14096-57-2Relevant academic research and scientific papers
Reactivity and biological properties of a series of cytotoxic PtI 2(amine)2 complexes, either cis or trans configured
Messori, Luigi,Cubo, Leticia,Gabbiani, Chiara,Alvarez-Valdes, Amparo,Michelucci, Elena,Pieraccini, Giuseppe,Rios-Luci, Carla,Leon, Leticia G.,Padron, Jose M.,Navarro-Ranninger, Carmen,Casini, Angela,Quiroga, Adoracion G.
, p. 1717 - 1726 (2012)
Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.
Multinuclear NMR study and crystal structures of complexes of the types cis- and trans-Pt(amine)2I2
Rochon, Fernande D.,Buculei, Viorel
, p. 2218 - 2230 (2004)
Complexes of the types cis- and trans-Pt(amine)2I2 were studied by spectroscopic methods, especially by multinuclear NMR spectroscopy. In 195Pt NMR, the cis diiodo compounds with primary amines were observed between -3342 and -3357 ppm in acetone, while the trans compounds were found between -3336 and -3372 ppm. For the secondary amines, the chemical shifts were observed at lower fields. In 1H NMR, the trans complexes were observed at higher fields than the cis compounds, while in 13C NMR, the reverse was observed. The 2J( 195Pt-1H) and 3J(195Pt- 1H) coupling constants are larger for the cis compounds (ave. 67 and 45 Hz, respectively) than for the trans isomers (ave. 59 and 38 Hz). In 13C NMR, the values of 2J(195Pt-13C) and 3J(195Pt-13C) were also found to be larger for the cis complexes (ave. 17 and 39 Hz versus 11 and 28 Hz). There seems to be a slight dependence of the pKa values of the protonated amines or the proton affinity in the gas phase with the δ(Pt) chemical shifts. The crystal structures of eight diiodo complexes were determined. These compounds are cis-Pt(CH3NH2)2I2, cis-Pt(n-C4H9NH2)2I2, cis-Pt(Et2NH)2I2, trans-Pt(n-C 3H7NH2)2I2, trans-Pt(iso-C3H7NH2)2I 2, trans-Pt(n-C4H9NH2) 2I2, trans-Pt(t-C4H9NH 2)2I2 and trans-Pt(Me2NH) 2I2. The Pt-N bond distances located in trans position to the iodo ligands were compared to those located in trans position to the amines. The Pt-N bond in cis-Pt(Et2NH)2I2 are much longer than the others, probably caused by the steric hindrance of the two very bulky ligands located in cis positions.
Structure-activity relationship studies for three new asymmetric cis-platinum(II) aminoethanol-based complexes
van Rijt, Sabine,van Zutphen, Steven,den Dulk, Hans,Brouwer, Jaap,Reedijk, Jan
, p. 4125 - 4129 (2006)
The design and synthesis of three asymmetrical platinum(II) analogues of cisplatin with substituents on the amine, varying in polarity and steric bulk is presented. Their biological activities, as studied using in vitro cytotoxicity studies in cisplatin sensitive and the corresponding cisplatin resistant cell lines, cellular uptake experiments and in a reaction with model DNA base GMP, are presented. All compounds exhibit promising cytotoxicity in the cisplatin sensitive cell lines albeit lower than cisplatin. On the other hand, the complexes partly overcome cisplatin resistance in the resistant cell lines. A direct correlation between cytotoxicity and cellular uptake was found. Conversely, the rate of reaction of all compounds with the model base GMP was found to be very similar and faster than cisplatin. It was therefore concluded that the difference in activity observed for these complexes is due to differential cellular uptake rather than the reactivity towards the cellular target of platinum complexes, nuclear DNA.
