- In vitro activity, stability, and lipophilicity changes of cisplatin through substitution of different amine ligands
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In this study, several cisplatin analogs were designed to investigate the antitumor activity and lipophilicity effects in amine change. The amines of the cisplatin molecule were substituted with aliphatic amines in different analogs. The cytotoxicity of analogs against human colon cancer (HCT116) was investigated using MTT assay, and spectroscopic methods were used to determine the DNA binding mode. Cytotoxicity studies revealed cis-dichloro-dimethylamine-platinum has a lower IC50 (48.87?μM) than carboplatin (68.46?μM) and more than cisplatin (21?μM) against human colon cancer cells (HCT116), respectively. DNA denaturation study indicated that the stability of DNA in the presence of these compounds diminished and substitution of propylamine and methylamine groups increased DNA denaturation. Further, the interaction of the desired compounds with DNA proved to be a spontaneous process. Tm analysis also revealed that cisplatin, cis-dichloro-dimethylamine-platinum, and cis-dichloro-dipropylamine-platinum complexes made DNA double helix unstable via covalent bond, while cis-dichloro-dibutylamine-platinum and cis-dichloro-diisobutylamine-platinum stabilized DNA via electrostatic binding to DNA. The results of fluorescence studies showed that the quenching nature of cisplatin and methyl and propyl systems was dynamic, while the static quenching was observed in the presence of cis-dichloro-dibutylamine-platinum and cis-dichloro-diisobutylamine-platinum. The molecular docking simulations and DFT analysis were performed to investigate the binding sites and chemical behavior of cisplatin analogs, respectively. Molecular docking demonstrated that except cis-dichloro-diisobutylamine-platinum, other complexes had higher negative docking energy than cisplatin for interaction with DNA, and methyl and propyl complexes may be good candidates for anticancer drugs. Graphical abstract: Some anticancer Pt(II) complexes as cisplatin analogs were synthesized with aliphatic amines to investigate the lipophilicity effects. In vitro cytotoxicity effects were tested against human colon cancer (HCT116). Moreover, the modes of DNA binding with synthesized compounds were investigated using fluorescence spectra, DFT and molecular docking. [Figure not available: see fulltext.]
- Divsalar, Adeleh,Eslami Moghadam, Mahboube,Mesbah, A. Wahid,Rahiminezhad, Arezo
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- A kinetic and mechanistic study of analogous bifunctional dialkylamine platinum(ii) complexes
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This study was aimed at investigating the comparative substitution behaviour of analogous cis/trans-Pt(ii) complexes with inert dialkylamine ligands. The rate of substitution of the aqua ligands by three nucleophiles, viz. thiourea (TU), 1,3-dimethylthiourea (DMTU) and 1,1,3,3-tetramethylthiourea (TMTU), for the complexes: [cis-Pt(OH2)2(NH3)2](ClO4)2 (cPt), [cis-Pt(OH2)2(NH2CH3)2](ClO4)2 (cPtM), [cis-Pt(OH2)2{NH2CH(CH3)2}2](ClO4)2 (cPtR), [trans-Pt(OH2)2(NH3)2](ClO4)2 (tPt), [trans-Pt(OH2)2(NH2CH3)2](ClO4)2 (tPtM) and [trans-Pt(OH2)2{NH2CH(CH3)2}2](ClO4)2 (tPtR) was investigated under pseudo first-order conditions as a function of concentration and temperature by stopped-flow and UV/visible spectrophotometry. The reactions of the cis-complexes proceed in two concerted steps whereas those of the trans-complexes followed a stepwise mechanism involving rate determining substitution of the first chloride followed by a fast second substitution step, with no intermediates being detected. The pseudo first-order rate constants, kobs obeyed the rate law: kobs = k2[nucleophile]. The trans-complexes were observed to be approximately 103 times more reactive than their corresponding cis-analogues. The electronic and the steric hindrance due to the geometries of the complexes controlled the overall reaction pattern. The order of reactivity of the complexes is tPt > tPtM > tPtR > cPt > cPtM > cPtR. The reactivity of the nucleophiles with the complexes decreases with an increase in steric demand in the order: TU > DMTU > TMTU. The trans-dialkylamine complexes formed distinctly different kinetic products relative to their cis-analogues. 195Pt NMR spectroscopic results confirmed the final kinetic products of each of the cis- and trans-complexes. The negative entropy of activation (ΔS≠) values in all the complexes investigated assert an associative substitution mechanism, with the mechanism being more pronounced in the cis-complexes than in their trans-analogues.
