Bis(platinum) complexes containing two platinum cis-diammine units.  Synthesis and initial DNA-binding studies

Farrell, Nicholas; Almeida, Sérgio Gama de; Skov, Kirsten A.

doi:10.1021/ja00223a019

Cited by 97 publications

(47 citation statements)

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“…Flexible alkyldiamine chains have been used to link two platinum moieties, each containing two cisconfigured reactive sites bound to chloride (Farrell et al 1988). These complexes are capable of forming DNA interstrand cross-links by binding one platinum unit to each DNA strand (Roberts et al 1989).…”

Section: Dinuclear and Trinuclear Complexesmentioning

confidence: 99%

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Jakupec

Galanski

Keppler

2003

Reviews of Physiology, Biochemistry and Pharmacology

383

349

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Thirty years after the onset of the first clinical studies with cisplatin, the development of antineoplastic platinum drugs continues to be a productive field of research. This article reviews the current preclinical and clinical status, including a discussion of the molecular basis for the activity of the parent drug cisplatin and platinum drugs of the second and third generation, in particular their interaction with DNA. Further emphasis is laid on the development of third generation platinum drugs with activity in cisplatin-resistant tumours, particularly on chelates containing 1,2-diaminocyclohexane (DACH) and on the promising and more recently evolving field of non-classic ( trans- and multinuclear) platinum complexes. The development of oral platinum drugs and drug targeting strategies using liposomes, polymers or low-molecular-weight carriers in order to improve the therapeutic index of platinum chemotherapy are also covered.

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Section: Dinuclear and Trinuclear Complexesmentioning

confidence: 99%

Tumour-inhibiting platinum complexes—state of the art and future perspectives

Jakupec

Galanski

Keppler

2003

Reviews of Physiology, Biochemistry and Pharmacology

383

349

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“…Among these is the antitumor activity of multinuclear platinum complexes, typically consisting of either two or three platinum centers that are linked through a bridging ligand [15][16][17][18][19][20][21][22][23][24][25]. The success of these systems is based on the ability of these complexes to form DNA adducts that are structurally different from those formed by cisplatin and its related analogues [26,27].…”

Section: Introductionmentioning

confidence: 99%

Influence of the bridging azine ligand on the rate of ligand substitution in a series of dinuclear platinum(II) complexes

Reddy

Jaganyi

2011

Int J of Chemical Kinetics

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A series of azine-bridged dinuclear platinum(II) complexes of the type [{trans-Pt(NH 3 ) 2 (OH 2 )} 2 (μ-azn)](ClO 4 ) 4 (where azn = pyrazine (pzn, Pt1), 2,3-dimethylpyrazine (2,3-pzn, Pt2), and 2,5-dimethylpyrazine (2,5-pzn, Pt3)) were synthesized to investigate the influence of the bridging azine ligand on the reactivity of the platinum(II) centers. The pK a values of the complexes were determined via acid-base titration, and the rate of substitution of the aqua moiety by a series of neutral nucleophiles, viz. thiourea (TU), 1,3-dimethyl-2-thiourea (DMTU), and 1,1,3,3-tetramethyl-2-thiourea (TMTU), was determined under pseudo-first-order conditions as a function of concentration and temperature using standard spectrophotometric techniques. The introduction of the methyl groups to the bridging azine linker in Pt2 and Pt3 leads to a moderate increase in the pK a values obtained for the first and second deprotonation steps, respectively, as a result of the increased σ-donor capacity of the bridging azine ligand trans to the aqua moiety. A comparison of the rate constants, k 1 and k 2 , at 298 K, obtained for the substitution of the aqua moieties from Pt1, Pt2, and Pt3 by TU, shows that the introduction of the σ-donating methyl groups on the bridging azine ligand in Pt2 and Pt3 results in a corresponding decrease in the reactivity, by ca. five times for the first substitution step and ca. 10 times for the second substitution step. Density functional theory calculations at the B3LYP/LACVP** level of theory for the complexes demonstrate that the introduction of electron-donating methyl groups results in (i) increased steric hindrance over the metal centers and (ii) decreased the positive charge on the metal center and increases energy separation of the frontier molecular orbitals (E HOMO -E LUMO ) of the ground-state platinum(II) complexes, leading to a less-reactive metal center. C

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“…Therefore, the search for structurally novel Pt(II) and Pd(II) compounds displaying antineoplastic activity is crucial, aiming at the design of more efficient and less toxic agents. Metal complexes comprising cisplatin-like moieties ([PtCl(NH 3 ) 2 ] or [Pt(NH3)Cl2]) linked by variable length alkanediamine chains have generated great interest in the last few years, as third-generation cDDP alternatives in cancer chemotherapy [2][3][4][5][6][7][8][9]. In fact, the polyamine bridging linkers may allow a more efficient interaction of the chelate with DNA, not…”

Section: Introductionmentioning

confidence: 99%