Chemical and biological properties of a novel bifunctional triplatinum phase I clinical agent

Farrell, N.; Menta, Ernesto; Valsecchi, Mariella; Domenico, Roberto Di; Re, G. Da; Manzotti, C.; Pezzoni, Gabriella; Giuliani, F; Spinelli, Silvano

doi:10.1016/s0162-0134(97)80051-7

Cited by 7 publications

(8 citation statements)

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“…Sample preparation BBR3464 was prepared according to literature procedures [13]. The self-complementary octamer 5¢-d(ATGTACAT)-3¢ was purchased from Midland Certified Reagent (Midland, Tex.).…”

Section: Methodsmentioning

confidence: 99%

“…The subsequent bending induced in DNA is recognized by high-mobility group domain (HMG) proteins and this recognition represents an attractive, if not unequivocally proven, pathway for processing and differential repair of cellular cis-DDP-DNA adducts [11]. The distance between Pt-Cl units in BBR3464 is 27.4 Å (from X-ray crystallographic data) [13], giving the drug the ability to form long-range interstrand and intrastrand cross-links, where the platinated nucleotides are separated by several intervening base pairs [5]. The distance between Pt-Cl units in BBR3464 is 27.4 Å (from X-ray crystallographic data) [13], giving the drug the ability to form long-range interstrand and intrastrand cross-links, where the platinated nucleotides are separated by several intervening base pairs [5].…”

Section: Introductionmentioning

confidence: 99%

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Cooperative effects in long-range 1,4 DNA-DNA interstrand cross-links formed by polynuclear platinum complexes: an unexpected syn orientation of adenine bases outside the binding sites

Scarsdale

Tran

et al. 2003

J Biol Inorg Chem

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The novel phase II anticancer drug BBR3464 ([[ trans-PtCl(NH(3))(2)](2)- micro -[ trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2)]](NO(3))(4)) forms a 1,4-interstrand cross-link adduct with the self-complementary DNA octamer 5'-d(ATG*TACAT)(2)-3', with the two platinum atoms coordinated in the major groove at the N7 positions of guanines that are four base pairs apart on opposite DNA strands. The "central" tetraamine linker [ trans-H(2)N(CH(2))(6)NH(2)Pt(NH(3))(2)NH(2)(CH(2))(6)NH(2)] was located in or close to the minor groove. The adduct was characterized and analyzed by MS, UV and NMR spectroscopy. NMR analysis of the adduct shows strong H8/H1' intraresidue crosspeaks observed for the A1 and A7 resonances, consistent with a syn conformation for these bases which is usually not observed for adenine residues and bases not directly involved in the cross-link in oligonucleotides. The strong intraresidue H8/H1' crosspeak is also observed for G3. Examination of the structure thus reveals unusual cooperative effects unique to this class of anticancer drugs and is the first demonstration of cooperative effects in solution for an anticancer drug. The significant characteristic of the structure is the lack of severe DNA distortion such as a kink, directed bend or significant unwinding of the helices which are characteristic for DNA adducts of mononuclear complexes. This may contribute to the lack of protein recognition of the cross-link by HMG-domain proteins, a biological consequence significantly different from that of mononuclear complexes such as cisplatin. Since DNA is the principal target in vivo for these Pt cross-linking agents, the unique structural perturbations induced by BBR3464 cross-links are likely related to its increased cytotoxicity and antitumor activity as compared to cisplatin ( cis-DDP).

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cooperative effects in long-range 1,4 DNA-DNA interstrand cross-links formed by polynuclear platinum complexes: an unexpected syn orientation of adenine bases outside the binding sites

Scarsdale

Tran

et al. 2003

J Biol Inorg Chem

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“…The chloride salt of the tetraentered clinical trials. [14] nuclear complex was obtained by quenching the reaction It has been suggested that the increased number of inwith an excess of LiCl. The excess of LiCl is later removed terstrand crosslinks is the reason for the high activity of by extraction with ethanol or methanol.…”

Section: Introductionmentioning

confidence: 99%

A Tetranuclear Platinum Compound Designed to Overcome Cisplatin Resistance

Jansen

Zwan

Reedijk³

et al. 1999

Eur. J. Inorg. Chem.

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The synthesis and characterisation of the first generation of a poly(propyleneimine) dendrimer DAB(PA)4, substituted with four trans‐diamminechloroplatinum moieties is reported. The compound DAB(PA‐tPt‐Cl)4 was designed to overcome two problems often associated with cisplatin resistance in cancer cells: (i) deactivation of the platinum species by intracellular thiolates and (ii) improved repair of crosslinks with DNA. The four‐armed molecule can be expected to form crosslinks with DNA that are very different from the adducts formed by cisplatin. Also, the tetranuclear compound has four leaving groups, while cisplatin has only two. Therefore, DAB(PA‐tPt‐Cl)4 would be less susceptible towards inactivation by reaction with intracellular thiolates. A reaction with an excess of the model nucleobase guanosine 5′‐monophosphate (GMP) confirmed that the tetranuclear compound is capable of binding a maximum of four nucleobases. Therefore, the inactivation of one or two arms would still leave the molecule with enough reactivity to form crosslinks with DNA. Cytotoxicity tests were performed on two mouse leukemia L1210 cell lines, both sensitive and resistant towards cisplatin, and in seven human tumor cell lines. In all cell lines, the tetranuclear compound showed a low cytotoxicity. It is suggested that the low activity is related to the structure of the compound. Probably the high charge (+6) at physiological pH and its branched structure hamper the molecule in crossing the cell membranes.

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“…Compared to their chloride precursors, only minor changes in chemical shifts are observed for the linker protons [2,9]. 195 Pt NMR spectra (Table 1) …”

Section: Synthesis and Characterizationmentioning

confidence: 99%

Synthesis and DNA conformational changes of non-covalent polynuclear platinum complexes

Harris

Hegmans

et al. 2004

Journal of Inorganic Biochemistry

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Chemical and biological properties of a novel bifunctional triplatinum phase I clinical agent

Cited by 7 publications

References 0 publications

Cooperative effects in long-range 1,4 DNA-DNA interstrand cross-links formed by polynuclear platinum complexes: an unexpected syn orientation of adenine bases outside the binding sites

Cooperative effects in long-range 1,4 DNA-DNA interstrand cross-links formed by polynuclear platinum complexes: an unexpected syn orientation of adenine bases outside the binding sites

A Tetranuclear Platinum Compound Designed to Overcome Cisplatin Resistance

Synthesis and DNA conformational changes of non-covalent polynuclear platinum complexes

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