cis-Tetrachlorido-bis(indazole)osmium(iv) and its osmium(iii) analogues: paving the way towards the cis-isomer of the ruthenium anticancer drugs KP1019 and/or NKP1339

Abstract

The relationship between cis-trans isomerism and anticancer activity has been mainly addressed for square-planar metal complexes, in particular, for platinum(II), e.g., cis- and trans-[PtCl2(NH3)2], and a number of related compounds, of which, however, only cis-counterparts are in clinical use today. For octahedral metal complexes, this effect of geometrical isomerism on anticancer activity has not been investigated systematically, mainly because the relevant isomers are still unavailable. An example of such an octahedral complex is trans-[RuCl4(Hind)2]−, which is in clinical trials now as its indazolium (KP1019) or sodium salt (NKP1339), but the corresponding cis-isomers remain inaccessible. We report the synthesis of Na[cis-OsIIICl4(κN2-1H-ind)2] (Na[1]) to show that cis-isomer of NKP1339 can in principle be prepared as well. The procedure involves heating (H2ind)[OsIVCl5(κN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with formation of cis-[OsIVCl4(κN2-1H-ind)2] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from κN1 to κN2 and stabilization of the 1H-indazole tautomer. Fully reversible spectroelectrochemical reduction of [1] in acetonitrile at 0.46 V vs NHE is accompanied by a change in electronic absorption bands indicating formation of cis-[OsIIICl4(κN2-1H-ind)2]− ([1]−). Chemical reduction of [1] in methanol with NaBH4 followed by addition of nBu4NCl afforded the osmium(III) complex nBu4N[cis-OsIIICl4(κN2-1H-ind)2] (nBu4N[1]). Metathesis reaction of nBu4N[1] with an ion exchange resin led to isolation of the water-soluble salt Na[1]. The X-ray diffraction crystal structure of [1]·Me2CO was determined and compared with that of trans-[OsIVCl4(κN2-1H-ind)]·2Me2SO (2·2Me2SO), also prepared in this work. EPR spectroscopy was performed on the OsIII complexes and the results analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison to trans-[OsIVCl4(κN1-2H-ind)] [3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 µM in different cancer cell lines (HT29, H446, 4T1 and HEK293). HT-29 cells are less sensitive to cisplatin than 4T1 cells, but more sensitive to [1] and Na[1], as shown by decreased proliferation and viability as well as an increased late apoptotic/necrotic cell population.

Current Practice and Emerging Molecular Imaging Technologies in Oral Cancer Screening

“…In the future, if high specificity is consistently shown, they could be used as diagnostic agents. 112…”

Recent Advances in the Development of Indazole‐based Anticancer Agents

“…Cytotoxic Pt II ‐based complexes 60 and 61 were found to be the most promising ones in this work (Figure ). Additionally, indazole osmium analogues with anticancer activity were also reported . In the research performed by Büchel et al., osmium(IV) complex 62 and its one‐electron‐reduced species 63 (osmium(III)) were found to have strong antiproliferative effects on tested cancer cells at concentrations between 30 and 300 μ m (Figure ).…”

“…Additionally,i ndazole osmium analogues with anticancer activity were also reported. [96] In the research performed by Büchel et al,o smium(IV) complex 62 and its one-electron-reduceds pecies 63 (osmium(III)) were found to have strong antiproliferative effects on tested cancer cells at concentrationsb etween 30 and 300 mm ( Figure 22). Specially, these two osmium complexes showeda higher antiproliferativea ctivity toward the HT29 cell line than that of cisplatin.…”

Photoluminescent Coordination Polymers Based on Group 12 Metals and 1H-Indazole-6-Carboxylic Acid

“…From the structural point of view, indazole is an aromatic heterocyclic molecule with a benzene ring fused to a pyrazole ring [9]. It shows three tautomeric forms (Scheme 1) being tautomer A favoured over B and C due to its higher degree of aromaticity [10]. H2L is presented here as an ideal candidate to form CPs or MOFs as it possesses multiple coordination possibilities, not only derived from its carboxylate group, but also from its pyrazole function.…”

“…From the structural point of view, indazole is an aromatic heterocyclic molecule with a benzene ring fused to a pyrazole ring [9]. It shows three tautomeric forms (Scheme 1) being tautomer A favoured over B and C due to its higher degree of aromaticity [10].…”