Synthesis and Antitumour Activity of Some Novel Platinum(II) Organoamides and Organometallics

Deacon, Glen B.

doi:10.1007/978-1-4899-0738-7_13

Cited by 7 publications

(5 citation statements)

References 19 publications

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“…From this preliminary bioactivity study the following conclusion can be drawn: replacement of at least one Cl of [(COD)PtCl 2 ] leads to active agents. Since the presented results confirm the early trials of Komiya et al, and in view of related findings by Deacon et al, we suggest that optimizing the ligand set in such organometallic platinum complexes might yield complexes with superior cytotoxicity compared to nonorganometallic derivatives. Further comparative tests will thus be undertaken in the future.…”

Section: Resultssupporting

confidence: 89%

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and Their Derivatives

et al. 2009

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The [(COD)M(R)] 14 VE complex fragments (COD = 1,5-cyclooctadiene, R = methyl or neopentyl (2,2-dimethylpropyl), M = Pd or Pt) bind to the nucleobases cytosine (Cyt) or uracil (Ura), to the methylated nucleobase derivatives 1-methylcytosine (1MeCyt) or 1-methyluracil (1MeUra), and to the related ligand caffeine (Caf) (1,3,7-trimethylxanthine). From the potentially bridging cytosinate ligand a binuclear platinum complex [(COD)(Me)Pt(N3-cytosinate-N1)Pt(Me)-(COD)] + was obtained. The solubility of the corresponding complexes in organic solvents allowed their characterization by multiple ( 1 H, 13 C, and 195 Pt) NMR spectroscopy and in some cases by crystal structure analysis. Relative ligand-metal bond strength were discussed in view of 1 H-195 Pt NMR coupling constants. Further focus lies on the observation of binding isomers, the formation of binuclear species, multiple substitution, and the observed differences between Pt and Pd derivatives. Cytotoxicity experiments on HT-29 colon carcinoma and MCF-7 breast cancer cell lines revealed promising activities for selected platinum COD complexes.

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Section: Resultssupporting

confidence: 89%

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and Their Derivatives

et al. 2009

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“…The antitumor activities of cis -bis(pyridine)platinum(II) complexes with organoamide ligands ( 12 , 13 ) were reported by Deacon and co-workers. , The activities of these complexes were attributed to the large steric effect of the organoamide ligand. The replacement of the bulky organoamide ligand by chloride as in cis -[Pt(pyridine) 2 Cl 2 ] reduced the cytotoxicity of the compound.…”

Section: 1 Sterically Hindered Pt Complexesmentioning

confidence: 83%

“…In a L1210/L1210cisR pair of cell lines, cis -[Pt(pyridine) 2 Cl 2 ] 61 was less cytotoxic than cis -bis(pyridine) organoamide platinum(II) complexes, which had comparable activity to cisplatin. A number of the complexes with different organoamide ligands, unsubstituted and methyl-substituted pyridine, were evaluated in both cisplatin-sensitive and -resistant cell lines. , There was no significant difference in activity with variation of the organoamide ligands. However, complexes with pyridine ligands having 2-methyl substitution were less active than similar complexes with pyridine or 4-methylpyridine ligands .…”

Section: 1 Sterically Hindered Pt Complexesmentioning

confidence: 99%

“…A number of the complexes with different organoamide ligands, unsubstituted and methyl-substituted pyridine, were evaluated in both cisplatin-sensitive and -resistant cell lines. , There was no significant difference in activity with variation of the organoamide ligands. However, complexes with pyridine ligands having 2-methyl substitution were less active than similar complexes with pyridine or 4-methylpyridine ligands . This is possibly due to the steric hindrance effect of the 2-methyl group during the formation of the Pt-DNA adduct.…”

Section: 1 Sterically Hindered Pt Complexesmentioning

confidence: 99%

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Current Status of Platinum-Based Antitumor Drugs

Wong¹,

1999

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Industrial Research Fellow, investigating the coordination of technetium and rhenium to peptides and the synthesis of low molecular weight radiopharmaceuticals. His research interests centered on the applications of technetium and rhenium radiopharmaceuticals to oncology and neurology. In 1998, he joined the platinum development team at AnorMed, Inc., as a Senior Developmental Scientist. His current research interests include the design and synthesis of new Pt antitumor agents and the design of efficient processes for large-scale manufacture of Pt compounds. Christen Giandomenico received his Ph.D. degree in Chemistry from Columbia University and has held Post-doctoral positions at the University of Chicago and the Stanford Research Institute. In 1985 he joined Johnson-Matthey where he was a co-inventor of JM216, the first orally active platinum anticancer drug. He is a named inventor on six patents and is the author of 19 scientific articles. In 1996 he helped found AnorMED, a company dedicated to the discovery and development of metal-based therapeutics. He is currently Director of Chemical Development at AnorMED.

