Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance

Margiotta, Nicola; Natile, Giovanni; Capitelli, Francesco; Fanizzi, Francesco Paolo; Boccarelli, Angelina; Rinaldis, P. De; Giordano, D.; Coluccia, Mauro

doi:10.1016/j.jinorgbio.2006.07.010

Cited by 37 publications

(20 citation statements)

References 27 publications

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“…Exceptions include [PtIA 2 L]I complexes, where A 2 ϭ 2,9-dimethyl-1,10-phenanthroline and L is an N-donor heterocyclic ligand. The compound in which L ϭ 1-methylcytosine is more toxic than cisplatin against a panel of 11 cell lines (15). Of significance in the present context is the observation that the greatest differential cytotoxicity occurred for the three colon cancer lines among the 11 that were investigated.…”

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confidence: 77%

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

Lovejoy

Todd

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

228

221

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We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH 3)2(py)Cl]؉ or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH ‫؍‬ trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH 3)2(py)} 2؉ bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5 side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)} 2؉ . cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.cancer therapy ͉ nucleotide excision repair ͉ organic cation transporter ͉ RNA polymerase II inhibition ͉ x-ray crystal structure

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confidence: 77%

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

Lovejoy

Todd

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

228

221

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“…[12] Interestingly, compound 2, one of the several platinum complexes with Me 2 phen investigated for antitumor activity, [12][13][14][15] was found to be endowed with a potent growth inibitory activity in a panel of 11 human tumor cell lines and was markedly more effective than cisplatin towards colon (COLO205: 19-fold; HCT116: 11-fold; KM12: 9-fold), breast (MDA: 16-fold), and ovary (SKOV-3: 14-fold) cancer cells. [11] Compound 2 was also able to completely overcome the acquired cisplatin resistance in A2780cisR and 41McisR ovarian cancer lines. Compound 2 could be an ideal substrate for the organic cation transporters (OCT) and therefore could be selectively delivered to tumors which overexpress these carriers, such as the human colorectal cancer.…”

Section: (Am)]mentioning

confidence: 95%

“…Finally, the reactivity of 1 towards guanosine 5'-monophosphate (5'-GMP) and glutathione was investigated to provide insights into its mechanism of action. We too prepared and tested some monofunctional cationic platinum complexes, which, however, differed from classical Hollis-type compounds for the lack of the amine ligands ([PtI-(Me 2 phen)(MeCY)]I, 2, Me 2 phen = 2,9-dimethyl-1,10-phenanthroline, MeCY = 1-methyl-cytosine; Figure 1) [11] or of the heterocyclic base ([Pt(NH 3 ) 2 (a-Tfm-Ala-N,O)](NO 3 ), a-Tfm-Ala = synthetic fluorinated aminoacid a-trifluoromethyl-alanine with R configuration). [12] Interestingly, compound 2, one of the several platinum complexes with Me 2 phen investigated for antitumor activity, [12][13][14][15] was found to be endowed with a potent growth inibitory activity in a panel of 11 human tumor cell lines and was markedly more effective than cisplatin towards colon (COLO205: 19-fold; HCT116: 11-fold; KM12: 9-fold), breast (MDA: 16-fold), and ovary (SKOV-3: 14-fold) cancer cells.…”

Section: (Am)]mentioning

confidence: 99%

Monofunctional Platinum(II) Complexes with Potent Tumor Cell Growth Inhibitory Activity: The Effect of a Hydrogen‐Bond Donor/Acceptor N‐Heterocyclic Ligand

et al. 2014

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In this paper we investigate the possibility of further increase the role of the N-donor aromatic base in antitumor Hollis-type compounds by conferring the possibility to act as a hydrogen-bond donor/acceptor. Therefore, we synthesized the Pt(II) complex cis-[PtCl(NH3 )2 (naph)]NO3 (1) containing the 1,8-naphthyridine (naph) ligand. The naphthyridine ligand is generally monodentate, and the second nitrogen atom can act as H-bond donor/acceptor depending upon its protonation state. The possibility of forming such an H-bond could be crucial in the interaction of the drug with DNA or proteins. Apart from the synthesis of the compound, in this study we evaluated its in vitro antitumor activity in a wide panel of tumor cell lines, also including cells selected for their sensitivity/resistance to oxaliplatin, which was compared with that of previously reported complex 2 ([PtI(2,9-dimethyl-1,10-phenanthroline)(1-methyl-cytosine)]I) and oxaliplatin and cisplatin as reference compounds. The cytotoxicity data were correlated with the cellular uptake and the DNA platination levels. Finally, the reactivity of 1 towards guanosine 5'-monophosphate (5'-GMP) and glutathione was investigated to provide insights into its mechanism of action.

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“…A greenish solid complex 3 was collected, washed with water and methanol followed by anhydrous diethyl ether, dried over P 4 …”

Section: Methodsmentioning

confidence: 99%

“…DNA targeting moieties such as DNA intercalators used as platinum carriers may also be a new strategy, possibly leading to a broadened spectrum activity [4] and exalting platinum intracellular uptake. Pt(II) complexes with polypyridyl 2-(2-benzimidazolyl)pyridine ligands [5], heterocycles endowed with hydrophobic properties, have been reported and an increase of hydrophobicity around the drug-DNA binding site has been assessed.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structural characterisation and biological studies of new mononuclear platinum(II) complexes with sterically hindered heterocyclic ligands

Rubino

Portanova

Giammalva

et al. 2011

Inorganica Chimica Acta

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a b s t r a c tThree novel cisplatin analogues were synthesized, designed according to an approach which violates the ''classical'' structure-activity relationship, by replacing the diamine ligands with a planar N donor heterocycle giving a sterically hindered complex. Moreover, the sterical hindrance of antitumor drug candidates potentially makes them less susceptible to deactivation by sulphur-containing proteins and helping to overcome resistance mechanisms. The resulting mononuclear complexes of sterically hindered polidentate heterocyclic N ligands [PtCl(bbp)have been prepared and structurally characterised. Both neutral and ionic complexes are present, with monofunctional (1) and bifunctional Pt(II) moieties (2) and coordinatively saturated Pt(II) ions in the mixed ligand complex (3), whose size and shape enable them to behave as novel scaffolds for DNA binding. All complexes were tested ''in vitro'' for their biological activity on human HT29 colorectal carcinoma and HepG2 hepatoma cells. The complexes (1) and (3), endowed with a positive charge, showed a potent cytotoxic activity and reduced cell viability with an efficacy higher than that of cisplatin; whilst the neutral bifunctional compound (2) was inactive. IC50 values have been calculated for the active compounds. The cytotoxic effects were confirmed by the accumulation of treated cells in subG0/G1 phase of cell cycle, by the loss of mitochondrial potential (Dw m ) and by the chromatin condensation or fragmentation observed by means of fluorescence microscopy after Hoechst 33258 nuclear staining. A study on intracellular platinum uptake in HT29 cell line has been also performed and data obtained strongly suggest that the cytotoxicity of new tested complexes reported in this work is based on a different pharmacodynamic pattern with respect to cisplatin.

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Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance

Cited by 37 publications

References 27 publications

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

Monofunctional Platinum(II) Complexes with Potent Tumor Cell Growth Inhibitory Activity: The Effect of a Hydrogen‐Bond Donor/Acceptor N‐Heterocyclic Ligand

Synthesis, structural characterisation and biological studies of new mononuclear platinum(II) complexes with sterically hindered heterocyclic ligands

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