- Olusegun, Moses Ariyo,Reddy, Desigan,Jaganyi, Deogratius
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p. 5138 - 5146
(2020/04/09)
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- Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes
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We report QSAR calculations using VolSurf descriptors to model the lipophilicity of 53 Pt(iv) 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 these data are shown to be inadequate, due to incompatibility of whole molecule descriptors between carboxylato and hydroxido 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 (R2 = 0.92) and robust model (Q2 = 0.87) of lipophilicity, that moreover highlights the importance of size and hydrophobicity terms and the modest relevance of hydrogen bonding.
- Ermondi, Giuseppe,Caron, Giulia,Ravera, Mauro,Gabano, Elisabetta,Bianco, Sabrina,Platts, James A.,Osella, Domenico
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supporting information
p. 3482 - 3489
(2013/03/28)
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- Activation of trans geometry in bifunctional mononuclear platinum complexes by a non-bulky methylamine ligand
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In order to shed light on the mechanism that underlies activity of bifunctional mononuclear PtII analogs of transplatin we examined in the present work a DNA binding mode of the analog of transplatin, namely trans-[Pt(CH3NH2)2Cl2], in which NH3 groups were replaced only by a small, non-bulky methylamine ligand. This choice was made because we were interested to reveal the role of the bulkiness of the amines used to substitute NH3 in transplatin to produce antitumor-active PtII drug. The results indicate that trans-[Pt(CH 3NH2)2Cl2] forms a markedly higher amount of more distorting intrastrand cross-links than transplatinwhich forms in DNA preferentially less distorting and persisting monofunctional adducts. Also importantly, the accumulation of trans-[Pt(CH3NH2) 2Cl2] in tumor cellswas considerably greater than that of transplatin and cisplatin. In addition, the results of the present work demonstrate that the replacement of ammine groups by the non-bulky methylamine ligand in the molecule of ineffective transplatin results in a radical enhancement of its activity in tumor cell lines including cisplatin-resistant tumor cells. Thus, activation of the trans geometry in bifunctionalmononuclear PtII complexes can be also accomplished by replacement of ammine groups in transplatin by non-bulkymethylamine ligands so that it is not limited only to the replacement by relatively bulky and stereochemically more demanding amino ligands.
- Frybortova, Michaela,Novakova, Olga,Stepankova, Jana,Novohradsky, Vojtech,Gibson, Dan,Kasparkova, Jana,Brabec, Viktor
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- SYNTHESIS OF (GLYCOLATO-O,O')DIAMMINEPLATINUM(II) AND ITS RELATED COMPLEXES
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Glycolatoplatinum(II) complexes, , having a novel five-membered ring structure were obtained by adding an equimolar quantity of glycolic acid to cis- (L: NH3, amines) in water followed by heating.These complexes have also been obtained by reaction of cis- with sodium glycolate in neutral aqueous solution.These complexes have been characterized by SIMS, IR, and NMR spectroscopy.
- Totani, Tetsushi,Aono, Katsutoshi,Komura, Michihiro,Adachi, Yasuko
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p. 429 - 432
(2007/10/02)
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- Effects of Geometric Configuration and Steric Hindrance on Rates and Mechanisms of Oxidation of Diaminedichloroplatinum(II) Complexes by Tetrachloroaurate(III) Ions
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The oxidation reactions of trans- and/or cis- by - in the presence of Cl have been kinetically investigated in acetonitrile (R=H,Me,Et,Prn,Pri,Bun,Bui,Bus,But,CH2But,CH2Ph, or cyclo-C6H11).The rate law for the oxidation of the trans complexes consists mainly of a third-order rate term, kc->->, whereas an additiona rate term, ka->->/(1+kb->), operates in the case of the cis complexes.A reaction scheme is proposed.The oxidation rates of both cis and trans complexes appear to be reduced by increasing the steric hindrance of the amine, cis complexes being more sensitive towards changes of steric hindrance than trans analogues.Approximate linear relationships correlate the reactivities (log k) of both cis and trans complexes with an amine steric hindrance parameter.
- Peloso, Arnaldo
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p. 1285 - 1290
(2007/10/02)
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