Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes

Farrell, Nicholas; Qu, Yun; Hacker, Miles P.

doi:10.1021/jm00170a021

Cited by 166 publications

(113 citation statements)

References 2 publications

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“…Farrell and co-workers have recently reported the synthesis and antitumor properties of several dinuclear Pt(II) complexes with bridging diamine linkers of varying chain lengths, 24,30 displaying high activity both in vitro and in vivo even against cisplatin-resistant cancer cell lines. These compounds, containing two PtCl(NH 3 ) 2 or PtCl 2 (NH 3 ) moieties linked by polyamine groups in a cis orientation, can be compared to complex IV presently studied, which comprises two cisplatin-like PtCl 2 (NH)(NH 2 ) fragments in a trans conformation instead.…”

Section: Resultsmentioning

confidence: 99%

“…However, it should be noted that conformity to these SAR rules is not essential for cytostatic activity to occur, since it was recently found that novel trans-dichloroplatinum(II) complexes also exhibit significative antitumor activity. 40 Among the complexes presently studied, both II and IV are dinuclear 2,2/c,c Pt(II) chelates; 24 i.e., they comprise two difunctional moieties at each metal center, in a cis position relative to the bridging ligand(s). However, while II has two distinct polyamine (spermidine) molecules, each one coordinated to a different platinum ion, IV contains only one tetraamine ligand (spermine) acting as a linker for both metal centers, yielding two identical six-membered intramolecular rings in a trans orientation relative to each other ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…These compounds, which have been the subject of intense study for the past few years, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] were found to be distinct from their mononuclear counterparts in terms of DNA binding features, yielding adducts containing "long-distance" intra-and interstrand cross-links not available to the conventional mononuclear platinum complexes. 9,23 Moreover, these polynuclear metal complexes have often been reported to overcome acquired cisplatin resistance [24][25][26][27] probably because of a distinct mechanism of DNA interaction that results in different types of drug-induced DNA lesions. The presence of more than one metal center in these Pt(II) multifunctional chelates is thus expected to lead to a higher efficacy and specificity regarding DNA binding (e.g., increased number of interstrand crosslinks, 28 possibly at more than one position).…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

et al. 2004

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Several polynuclear Pt(II) chelates with biogenic polyamines were synthesized and screened for their potential antiproliferative and cytotoxic activity in different human cancer cell lines. To gather information regarding the structure-activity relationships underlying their biological activity, the complexes studied were designed to differ in geometrical parameters such as the nature of the ligand and the number and chemical environment of the metal centers. Distinct effects were found for different cell lines and different structural characteristics of the complexes; chelates II, III, and IV displayed specificity toward the HeLa and HSC-3 epithelial-type cells, while V, VI, and VII were clearly more effective against the THP-1, MOLT-3, and CCRF-CEM leukemia cell lines. The toxicity of these Pt(II) complexes on noncancer cells was, in all cases, found to be reversed upon drug removal.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

et al. 2004

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“…[6,15,17,18] In addition, it was verified that linkage of some of these molecules to previously tested anticancer drugs leads to a higher cytotoxic effect and, in some cases, even to an enhancement of the efficacy of the long-used first-generation drug cisplatin [cis-diamine dichloroplatinum(II)]. [19][20][21][22][23][24][25][26][27] Recently, it was also demonstrated that polyamines may exert insulinlike activity by interacting with receptors on fat-cell membranes. [28] Despite the vital role of polyamines in living cells, little is known about their structure at a molecular level.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and Theoretical Studies on Solid 1,2‐Ethylenediamine Dihydrochloride Salt

Amado¹,

Otero²,

Marques³

et al. 2004

ChemPhysChem

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A structural study of [H3N(CH2)2NH3)]2+⋅2Cl−, the smallest element of the homologous series of the α,ω‐diamine dihydrochlorides, was carried out by means of Raman and FTIR spectroscopy coupled to ab initio molecular orbital (MO) calculations. As a primary concern, an adequate molecular model for the representation of these solid amine salts was chosen. Thus, several models, varying in the number and position of the counterions as well as in the number of diamine units, were considered. It was found that the best molecular system (i.e., that yielding the best compromise between accuracy and computational requirements) consists of one ethylenediamine cation surrounded by six chloride ions in an arrangement based on the crystal structure reported in the literature for [H3N(CH2)2NH3)]2+⋅2Cl−. This conclusion will hopefully allow for a better understanding of the conformational preferences, in the solid state, of these biologically relevant linear polyamines.

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“…[1][2][3][4][5][6] This class includes the trinuclear [{trans-PtCl-(NH 3 ) 2 } 2 (μ-trans-Pt(NH 3 ) 2 {NH 2 (CH 2 ) n NH 2 } 2 )] 4+ (1,0,1/t,t,t, n=6, or BBR3464), which has undergone Phase II clinical trials (summarized in refs [1,[7][8][9]). The overall charge as well as the linker flexibility and hydrogen-bonding capability of these compounds are thought to be related to their improved cytotoxic and antitumor properties relative to cisplatin and its derivatives.…”

Section: Introductionmentioning

confidence: 99%

Effects of Geometric Isomerism and Anions on the Kinetics and Mechanism of the Stepwise Formation of Long‐Range DNA Interstrand Cross‐Links by Dinuclear Platinum Antitumor Complexes

Zhang¹,

Thomas²,

Berners‐Price³

et al. 2008

Chemistry A European J

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Reported herein is a detailed study of the kinetics and mechanism of formation of a 1,4-GG interstrand cross-link by the dinuclear platinum anticancer compound [ 15 N][{cis-PtCl-(NH 3 ) 2 } 2 {μ-NH 2 (CH 2 ) 6 NH 2 }] 2+ (1,1/c,c (1)). The reaction of [ 15 N]1 with 5′-{d(ATATGTACATAT) 2 } (I) has been studied by [ 1 H, 15 N] HSQC NMR spectroscopy in the presence of different concentrations of phosphate. In contrast with the geometric trans isomer (1,1/t,t), there was no evidence for an electrostatic preassociation of 1,1/c,c with the polyanionic DNA surface, and the pseudo-first-order rate constant for the aquation of [ 15 N]1 was actually slightly higher (rather than lower) than that in the absence of DNA. When phosphate is absent, the overall rate of formation of the cross-link is quite similar for the two geometric isomers, occurring slightly faster for 1,1/t,t. A major difference in the DNA binding pathways is the observation of phosphate-bound intermediates only in the case of 1,1/c,c. 15 mM phosphate causes a dramatic slowing in the overall rate of formation of DNA interstrand cross-links due to both the slow formation and slow closure of the phosphate-bound monofunctional adduct. A comparison of the molecular models of the bifunctional adducts of the two isomers shows that helical distortion is minimal and globally the structures of the 1,4 interstrand cross-links are quite similar. The effect of carrier ligand was investigated by similar studies of the ethylenediamine derivative [ 15 N]1-en. A pK a value of 5.43 was determined for the [ 15 N]1,1/c,c-en diaquated species. The rate of reaction of [ 15 N]1-en with duplex I is similar to that of 1,1/c,c and the overall conformation of the final adduct appears to be similar. The significance of these results to the development of "second-generation" polynuclear platinum clinical candidates based on the 1,1/ c,c chelate (dach) series is discussed.

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Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes

Cited by 166 publications

References 2 publications

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

Spectroscopic and Theoretical Studies on Solid 1,2‐Ethylenediamine Dihydrochloride Salt

Effects of Geometric Isomerism and Anions on the Kinetics and Mechanism of the Stepwise Formation of Long‐Range DNA Interstrand Cross‐Links by Dinuclear Platinum Antitumor Complexes

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