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]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H2ind)[OsIVCl5(κN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the 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 the 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]). A metathesis reaction of nBu4N[1] with an ion exchange resin led to the 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)2]·2Me2SO (2·2Me2SO), also prepared in this work. EPR spectroscopy was performed on the OsIII complexes and the results were analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison with trans-[OsIVCl4(κN1-2H-ind)2] [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.
Highlights
Indazole derivatives are characterized by a variety of applications as anti-inflammatory, antimicrobial, antihypertensive, antiprotozoal, antiobesity, and antifungal agents.1–3 They have been found to be active as inhibitors of nitric oxide synthase (NOS),4 bacterial gyrases,5 hydrolases,6 and various kinases.7–9 The ruthenium(III) complexes H2ind[trans-RuCl4(κN2-1H-indazole)2] (KP1019) and Na[trans-RuCl4(κN2-1H-indazole)2] (NKP1339) are in clinical trials as potential anticancer agents.10 Indazole, usually referred to as 1H-indazole, exists in three tautomeric forms (Chart 1). 1HIndazole is the dominant tautomer in the gas phase and aqueous solution,11,12 as well as in metal complexes, some substituted organic 2H-indazoles are known13 as well as rare, inorganic examples such as an organoruthenium(II) complex with 2-methyl-indazole,14 and the osmium(IV) complexes trans-[OsIVCl4(κN1-2H-ind)2],15 and (H2ind)[OsIVCl5(κN1-2Hind)].16 The synthesis of the latter complex along with (H2ind) [OsIVCl5(κN2-1H-ind)] made an estimation of the effect of indazole tautomer identity on the antiproliferative activity of osmium(IV) complexes in different human cancer cell lines possible.After the discovery of the antiproliferative activity of cisplatin in 1965,17 the cis-geometry was long believed to be a prerequisite for the anticancer activity of metal compounds.18,19 Even though this situation changed over the years as several trans-isomers were synthesized and discovered to exhibit higher antiproliferative potency than their cis-congeners,20 with some of them having the advantage of not showing cross resistance to cisplatin,21 there are no trans-isomers in clinical use today
Even though this situation changed over the years as several trans-isomers were synthesized and discovered to exhibit higher antiproliferative potency than their cis-congeners,20 with some of them having the advantage of not showing cross resistance to cisplatin,21 there are no trans-isomers in clinical use today
The NMR resonances of the osmium(III) complexes nBu4N[1] and Na[1] were considerably broadened due to the rapid nuclear relaxation induced by the paramagnetism of these compounds, which could be expected from the LS d5 electron configuration of the central metal.33b,c electron paramagnetic resonance (EPR) is a valuable technique to unravel the underlying mechanisms of action of paramagnetic anticancer drugs and, in particular, those of ruthenium(III)
Summary
Indazole derivatives are characterized by a variety of applications as anti-inflammatory, antimicrobial, antihypertensive, antiprotozoal, antiobesity, and antifungal agents.1–3 They have been found to be active as inhibitors of nitric oxide synthase (NOS),4 bacterial gyrases,5 hydrolases,6 and various kinases.7–9 The ruthenium(III) complexes H2ind[trans-RuCl4(κN2-1H-indazole)2] (KP1019) and Na[trans-RuCl4(κN2-1H-indazole)2] (NKP1339) are in clinical trials as potential anticancer agents.10 Indazole, usually referred to as 1H-indazole, exists in three tautomeric forms (Chart 1). 1HIndazole is the dominant tautomer in the gas phase and aqueous solution,11,12 as well as in metal complexes, some substituted organic 2H-indazoles are known13 as well as rare, inorganic examples such as an organoruthenium(II) complex with 2-methyl-indazole,14 and the osmium(IV) complexes trans-[OsIVCl4(κN1-2H-ind)2],15 and (H2ind)[OsIVCl5(κN1-2Hind)].16 The synthesis of the latter complex along with (H2ind) [OsIVCl5(κN2-1H-ind)] made an estimation of the effect of indazole tautomer identity on the antiproliferative activity of osmium(IV) complexes in different human cancer cell lines possible.After the discovery of the antiproliferative activity of cisplatin in 1965,17 the cis-geometry was long believed to be a prerequisite for the anticancer activity of metal compounds.18,19 Even though this situation changed over the years as several trans-isomers were synthesized and discovered to exhibit higher antiproliferative potency than their cis-congeners,20 with some of them having the advantage of not showing cross resistance to cisplatin,21 there are no trans-isomers in clinical use today. The UV–vis spectrum of the osmium(III) species [1]− generated electrochemically exhibits an absorption maximum at a slightly higher wavelength (318 nm in acetonitrile and 325 nm in Me2SO) compared to its analogue trans-[OsIIICl4(κN1-2H-ind)2]− ([3] in Me2SO) reported previously29 with λmax at 301 nm.
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