BIOIXORGANICCHEMISTRY
S, Sl-58
(1975)
51
Platinum Complexes of Nixckotides PI-CHANG
KONG and THEOPHILE THEOPHANIDES
Department of Chemistry. University of Montreal, Montreal, Quibec, Canada, HSCSVI.
ABSTRACT The reaction of [Pt(dien)Cl]Cl
(dien = NH,CH,CH,NHCH,CH,NH,) with nucleotides has been studied by nuclear magnetic resonance. It has been found that the CMP (cytidine 5’-monophosphate) and GMP (guanosine 5’-monophosphate) coordinate to the platinum atom through N, and N,, respectively. The reaction of the platinum salt with the nucleotide is complete when one to one ratio of platinum to nucleotide is used and no evidence of phosphate group binding to platinum has been found- No additional binding sites have been detected except the N, site on the guanylic group of GMP even in the presence of a large excess of [ Pt(dien)Cl] CI. The AMP (adenosine 5’ monophosphate) coordinates to the platinum at the N, and/or N, sites- The reaction of AhiP and platinum is complete at a ratio of four platinum to one AMP.
INTRODUCTION Certain platinum compounds have been found to inhibit selectively the synthesis of DNA [ 1,2] _ As a consequence, the binding of platinum to DNA [3] and its constituents 14-61 has become an interesting field of research_ In our previous work [Sl , we have studied the interaction of [Pt(dien)Cl] Cl (dien = NH? (CHa CHa NHCHZ CH*NH* ) and nucleosides. It was found earlier [4,5 1 that adenosine and purine riboside were bidentate ligands with Nr and N, coordinating to different platinum atoms. Since [Pt(dien)CllCl has only one chlorine atom in the inner sphere to be displaced, the possibility of chelation is excluded. Consequently, the cation [Pt(dien)Cll+ could serve as a simple model for studying the binding of platinum to nucleosides, nucleotides and DNA. The present work was undertaken in order to investigate the interaction of IPt(dien)Cll Cl with nucleotides, which are generally more soluble in water than the corresponding nucleosides. We are therefore able to study the nucleotides at higher concentrations due to their solubility in water. The study of piatinumnucleotides at higher concentrations of nucleotide is of greater biological significance due to the fact that the nucleotide is always in excess in the body with respect to the platinum drug. This study was also started in order to see if the phosphate group of the nucleotide interacted as well with platinum. 0 American Ekvier
Publishing Company, Inc., 1975
58
-
P-4,
KONG AND T.
PIat
i num
THEOPHAMDES
/Adsnosi
ne
FIG. 4_ The change in percentage of each peak with adenosiner peak 1, - peak 2, Q; peak 3, & peak 4. D.
. 1. 7, 3_ 4_ 5. 6_ 7. 8.
9. 10. 11.
the ratios of IPt(dien)Cf]CI
to
REFERENCES
H. C. Harder and B_ Rosenberg, irzt. J. G.R_Gale,J,A_Howie,andE.M.
CQnCer 6, 207 (1970). Walker, Jr.,CuncerRes. 31,950
(1971).
3. P. Macquet and T. Theophanides, Biopolymers, 14,781 (1975). P. C_ Kong and T. Theophanides, Inorg Chem. 13,1167 (1974). P. C_ Kong and T. Theophanides, Inorg. Chem. 13, 1981(1974). S. Mansy, B_ Rosenberg, and A. J. Thomson,/. Amer_ Chem Sot. 95,1633 (1973). M_ P. Schweizer. S. I. Ghan, G. K. Helmkamp, and P. 0. P. Ts’o, 1: Amer. Chem Sot. 86,696 (1964). (a) P. 1). Kaplan, P. Schmidt, A Brause. and M_ Orchin, .L Am-er. Chem. Sot. 91 85 (1969); (b) A. B. Brause, F. Kaplan, and M. Orchin, J. Amer. Chem. SOC. 89, 2661 (1967). G. R Clark and J. D. OrbelL J.CS. Chem. Comm., 139 (1974). M. Ogawa and T. Sakaguch, Chem. pharm Buli X9,1650 (1971). F_ G. Mann. .L Chem. Sot., 466 (1934).
