value………………………………………………………….25 Figure 2.1: Schematic structures of complexes used in this study…………………………… 29 Figure 2.2: H-NMR spectroscopy of Complex in D20……………………………………… 31 Figure 2.3: 1H-NMR spectroscopy of Complex in D20……………………………………….32 Figure 2.4: 1H-NMR spectroscopy of Complex in D20……………………………………….33 Figure 2.5: 1H-NMR spectroscopy of Complex in D20……………………………………….33 Figure 2.6: 1H-NMR spectroscopy of Complex in D20……………………………………….34 Figure 2.7: 1H-NMR spectroscopy of Complex in D20……………………………………….35 Figure 2.8: 1H-NMR spectroscopy of Complex in D20……………………………………….36 Figure 2.9: 1H-NMR spectroscopy of Complex in D20……………………………………….37 7 Figure 2.10: Fluorescence spectrum of [Pt(dien)(pyridine)]NO3 stacking with tryptophan…………………………………………………………………………………………… 38 Figure 2.11: Fluorescence spectrum of [Pt(dien)(4-picoline)]NO3 stacking with L-acetyl tryptophan……………………………………………………………………………………….39 Figure 2.12: Fluorescence spectrum of [Pt(dien)(4-methoxypyridine)]NO3 stacking with L-acetyl tryptophan……………………………………………………………………………………… 40 Figure 2.13: Fluorescence spectrum of Pt(dien)(4-Dimethylaminopyridine)](NO3) stacking with L-acetyl tryptophan………………………………………………………………………………42 Figure 2.14: Fluorescence spectrum of [Pt(dien)(cyanopyridine)]NO3 stacking with L-acetyl tryptophan……………………………………………………………………………………… 43 Figure 2.15: Fluorescence spectrum of [Pt(dien)(thiazole)]NO3 stacking with L-acetyl tryptophan……………………………………………………………………………………… 44 Figure 2.16: Fluorescence spectrum of [Pt(dien)(benzothiazole)](NO3) stacking with L-acetyl tryptophan……………………………………………………………………………………… 46 Figure 2.17: Fluorescence spectrum of [Pt(dien)(quinoline)](NO3) stacking with L-acetyl tryptophan……………………………………………………………………………………… 47 Figure 2.18: % fluorescence quenching of tryptophan by [Pt(dien)nucleobase]NO3 complexes……………………………………………………………………………………… 54 List of Schemes Page Scheme 2.1: Platination of nucleobases…………………………………………………………49 List of Tables Page Table 1: Pt(dien)L data………………………………………………………………………… 53 8 Table 2: 195Pt coupling (J) values (Hz)………………………………………………………….53 List of Abbreviations D20 Deuterium Oxide Dien Diethylenetriamine DMF Dimethyl foramide DNA Deoxy riboNucleic Acid 9-EtGH 9-ethyl guanine eV Electron Volts HNPCC Nonpolyposis Colorectal Cancer HOMO Highest Occupied Molecular Orbital ITC Isothermal Titration Calorimetry Ka Association constant LUMO Lowest Unoccupied Molecular Orbital MDM2 Murine Double Minute gene 1-MeCyt 1-Methyl cytosine MMR DNA mismatch repair NCp7 Nucleocapsid protein N-AcTrp N-Acetyl Tryptophan NMR Nuclear Magnetic Resonance Phe Phenylalanine ppm Parts per million py Pyridine p53 Tumor protein 53 or protein 53 RNA RiboNucleic Acid TAQ Thermus aquaticus 9 Abstract Non-covalent interactions involving π-π stacking play an essential role in self-assembly and molecular recognition processes such as protein folding and DNA/RNA-protein selective recognition The knowledge gained from these studies could provide insight into possible site recognition complexes, inhibiting or mimicking protein-protein or