Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy

Filak, Lukas K.; Mühlgassner, Gerhard; Jakupec, Michael A.; Heffeter, Petra; Berger, Walter; Arion, Vladimir B.; Keppler, Bernhard K.

doi:10.1007/s00775-010-0653-y

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Organometallic indolo[3,2- c]quinolines versus indolo[3,2- d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy

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Author(s): Lukas K. Filak ¹ , Gerhard Mühlgassner ¹ , Michael A. Jakupec ¹ ^, ³ , Petra Heffeter ² ^, ⁴ , Walter Berger ² ^, ⁴ , Vladimir B. Arion ¹ ^, , Bernhard K. Keppler ¹ ^, ³

Publication date (Electronic): 6 April 2010

Journal: Journal of Biological Inorganic Chemistry

Publisher: Springer-Verlag

Keywords: Indolo[3,2-d]benzazepines, Indolo[3,2-c]quinolines, Osmium, Ruthenium

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Abstract

The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2- c]quinolines N-(11 H-indolo[3,2- c]quinolin-6-yl)-ethane-1,2-diamine ( L ¹) and N′-(11 H-indolo[3,2- c]quinolin-6-yl)- N, N-dimethylethane-1,2-diamine ( L ²) and indolo[3,2- d]benzazepines N-(7,12-dihydroindolo-[3,2- d][1]benzazepin-6-yl)-ethane-1,2-diamine ( L ³) and N′-(7,12-dihydroindolo-[3,2- d][1]benzazepin-6-yl)- N, N-dimethylethane-1,2-diamine ( L ⁴) of the general formulas [(η ⁶- p-cymene)M ^II( L ¹)Cl]Cl, where M is Ru ( 4) and Os ( 6), [(η ⁶- p-cymene)M ^II( L ²)Cl]Cl, where M is Ru ( 5) and Os ( 7), [(η ⁶- p-cymene)M ^II( L ³)Cl]Cl, where M is Ru ( 8) and Os ( 10), and [(η ⁶- p-cymene)M ^II( L ⁴)Cl]Cl, where M is Ru ( 9) and Os ( 11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography ( L ¹·HCl, 4·H ₂O, 5, and 9·2.5H ₂O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2- c]quinolines inhibit cancer cell growth in vitro, with IC ₅₀ values in the high nanomolar range, whereas those of the related indolo[3,2- d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L ¹ and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L ⁴ and 11, arguing for additional targets and molecular effects, such as intercalation into DNA.

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Most cited references 44

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Inhibition of cancer cell growth by ruthenium(II) arene complexes.

R E Morris, R Aird, P del S Murdoch … (2001)

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(eta(6)-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p-cymene)RuCl(2)(isonicotinamide)] (7), and [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) are reported. They have "piano stool" geometries with eta(6) coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru-Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.

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Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity.

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The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).

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Mechanisms of action of flavopiridol.

H.H. Sedlacek, Ivan Boubriak (2001)

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin dependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kinases (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal transducing kinases (PKC and Erk-1). Although the inhibiting activity of flavopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is not limited to cycling cells. Resting cells are also killed. This fact suggests that inhibition of cdks involved in the control of cell cycle is not the only mechanism of action. Inhibition of cdk's with additional functions (i.e. involved in the control of transcription or function of proteins that do not control cell cycle) may contribute to the antitumoral effect. Moreover, direct and indirect inhibition of receptor activation (EGFR) and/or a direct inhibition of kinases (pp60 Src, PKC, Erk-1) involved in the signal transduction pathway could play a role in the antiproliferative activity of flavopiridol. From pharmacokinetic data in patients it can be concluded that the inhibitory activity (IC50) of flavopiridol on these kinases is in the range of concentrations that might be achieved intracellularly after systemic application of non-toxic doses of flavopiridol. However, no in situ data from flavopiridol treated cells have been published yet that prove that by inhibition of EGFR, pp60 Src, PKC and/or Erk-1 (in addition to inhibition of cdk's) flavopiridol is able to induce apoptosis. Thus many questions regarding the detailed mechanism of antitumoral action of flavopiridol are still open. For the design of protocols for future clinical studies this review covers the essential information available on the mechanism of antitumoral activity of flavopiridol. The characteristics of this antitumoral activity include: High rate of apoptosis, especially in leukemic cells; synergy with the antitumoral activity of many cytostatics; independence of its efficacy on pRb, p53 and Bcl-2 expression; lack of interference with the most frequent multidrug resistance proteins (P-glycoprotein and MRP-190); and a strong antiangiogenic activity. Based on these pharmacological data it can be concluded that flavopiridol could be therapeutically active in tumor patients: independent on the genetic status of their tumors or leukemias (i.e. mutations of the pRb and/or p53, amplification of bcl-2); in spite of drug resistance of their tumors induced by first line treatment (and caused by enhanced expression of multidrug resistance proteins); in combination with conventional chemotherapeutics preferentially given prior to flavopiridol; and due to a complex mechanism involving cytotoxicity on cycling and on resting tumor cells, apoptosis and antiangiogenic activity. In consequence, flavopiridol is a highly attractive, new antitumoral compound and deserves further elucidation of its clinical potency.