Received I6 October 1974
S, Sl-58
(1975)
51
Platinum Complexes of Nixckotides PI-CHANG
KONG and THEOPHILE THEOPHANIDES
Department of Chemistry. University of Montreal, Montreal, Quibec, Canada, HSCSVI.
ABSTRACT The reaction of [Pt(dien)Cl]Cl
(dien = NH,CH,CH,NHCH,CH,NH,) with nucleotides has been studied by nuclear magnetic resonance. It has been found that the CMP (cytidine 5’-monophosphate) and GMP (guanosine 5’-monophosphate) coordinate to the platinum atom through N, and N,, respectively. The reaction of the platinum salt with the nucleotide is complete when one to one ratio of platinum to nucleotide is used and no evidence of phosphate group binding to platinum has been found- No additional binding sites have been detected except the N, site on the guanylic group of GMP even in the presence of a large excess of [ Pt(dien)Cl] CI. The AMP (adenosine 5’ monophosphate) coordinates to the platinum at the N, and/or N, sites- The reaction of AhiP and platinum is complete at a ratio of four platinum to one AMP.
INTRODUCTION Certain platinum compounds have been found to inhibit selectively the synthesis of DNA [ 1,2] _ As a consequence, the binding of platinum to DNA [3] and its constituents 14-61 has become an interesting field of research_ In our previous work [Sl , we have studied the interaction of [Pt(dien)Cl] Cl (dien = NH? (CHa CHa NHCHZ CH*NH* ) and nucleosides. It was found earlier [4,5 1 that adenosine and purine riboside were bidentate ligands with Nr and N, coordinating to different platinum atoms. Since [Pt(dien)CllCl has only one chlorine atom in the inner sphere to be displaced, the possibility of chelation is excluded. Consequently, the cation [Pt(dien)Cll+ could serve as a simple model for studying the binding of platinum to nucleosides, nucleotides and DNA. The present work was undertaken in order to investigate the interaction of IPt(dien)Cll Cl with nucleotides, which are generally more soluble in water than the corresponding nucleosides. We are therefore able to study the nucleotides at higher concentrations due to their solubility in water. The study of piatinumnucleotides at higher concentrations of nucleotide is of greater biological significance due to the fact that the nucleotide is always in excess in the body with respect to the platinum drug. This study was also started in order to see if the phosphate group of the nucleotide interacted as well with platinum. 0 American Ekvier
Publishing Company, Inc., 1975
58
-
P-4,
KONG AND T.
PIat
i num
THEOPHAMDES
/Adsnosi
ne
FIG. 4_ The change in percentage of each peak with adenosiner peak 1, - peak 2, Q; peak 3, & peak 4. D.
. 1. 7, 3_ 4_ 5. 6_ 7. 8.
9. 10. 11.
the ratios of IPt(dien)Cf]CI
to
REFERENCES
H. C. Harder and B_ Rosenberg, irzt. J. G.R_Gale,J,A_Howie,andE.M.
CQnCer 6, 207 (1970). Walker, Jr.,CuncerRes. 31,950
(1971).
3. P. Macquet and T. Theophanides, Biopolymers, 14,781 (1975). P. C_ Kong and T. Theophanides, Inorg Chem. 13,1167 (1974). P. C_ Kong and T. Theophanides, Inorg. Chem. 13, 1981(1974). S. Mansy, B_ Rosenberg, and A. J. Thomson,/. Amer_ Chem Sot. 95,1633 (1973). M_ P. Schweizer. S. I. Ghan, G. K. Helmkamp, and P. 0. P. Ts’o, 1: Amer. Chem Sot. 86,696 (1964). (a) P. 1). Kaplan, P. Schmidt, A Brause. and M_ Orchin, .L Am-er. Chem. Sot. 91 85 (1969); (b) A. B. Brause, F. Kaplan, and M. Orchin, J. Amer. Chem. SOC. 89, 2661 (1967). G. R Clark and J. D. OrbelL J.CS. Chem. Comm., 139 (1974). M. Ogawa and T. Sakaguch, Chem. pharm Buli X9,1650 (1971). F_ G. Mann. .L Chem. Sot., 466 (1934).
Received I6 October 1974