protein-DNA interactions Based on molecular modeling as well as HOMO and LUMO energies, several chromophores were selected with a variety of ∆ε values (∆ε= |εHOMO,NAcTrp – εLUMO,chromophores|), high and low, to establish a correlating trend with the modeling and experimental data The corresponding Pt(dien) compounds were synthesized and their ability to stack to N-acetyl tryptophan was evaluated by fluorescence quench experiments Attaching a strong electron donating/withdrawing group or extending the π system of pyridine or thiazole by means of a benzene ring (quinoline and benzothiazole) was found to enhance the π-π interaction with Nacetyl tryptophan 45 b Figure 2.15 (a) absorbance spectrum of [Pt(dien)(thiazole)](NO3)2 at 7mM concentration (b)Fluorescence spectrum of [Pt(dien)(thiazole)](NO3)2 (7mM) stacking with L-acetyl tryptophan(5µM) after excitation at 280nm First line is the emission of just tryptophan; last line is [quencher]/[tryptophan] at 100:10; after ten additions of quencher (7mM) Extending these two π systems further improved the stacking with tryptophan The two compounds examined were benzothiazole and quinoline, just an addition of benzene to the previous two compounds [Pt(dien)(benzothiazole)](NO3) showed a % fluorescence quenching of 36.24 (figure 2.16) and [Pt(dien)(quinoline)](NO3) showed a % fluorescence quenching of 29.41 (Figure 2.17) 46 a b Figure 2.16 (a) absorbance spectrum of Pt(dien)(benzothiazole)](NO3)2 at 7mM concentration (b)Fluorescence spectrum of [Pt(dien)(benzothiazole)](NO3)2 (7mM) stacking with L-acetyl tryptophan (5µM) after excitation at 280nm First line is the emission of just tryptophan; last line is [quencher]/[tryptophan] at 100:10; after ten additions of quencher (7mM) 47 a b Figure 2.17 (a) absorbance spectrum of [Pt(dien)(quinoline)](NO3)2 at 7mM concentration(b)Fluorescence spectrum of [Pt(dien)(quinoline)](NO3)2 (7mM) stacking with Lacetyl tryptophan (5µM) after excitation at 280nm First line is the emission of just tryptophan; last line is [quencher]/[tryptophan] at 100:10; after ten additions of quencher (7mM) 48 2.5 Experimental Section Materials Quinoline, 4-Dimethylaminopyridine, Benzothiazole, 4-Methoxypyridine, Pyridine, 4-Picoline, Thiazole, 4-Cyanopyridine, 9-Ethylguanine and N-Acetyltrypotophan were Alfa Aesar, Sigma Aldrich and TCI America; complex [Pt(dien)(NO3)](NO3) was synthesized according to reported procedures.[49] Nuclear Magnetic Resonance experiments 1H NMR spectra were recorded on a Varian Mercury series 300 MHz Spectrometer using a 5-mm tube; chemical shifts were referenced to a residual signal in D2O (4.79ppm) and DMF-d7 (8.00 ppm) 195 Pt-NMR were recorded on a Varian Mercury series 300 MHz Spectrometer using a 10-mm tube Chemical shifts were referenced to K2[PtCl6] The scanning frequency for 195Pt nuclei was set at 64.32 MHz Fluorescence Experiments In a typical experiment, mL of N-AcTrp (5 µM) were titrated with aliquots of the corresponding quenching compound (7 mM) with a ratio of ([quencher]/[NAcTrp]) 100-10; 10.5 mM Phosphate buffer adjusted with a few drops of HCL was used in all experiments (pH 7.0) The maximum intensity of the spectrum (ca 357 nm) was measured for each addition, and the association constants for each system were obtained from the analysis of the Eadie-Hofstee plots.