How to modify 7-azaindole to form cytotoxic Pt(II) complexes: Highly in vitro anticancer effective cisplatin derivatives involving halogeno-substituted 7-azaindole

Štarha, Pavel; Trávníček, Zdeněk; Popa, Alexandr; Popa, Igor; Muchová, Tereza; Brabec, Viktor

doi:10.1016/j.jinorgbio.2012.05.006

Cited by 47 publications

(51 citation statements)

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“…With respect to these findings and to the promising results of anticancer screening of platinum(II) dichlorido complexes containing the 7-azaindole derivatives reported previously by our group [16–18] and others [19–20], we decided to study a series of cis -[PtI 2 ( n aza) 2 ] ( 1 – 8 ; Fig 1) complexes and further evaluate their in vitro and in vivo activities and mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

et al. 2016

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A series of platinum(II) diiodido complexes containing 7-azaindole derivatives, having the general formula cis-[PtI2(naza)2] (1–8), has been prepared and thoroughly characterized, including X-ray structure analysis of cis-[PtI2(2Me4Claza)2]∙DMF (8∙DMF; 2Me4Claza = 2-methyl-4-chloro-7-azaindole). Complexes showed high in vitro cytotoxicity against nine human cancer cell lines (IC50 ranging from 0.4 to 12.8 μM), including the cisplatin-resistant ovarian cancer cell line (A2780R; IC50 = 1.0–3.5 μM). The results of in vivo testing, using the L1210 lymphocytic leukaemia model, at the equimolar doses of Pt with cisplatin (2 mg/kg) confirmed the activity of complex 8 comparable to cisplatin. From the mechanistic point of view, evaluated ex vivo by Western blot analyses on the samples of isolated tumour tissues, the treatment of the animals with complex 8, contrary to cisplatin, decreased the levels of tumour suppressor p53 and increased significantly the amount of intracellular anti-apoptotic protein MCL-1L (37 kDa). Additionally, the active form of caspase 3 was significantly elevated in the sample of tumour tissues treated with complex 8, indicating that the activation of p53-independent cell-death pathway was initiated. The light and electron microscopy observations of the cancerous tissues revealed necrosis as a dominant mechanism of cell death, followed by scarce signs of apoptosis. The additional results (e.g. in vitro interaction experiments with selected biomolecules, cell cycle perturbations, gel electrophoretic studies on pUC19 plasmid DNA) supported the hypothesis that the complexes might be involved in the mechanism of action quite different from cisplatin.

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Section: Introductionmentioning

confidence: 99%

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

et al. 2016

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“…Although, the preparation of cis-isomers was the main goal of this work, only the pure trans-isomers were isolated. This was quite surprising because two series of cis-[PtCl 2 (L) 2 ] complexes with differently substituted N6-benzyladenine derivatives [16] or with 7-azaindole derivatives [17] were formerly prepared by the same procedure, i.e., the reaction of K 2 [PtCl 4 ] with the corresponding N-donor ligand. This unexpected behaviour may be connected with very low thermodynamic stability of the cis-isomers, which probably transform instantly into the trans-isomers.…”

Section: Characterizations and General Properties Of The Complexesmentioning

confidence: 99%

N6-Benzyladenosine Derivatives as Novel N-Donor Ligands of Platinum(II) Dichlorido Complexes

et al. 2013

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Abstract:The platinum(II) complexes trans-[PtCl 2 (L n ) 2 ]·xSolv 1-13 (Solv = H 2 O or CH 3 OH), involving N6-benzyladenosine-based N-donor ligands, were synthesized; L n stands for N6-(2-methoxybenzyl)adenosine (L 1 , involved in complex 1), , 11), 2-chloro-N6-(2-hydroxy-3-methoxybenzyl)adenosine (L 12 , 12) and 2-chloro-N6-(2-hydroxy-5-methylbenzyl)adenosine (L 13 , 13). The compounds were characterized by elemental analysis, mass spectrometry, IR and multinuclear ( N-) and two-dimensional NMR spectroscopy, which proved the N7-coordination mode of the appropriate N6-benzyladenosine derivative and trans-geometry of the title complexes. The complexes 1-13 were found to be non-toxic in vitro against two selected human cancer cell lines (HOS and MCF7; with IC 50 > 50.0 µM). However, they were found (by ESI-MS study) to be able to interact with the physiological levels of the sulfur-containing biogenic biomolecule L-methionine by a relatively simple 1:1 exchange mechanism (one L n molecule was replaced by one L-methionine molecule), thus forming a mixed-nitrogen/sulfur-ligand dichlorido-platinum(II) coordination species.

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“…Platinum therapy associated inadequacies such as acquired resistance [3] and toxic side effects [4] emphasizes the need for new anticancer drugs with new mechanisms of action. Several research groups showed that platinum (II) complexes have significant anti-tumor activities against different types of cancers in vitro and in vivo [5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Anti-growth effect of a novel trans-dichloridobis[2-(2-hydroxyethyl)pyridine]platinum (II) complex via induction of apoptosis on breast cancer cell lines

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Sarimahmut

et al. 2015

Bioorganic & Medicinal Chemistry

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How to modify 7-azaindole to form cytotoxic Pt(II) complexes: Highly in vitro anticancer effective cisplatin derivatives involving halogeno-substituted 7-azaindole

Cited by 47 publications

References 32 publications

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

N6-Benzyladenosine Derivatives as Novel N-Donor Ligands of Platinum(II) Dichlorido Complexes

Anti-growth effect of a novel trans-dichloridobis[2-(2-hydroxyethyl)pyridine]platinum (II) complex via induction of apoptosis on breast cancer cell lines

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