Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents

Giandomenico, Christen M.; Abrams, Michael J.; Murrer, Barry A.; Vollano, Jean F.; Rheinheimer, Melanie I.; Wyer, Sandra B.; Bossard, Gerald E.; Higgins, John

doi:10.1021/ic00109a004

Cited by 245 publications

(261 citation statements)

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“…I.) tract (31,36). One such compound, cis,trans,cis-amine(cyclohexylamine) diacetatodichloroplatinum(IV), or satraplatin, is currently in a Phase III clinical trial for hormone-refractory prostate cancer (37).…”

Section: Synthesis and Characterization Of Pt(iv)-peptide Conjugatesmentioning

confidence: 99%

Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor Vasculature

et al. 2007

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The integrins α v β 3 and α v β 5 and the membrane-spanning surface protein aminopeptidase-N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (ArgGly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono-and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing either RGD, CRGDC, (RGDfK)c or NGR, is appended as a 'tumor-homing device' to target tumor endothelial cells selectively over healthy cells. Platinum(IV)-peptide complexes with non-specific amino acids or peptide moieties were prepared as controls. Concentration-response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinumbased chemotherapeutic agent. The Pt(IV)-RGD conjugates were highly and specifically cytotoxic to α v β 3 and α v β 5 containing cell lines, approaching the activity of cisplatin. The Pt(IV)-NGR complexes were less active than Pt(IV)-RGD-containing compounds but more active than nonspecific Pt-peptide controls. Integrin α v β 3 mediated, at least in part, the anti-proliferative effect of an Pt(IV)-RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of α v β 3 /α v β 3 -specific RGD pentapeptides, or (2) transfected with RNAi for β 3 , but not β 1 , integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.

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Section: Synthesis and Characterization Of Pt(iv)-peptide Conjugatesmentioning

confidence: 99%

Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor Vasculature

et al. 2007

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“…25 The same approach failed when applied to the whole series of 1-53 30 complexes. This is probably due to the increased heterogeneity of the training set, in turn due to the different axial ligands present in 1-22 with respect to 23-53 compounds (OH instead of carboxylates) that enormously enlarge the chemical domain of the molecules.…”

Section: Qsrr Analysismentioning

confidence: 89%

“…4 Lipophilicity of a molecule is generally thought to arise from its size and polarity. Thus, a large, apolar molecule will have a tendency to 30 partition into the organic phase, where formation of cavities is easier, while a more polar molecule will tend to partition into water, the more polar and hydrogen bonding solvent. 5 Although a lipophilicity experiment, by using the traditional shake-flask method seems at a first glance simple and easy, it is 35 not a trivial matter because data can vary significantly with experimental conditions.…”

Section: Introductionmentioning

confidence: 99%

“…15 In a previous study, a relationship between cytotoxicity and both reduction potential Ep and partition coefficient log Po/w of 25 Pt(IV) complexes has been established: the easier the reduction and the higher the lipophilicity, the higher the cytotoxicity. 16 These two chemico-physical properties, in turn related to cellular uptake and activation by reduction in cytosol, can be tuned through choice of the six ligands around the Pt(IV) centre, 30 especially the axial ones. 11,17. These ligands can also act as carriers or adjuvant agents, offering interesting applications in the controlled release and in the drug targeting and delivery.…”

Section: Introductionmentioning

confidence: 99%

“…In the present work 22 dihydroxido Pt(IV) complexes (1-22 in Figure 1) have been newly synthesised or, in some cases, re-synthesised according to standard methods. 27,28,29,30 Their extrapolated capacity factors log k'0 were 55 measured and in silico properties evaluated by QSRR (Quantitative Structure-Retention Relationship) methods together with the previously studied Pt(IV) complexes (23-53 in Figure 1). Figure 1 shows the entire set of the studied complexes.…”

Section: Introductionmentioning

confidence: 99%

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Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes

Ermondi¹,

Caron²,

Ravera

et al. 2013

Dalton Trans.

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We report QSAR calculations using VolSurf descriptors to model the lipophilicity of 53 Pt (IV) 5 complexes with a diverse range of axial and equatorial ligands. Lipophilicity is measured using an efficient HPLC method. Previous models based on a subset of this data are shown to be inadequate, due to incompatibility of whole molecule descriptors between axial carboxylate and hydroxo ligands. Instead, the interaction surfaces of complexes with various probes are used as independent descriptors. Partial least squares modelling using three latent variables results in an accurate (R 2 = 0.92) and robust model 10 (Q 2 = 0.87) of lipophilicity, that moreover highlights the importance of size and hydrophobicity terms and the modest relevance of hydrogen bonding.3

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Carboxylation of 2-Hydroxyethyl-Substituted Tetrachloro(ethane-1,2-diamine)platinum(IV) Complexes — A New Synthetic Approach to Anticancer Platinum Compounds

Galanski

Zimmermann

Berger

et al. 2002

Eur. J. Inorg. Chem.

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The present study has focused on a general reaction procedure for the derivatization of hydroxyethyl‐substituted tetrachloro(ethane‐1,2‐diamine)platinum(IV) compounds at peripheral hydroxyl groups using acyl chlorides. A new class of platinum(IV) complexes could be synthesized which now opens the possibility for the first time to couple the cytotoxic platinum(IV) moiety to carrier molecules like proteins and antibodies in a very selective way. Moreover, it is now possible to synthesize platinum(IV) complexes with ligands in the equatorial plane which are not very stable in the presence of oxidizing agents.

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Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents

Cited by 245 publications

References 1 publication

Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor Vasculature

Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor Vasculature

Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes

Carboxylation of 2-Hydroxyethyl-Substituted Tetrachloro(ethane-1,2-diamine)platinum(IV) Complexes — A New Synthetic Approach to Anticancer Platinum Compounds

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