Synthesis and characterization of complexes of the type [Pt(amine)4]I2 and trans-[Pt(CH3NH2)2(H3C{single bond}N{double bond, long}C(CH3)2)2]I2 by crystallography and multinuclear magnetic resonance spectroscopy
Rochon, Fernande D.,Tessier, Christian,Buculei, Viorel
, p. 2255 - 2264 (2007)
Complexes of the type [Pt(amine)4]I2 were synthesized and characterized mainly by multinuclear (195Pt, 1H and 13C) magnetic resonance spectroscopy. The compounds were prepared with different primary amines, but not with bulky amines, due to steric hindrance. In 195Pt NMR, the signals were observed between -2715 and -2769 ppm in D2O. The coupling constant 3J(195Pt-1H) for the MeNH2 complex is 42 Hz. In 13C NMR, the average values of the coupling constants 2J(195Pt-13C) and 3J(195Pt-13C) are 18 and 30 Hz, respectively. The crystal structure of [Pt(EtNH2)4]I2 was determined by X-ray diffraction methods. The Pt atom is located on an inversion center. The structure is stabilized by H-bonding between the amines and the iodide ions. The compound with n-BuNH2 was found by crystallographic methods to be [Pt(n-BuNH2)4]2I3(n-BuNHCOO). The crystal contains two independent [Pt(CH3NH2)4]2+ cations, three iodide ions and a carbamate ion formed from the reaction of butylamine with CO2 from the air. When the compound [Pt(CH3NH2)4]I2 was dissolved in acetone, crystals identified as trans-[Pt(CH3NH2)2(H3C{single bond}N{double bond, long}C(CH3)2)2]I2 were isolated and characterized by crystallographic methods. Two trans bonded MeNH2 ligands had reacted with acetone to produce the two N-bonded Schiff base Pt(II) compound.
Synthesis, characterization, and antitumor activity of platinum(II) complexes of mixed ammine/amine with bidentate carboxylates
Zhang, Jinchao,Gong, Yuqin,Zheng, Xiaoming
, p. 49 - 57 (2002)
Complexes of the type Pt(II)(CH3NH2)(NH3)[(OC)2 (CH2)n]·0.5H2O [(1)-(3)] (n = 0, 1 and 2) have been synthesized for the first time. At the same time, we also have synthesized thr
In vitro activity, stability, and lipophilicity changes of cisplatin through substitution of different amine ligands
Divsalar, Adeleh,Eslami Moghadam, Mahboube,Mesbah, A. Wahid,Rahiminezhad, Arezo
, (2022/02/09)
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.]
A kinetic and mechanistic study of analogous bifunctional dialkylamine platinum(ii) complexes
Olusegun, Moses Ariyo,Reddy, Desigan,Jaganyi, Deogratius
, p. 5138 - 5146 (2020/04/09)
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.
Improving of Anticancer Activity and Solubility of Cisplatin by Methylglycine and Methyl Amine Ligands Against Human Breast Adenocarcinoma Cell Line
Shams Abyaneh, Fatemeh Safa,Eslami Moghadam, Mahboube,Divsalar, Adeleh,Ajloo, Davood,Hosaini Sadr, Moyaed
, p. 271 - 291 (2018/03/12)
Methylglycine, also known sarcosine, is dramatically used in drug molecules and its metal complexes can interact to DNA and also do cleavage. Hence, to study the influence of methylglycine ligand on biological behavior of metal complexes, two water-solubl
Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes
Ermondi, Giuseppe,Caron, Giulia,Ravera, Mauro,Gabano, Elisabetta,Bianco, Sabrina,Platts, James A.,Osella, Domenico
supporting information, p. 3482 - 3489 (2013/03/28)
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.
Stepwise assembly of platinum-folic acid conjugates
Gabano, Elisabetta,Ravera, Mauro,Cassino, Claudio,Bonetti, Samuele,Palmisano, Giovanni,Osella, Domenico
, p. 1447 - 1455 (2008/10/09)
Folates and folate-like molecules represent a class of vectors for drug targeting and delivery. The folate receptor (FR) is overexpressed in many human cancers, therefore folate-cytotoxic drug conjugates can deliver therapeutic agents specifically to FR positive tumours. We have linked, directly through one of the carboxylate functionalities of the folic acid (α or γ), two different chelating arms for a cytotoxic platinum moiety, namely a diamine and a dicarboxylate. Five different derivatives were synthesised by multi-step procedures, purified and characterised; unfortunately, they resulted barely soluble in water, thereby precluding any biochemical and biological tests.