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“…However, if this hindrance on the N atom is not present, as is the case with the “nonclassical” complexes containing aromatic ligands (such as bmic or pyridine), the close interaction with DNA is not hindered and Pt binding can occur relatively fast. The introduction of alkyl substituents on the pyridine ligands of the organoamide complexes results in reduced antitumor activity, probably as a result of increased steric hindrance upon binding to DNA. So, for this new class of Pt compounds, the presence of an NH group is not necessary, because of the absence of steric hindrance around the nitrogen.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, and of the Inactive Analog Dichloro(N¹,N^1‘-dimethyl-2,2‘-biimidazole)platinum(II)

et al. 1996

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To obtain insight into the structure−activity relationships of new antitumor active platinum compounds the X-ray structure of the antitumor active Pt compound [Pt(bmic)Cl2] (bmic = bis-(N-methylimidazol-2-yl)carbinol) (1) and its interaction with short DNA fragments has been investigated using NMR spectroscopy. For comparison also the structurally related compound [Pt(bmi)Cl2] (bmi = N 1,N 1‘-dimethyl-2,2‘-biimidazole) (2), which is not antitumor active, has been studied. The structure of the compound [Pt(bmic)Cl2] (1) was characterized by single-crystal X-ray structure determination. Compound 1 crystallizes in the monoclinic space group P21/n, with a = 10.055(3) Å, b = 11.802(3) Å, c = 10.620(3) Å, β = 103.78(2)°, V = 1224.0(6) Å3 and Z = 4. Convergence was reached at wR2 = 0.1148 (all data) and R1 = 0.0476 (I > 2 (I)) for 2433 independent reflections and 156 adjustable parameters. The platinum atom is coordinated by two nitrogen and two chlorine atoms, resulting in a square planar PtN2Cl2 coordination sphere. The two best least-squares planes through the two imidazole rings of the bmic ligand show a dihedral angle of 30.6°. The in vitro and in vivo antitumor activity of 1 is significant whereas for compound 2 no antitumor activity could be detected. In P388 mice leukemia an increase of lifespan of 56% was found for complex 1. The antitumor active Pt compound [Pt(bmic)Cl2] binds to G bases in a similar fashion as cisplatin with a clear preference for N7. In reaction with d(GpG) two stereoisomers are formed, due to the unsymmetric bmic complex and the chiral d(GpG) molecule. Stereoisomer A, i.e. the isomer with the OH group of the bmic and the O6 of the G bases oriented on the same side of the Pt−N4 plane, is preferentially formed. Modeling studies suggest that this preference is due to the presence of H bonds from the OH of the bmic moiety toward the O6 of the G bases. The presence of many conformers, present in solution, could also be due to these H bonds. For the inactive complex [Pt(bmi)Cl2] only one GG-N7,N7 chelate is observed. Differences in reactivity toward G bases were also detected for the two platinum complexes. The inactive bmi complex proves to be the most reactive one, whereas the antitumor active bmic compound is less reactive. Thus both structural and kinetic properties may explain the different biological properties of these new platinum compounds.

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Synthesis and Antitumour Activity of Some Novel Platinum(II) Organoamides and Organometallics

Cited by 7 publications

References 19 publications

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and Their Derivatives

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and Their Derivatives

Current Status of Platinum-Based Antitumor Drugs

Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, and of the Inactive Analog Dichloro(N¹,N^1‘-dimethyl-2,2‘-biimidazole)platinum(II)

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Synthesis and Antitumour Activity of Some Novel Platinum(II) Organoamides and Organometallics

Cited by 7 publications

References 19 publications

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and Their Derivatives

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and Their Derivatives

Current Status of Platinum-Based Antitumor Drugs

Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, and of the Inactive Analog Dichloro(N1,N1‘-dimethyl-2,2‘-biimidazole)platinum(II)

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Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, and of the Inactive Analog Dichloro(N¹,N^1‘-dimethyl-2,2‘-biimidazole)platinum(II)