Organometallic 3-(1 H-Benzimidazol-2-yl)-1 H-pyrazolo[3,4- b]pyridines as Potential Anticancer Agents

Abstract

Six organometallic complexes of the general formula [M ^IICl(η ⁶- p-cymene)(L)]Cl, where M = Ru ( 11a, 12a, 13a) or Os ( 11b, 12b, 13b) and L = 3-(1 H-benzimidazol-2-yl)-1 H-pyrazolo[3,4- b]pyridines ( L1– L3) have been synthesized. The latter are known as potential cyclin-dependent kinase (Cdk) inhibitors. All compounds have been comprehensively characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, UV–vis spectroscopy, ESI mass spectrometry, and X-ray crystallography ( 11b and 12b). The multistep synthesis of 3-(1 H-benzimidazol-2-yl)-1 H-pyrazolo[3,4- b]pyridines ( L1– L3), which was reported by other researchers, has been modified by us essentially (e.g., the synthesis of 5-bromo-1 H-pyrazolo[3,4- b]pyridine-3-carboxylic acid ( 3) via 5-bromo-3-methyl-1 H-pyrazolo[3,4- b]pyridine ( 2); the synthesis of 1-methoxymethyl-2,3-diaminobenzene ( 5) by avoiding the use of unstable 2,3-diaminobenzyl alcohol; and the activation of 1 H-pyrazolo[3,4- b]pyridine-3-carboxylic acids ( 1, 3) through the use of an inexpensive coupling reagent, N, N′-carbonyldiimidazole (CDI)). Stabilization of the 7b tautomer of methoxymethyl-substituted L3 by coordination to a metal(II) center, as well as the NMR spectroscopic characterization of two tautomers 7b- L3 and 4b′- L3 in a metal-free state are described. Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells, as well as Cdk inhibitory activity, are also reported.

Abstract

Three organic compounds L1−L3, known as potential Cdk inhibitors, and six novel complexes of the general formula [M ^IICl(η ⁶- p-cymene)(L)]Cl, where M = Ru ( 11a, 12a, 13a) or Os ( 11b, 12b, 13b) and L = L1−L3, correspondingly, have been synthesized and comprehensively characterized by elemental analysis, ESI mass-spectrometry, spectroscopic and X-ray diffraction methods. Structure−activity relationships, with regard to cytotoxicity and cell cycle effects, in human cancer cells, as well as Cdk inhibitory activity, are reported.