[50] Measurements were made at 20°C, and the reported % fluorescence quenching of tryptophan were averaged over a number of three different experiments Fluorescence spectra were recorded in the range of 320-420 nm with a scan rate of 120nm/min 49 2.5.1 Synthesis and Characterization of complexes Cl Cl Cl H2O Pt I K2 2DMSO Cl Pt Cl 2KCl DMSO Cl DMSO NH2 Cl II HN Pt Cl DMSO N H H2N NH2 Pt Methanol Cl NH2 DMSO NH2 III NH Pt NH2 Cl 2AgNO3 Cl NH NO3 Pt NO3 AgCl H2O NH2 NH2 NH2 IV NH Pt NH2 NO3 NO3 X NH Pt NO3 X H2O/DMF NH2 NH2 OCH3 N N S X= N N N O CN S N N N HN N Scheme 2.1 Platination of nucleobases N H2N N N Cl 50 Pt(Cl2)(DMSO2) Pt(Cl2)(DMSO2) prepared similar to a reported procedure.[51] K2PtCl4 was suspended in 10 mL H2O and reacted with a 1:1 molar ratio of DMSO at room temperature for 24 hrs Precipitate was filtered and washed with water, ethanol, and ether and dried in vacuo (84% yield).1H-NMR (D2O) δ 3.65 [Pt(dien)Cl]Cl [Pt(dien)Cl]Cl was prepared similar to a reported procedure.[52] PtCl2DMSO2 was suspended in 120 mL methanol and reacted with a 1:1 molar ratio of diethyltriamine at reflux for hrs Solution was evaporated down to ~10 mL and 5ml of methanol was added After this ether was added and white solid appeared Centrifuge was used to obtain the solid Solid was then dried in vacuo (86% yield) 1H-NMR (D2O) δ 2.8 [Pt(dien)(Quinoline)](NO3)(1) [Pt(dien)(Quinoline)](NO3) was prepared similar to a reported procedure.[53] Two equivalents of AgNO3 were added to a solution of [Pt(dien)Cl]Cl in H2O and solution stirred overnight to remove the chloride ligands and produce the complex [Pt(dien)NO3]NO3 in situ The solution was then filtered and lyophilized to produce a white solid The white solid was dissolved in DMF and Quinoline was then added in 3-1 molar amounts and the mixture was stirred overnight Solution was evaporated down to ~5 mL and mL of methanol was added and an off white solid was obtained upon addition of ether and centrifugation Solid dried in vacuo (50% yield) 1H-NMR (D2O) δ 3.0, 7.6, 7.9, 8.1, 8.3, 8.5, 9.5 Calcd for C13H20N6O6Pt: C, 28.32; H, 3.66 ; N, 15.24 Found: C 27.76; H, 3.45; N, 14.88% 51 [Pt(dien)(4-Dimethylaminopyridine)](NO3)(2) [Pt(dien)(4-Dimethylaminopyridine)](NO3) was prepared similar to that of [Pt(dien)(Quinoline)](NO3) using 4-Dimethylaminopyridine as the nucleobase and H2O as the solvent (26% yield) 1H-NMR (D2O) δ 3.0, 6.6, 8.0 Calcd for C11H23N7O6Pt: C, 24.27; H, 4.26; N, 18.01 Found: C, 23.91; H, 4.89; N,19.62 % [Pt(dien)(Benzothiazole)](NO3)(3) [Pt(dien)(Benzothiazole)](NO3) was prepared similar to that of [Pt(dien)(4-Dimethylaminopyridine)](NO3) using benzothiazole as the nucleobase (29% yield) 1H-NMR (D2O) δ 3.0, 7.7, 7.8, 8.1, 8.8, 9.7 Calcd for C11H18N6O6Pt: C, 23.70; H, 3.25; N, 15.08 Found: C, 23.14; H, 3.29; N, 14.26 % [Pt(dien)(4-Methoxypyridine)](NO3)(4) [Pt(dien)(4-Methoxypyridine)](NO3) was prepared similar to that of [Pt(dien)(4-Dimethylaminopyridine)](NO3) using 4-mehtoxypyridine as the nucleobase (24% yield) 1H-NMR (D2O) δ 3.0, 3.9, 7.1, 8.4 Calcd for C10H20N6O7Pt: C, 22.60; H, 3.79; N, 15.82 Found: C, 21.31; H, 3.91; N, 15.41 % [Pt(dien)(pyridine)](NO3)(5) [Pt(dien)(pyridine)](NO3) was prepared similar to that of [Pt(dien)(4-Dimethylaminopyridine)](NO3) using pyridine as the nucleobase (62% yield) 1HNMR (D2O) δ 3.0, 7.5, 8.0, 8.7 Calcd for C9H18N6O6Pt: C, 21.56; H, 3.62; N, 16.76 Found: C 21.28; H, 3.34; N, 15.86% [Pt(dien)(4-picoline)](NO3)(6) [Pt(dien)(4-picoline)](NO3) was prepared similar to that of [Pt(dien)(4-Dimethylaminopyridine)](NO3) using 4-picoline as the nucleobase (48% yield) 1H- 52 NMR (D2O) δ 2.4, 3.0, 7.38, 8.5 Calcd for C10H20N6O6Pt: C, 23.30; H, 3.91; N, 16.31 Found: C, 22.82; H, 3.69; N, 15.39% [Pt(dien)(Thiazole)](NO3)(7) [Pt(dien)(Thiazole)](NO3) was prepared similar to that of [Pt(dien)(4-Dimehtylaminopyridine)](NO3) using thiazole as the nucleobase (39% yield) 1HNMR (D2O) δ 3.0, 7.75, 7.94, 9.2 Calcd for C7H16N6O6PtS: C, 16.57; H, 3.18; N, 16.56 Found: C, 16.74; H, 2.67; N, 16.07% [Pt(dien)(4-Cyanopyridine)](NO3)(8) [Pt(dien)(4-Cyanopyridine)](NO3) similar to that of [Pt(dien)(4-Dimethylaminopyridine)](NO3) using 4-cyanopyridine as the nucleobase and heating at 40°C (23% yield) 1H-NMR (D2O) δ 3.0, 7.94, 9.0 Calcd for C10H17N7O6Pt: C, 22.82; H, 3.26; N, 18.63 Found: C, 21.93; H, 3.19; N, 18.11% [Pt(dien)(9-Ethylguanine)](NO3)(9) was a gift from Dr Q.A dePaula Table Pt(dien)L data L Benzothiazole 4-Cyanopyridine 4-Dimethylaminopyridine 4-Methoxypyridine 4-Picoline Quinoline Pyridine Thiazole δ195Pt (ppm) -2861 -2839 -2816 -2824 -2835 -2837 -2833 -2820 λmax (nm) 262.5 274 277.5 257 257.5 305.5 257.5 258.5 pKa’s of L ɛ @ λmax ɛ @ λmeasured 1.2 1.92 9.2 6.56 6.25 4.85 5.14 2.44 2625000 2740000 2775000 2570000 2575000 3055000 2575000 2585000 3570000 3570000 3570000 3570000 3570000 3570000 3570000 3570000 53 Table 195Pt coupling (J) values (Hz) L Benzothiazole 4-Cyanopyridine 4-Dimethylaminopyridine 4-Methoxypyridine 4-Picoline Quinoline Pyridine Thiazole 195 Pt coupling ( 3J (Pt-H)) value (Hz) 48.568 55.715 52.391 55.368 56.154 101.883 58.424 44.959 2.6. 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Acta, 2002. 339: p. 400‐410. 57 VITA Education _ • Master of Science in Chemistry, Virginia Commonwealth University (VCU) Richmond, VA GPA: 3.02 Thesis Advisor: Dr Nicholas P Farrell • Bachelors of Science in Chemistry, Salisbury University Salisbury, MD GPA: 3.0 Advisor: Dr Miguel Mitchell “Quanternized promazine/promethazine derivatives in inhibiting NADH II production” Relative Work Experience Research Assistant, VCU, Richmond, VA, 01/08-12/09 • Synthesis and characterization of platinum(II) antitumor complexes Teaching Assistant, VCU, Richmond, VA, 07/07-12/09 • Assisted in teaching General chemistry I and II, Organic I and II laboratory Research Assistant, Salisbury University, Salisbury, MD, 01/06-06/07 • Synthesis and characterization of promazine/promethazine derivatives in inhibiting NADH II production Presentations and Seminars • Aaron B Bate, “ Noncovalent Interaction of Platinum Planar Amine Compounds with Tryptophan: As a Strategy to Interfere with p53-MDM2 Interactions” poster presentation at Virginia Commonwealth University, October 2008 • Non-Thesis Research Seminar presentation titled, “Delivery Applications of Gold Nanoparticles.” Virginia Commonwealth University, April 2008 • Senior Research Seminar titled, “Halogen Bonding.” Salisbury Universitiy, May 2007 • Aaron B Bate, “Synthesis and Biological Study of Quaternized Promazine and Promethazine derivatives” Salisbury University Research Conference May 2007 58 • Aaron B Bate, “Synthesis and Biological Study of Quaternized Promazine and Promethazine derivatives” Intercollegiate Student Chemists Convention, Ursinus College PA, April 2007 Publications _ • Aaron B Bate, Jay H Kalin, Eric M Fooksman, Erica L Amorose, Cristofer M Price, Heather M Williams, Michael J Rodig, Miguel O Mitchell, Sang Hyun Cho Yuehong Wang and Scott G Franzblau, “Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives” Bioorganic and Medicinal Chemistry Letters 2007 Awards and Scholarships _ • Philip Morris first year research scholarship (2008) • Dean’s List (2007) • Senatorial Scholarship (2003-2007) • State Scholarship (2003-2007) Additional Skills _ • Spectroscopic methods of characterization: UV/VIS spectroscopy, IR spectroscopy, Raman spectroscopy, Fluorescence spectroscopy, Isothermal Titration Calorimetry, Nuclear Magnetic Resonance Spectroscopy (1D and 2D) • Computer skills: Several versions of MS-Windows, Word, Excel, PowerPoint, Photoshop • Visualization programs: MestReC, ChemOffice, PyMol 59 Supplemental Information Table Pt(dien)L data L Benzothiazole 4-Cyanopyridine 4-Dimethylaminopyridine 4-Methoxypyridine 4-Picoline Quinoline Pyridine Thiazole δ195Pt (ppm) -2861 -2839 -2816 -2824 -2835 -2837 -2833 -2820 λmax (nm) 262.5 274 277.5 257 257.5 305.5 257.5 258.5 pKa’s of L ɛ @ λmax ɛ @ λmeasured 1.2 1.92 9.2 6.56 6.25 4.85 5.14 2.44 2625000 2740000 2775000 2570000 2575000 3055000 2575000 2585000 3570000 3570000 3570000 3570000 3570000 3570000 3570000 3570000 Table 195Pt coupling (J) values (Hz) L Benzothiazole 4-Cyanopyridine 4-Dimethylaminopyridine 4-Methoxypyridine 4-Picoline Quinoline Pyridine Thiazole 195 Pt coupling ( 3J (Pt-H)) value (Hz) 48.568 55.715 52.391 55.368 56.154 101.883 58.424 44.959 ... Aaron Bate 2009 All Rights Reserved 2 NONCOVALENT INTERACTION OF PLATINUM PLANAR AMINE COMPOUNDS WITH TRYPTOPHAN: A STRATEGY TO INTERFERE WITH P53-MDM2 INTERACTIONS AND TARGETING RETROVIRAL... of tryptophan is an estimate of the strength of the π-π stacking interaction. [45, 46] The fluorescence data can be used to calculate the association constant, Ka; a mathematical constant that... Pictorial representation of the electrostatic interactions.[7] 12 These electrostatic and Van der Waals interactions are essentially attractive forces but are dependent on distance, with their