A minimal structural variation can overcome tumour resistance of oxaliplatin: the case of 4,5-dehydrogenation of the cyclohexane ring

Papadia, Paride; Gandin, Valentina; Barbanente, Alessandra; Ruello, Alessandro G.; Marzano, Cristina; Micoli, Katia; Hoeschele, James D.; Natile, Giovanni; Margiotta, Nicola

doi:10.1039/c9ra07760j

Cited by 8 publications

(14 citation statements)

References 21 publications

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“…[Pt(OXA)(DACHEX)] and PhICl 2 [10] were synthesized according to previously reported procedures. [Pt(OXA)(DACHEX)] (114 mg, 0.288 mmol) was suspended in 74 mL of water.…”

Section: Starting Materials and Instrumental Detailsmentioning

confidence: 99%

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Platinum(IV) Complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance

Papadia

Micoli

Barbanente

et al. 2020

IJMS

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Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5–8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells.

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“…[Pt(OXA)(DACHEX)] and PhICl 2 [10] were synthesized according to previously reported procedures. [Pt(OXA)(DACHEX)] (114 mg, 0.288 mmol) was suspended in 74 mL of water.…”

Section: Starting Materials and Instrumental Detailsmentioning

confidence: 99%

“…The complexes proved to have, in general, equal if not better cytotoxic activity than cisplatin and oxaliplatin and were able to overcome the oxaliplatin-resistance. Moreover, the oxalate-derivative induced lipid droplets formation in LoVo OXP cells thus suggesting the involvement of metabolic stress in its mechanism of action [10].…”

Section: Introductionmentioning

confidence: 96%

Platinum(IV) Complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance

Papadia

Micoli

Barbanente

et al. 2020

IJMS

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“…Another interesting ligand that we have recently investigated is the trans -1,2-diamino-4-cyclohexene (1,2-DACHEX) [ 26 , 31 ]. With respect to 1 R ,2 R -DACH, this ligand contains a double bond in the cyclohexane ring that greatly reduces its flexibility while extending its planarity.…”

Section: Resultsmentioning

confidence: 99%

“…Four Pt(II) complexes with general formula [PtX 2 (1,2-DACHEX)] (X 2 = Cl 2 , I 2 , 1,1′-cyclobutanedicarboxylate, and oxalate) were synthesized and tested against a panel of human tumor cell lines. They proved to have, in general, equal if not better cytotoxic activity than cisplatin and oxaliplatin and to be able to overcome the oxaliplatin resistance, thus showing how a limited structural variation at the diamine carrier ligand can deeply impact on the spectrum of activity of platinum drugs [ 26 ]. It is also worth mentioning that very recently, Hoeschele et al have evaluated the role of the size of the alkane ring in complexes of general formula [PtCl 2 ( cis -1,3-diaminocycloalkane)], where the cycloalkane is cyclobutane, cyclopentane, or cyclohexane.…”

Section: Introductionmentioning

confidence: 99%

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

et al. 2021

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Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.

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“…The effects of the non-leaving ligand(s) modifications have also been investigated but mostly on aromatic systems [17] and/or the interest has been focused on their antiproliferative and anticancer activities. [18][19][20][21][22] Kinetic aspects of non-aromatic non-leaving ligands have been explored less frequently [23][24][25] being often compared with the NH 3 groups in cisplatin. [26,27] However, it is hard to exactly compare the data about the influence of the ligands on the reactivity of Pt(II) complexes from different studies due to a diversity of experimental conditions and theoretical models.…”

Section: Introductionmentioning

confidence: 99%

Tuning the Reactivity and Bonding Properties of the Pt(II) Complexes by the Substitution(s) on the Trans‐Coordinated Non‐Aromatic Amine Ligand

Dvořáčková

Chval

2021

ChemistrySelect

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Kinetics of the hydration reaction and the bonding properties of the trans-[Pt(NH 3 ) 2 (NH 2 X)Cl] + complexes (X = H, CH 3 , F, Cl, Br, NH 2 , NO 2 , OH, dimethylamine (DMA), cyclopropyl (CyP), cyclohexyl (CyH)) were studied theoretically by DFT methodology in the gas phase and the water solution. The electrondonating and electron-withdrawing X substituents lower and increase, respectively, the activation free energy (ΔG � ) and Pttrans ligand binding energies (BEs) to a similar extent as meta and para substituents of the pyridine ligand studied previously (ACS Omega, 2020, 5, 11768). For the saturated hydrocarbon X substituents (X = H, CH 3 , CyP, CyH), the ΔG � values and Pt-trans ligand BEs decrease with the logarithm of the X substituent size being best quantified by the number of electrons. The additivity of the substituent effects was studied on the NF 3 ligand and worked well for ligand charges and PtÀ trans ligand BEs. The influence of chelation was evaluated by the comparison of the CyH system and the complexes with the cyclohexanediamine (DACH) ligand. Finally, the effect of isomerization was studied on the complexes with the 1,2-bis (aminomethyl)cyclobutane (BAMCB) ligand. Thus, this study also evaluates the influence of the non-leaving ligands present in cisplatin, oxaliplatin, lobaplatin, JM118, and JM11 drugs on the reactivity of the Pt(II) complexes in the same ligand environment.

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A minimal structural variation can overcome tumour resistance of oxaliplatin: the case of 4,5-dehydrogenation of the cyclohexane ring

Abstract: A new family of anticancer compounds has been derived from oxaliplatin by inserting a double-bond between carbons 4 and 5 of the 1,2-diaminocyclohexane ring.

Cited by 8 publications

References 21 publications

Platinum(IV) Complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance

Platinum(IV) Complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Tuning the Reactivity and Bonding Properties of the Pt(II) Complexes by the Substitution(s) on the Trans‐Coordinated Non‐Aromatic Amine Ligand

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