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The Synthesis of Indolo[2,3-B]Quinoline Derivatives

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The Synthesis of Indolo[2,3-B]Quinoline Derivatives European Journal of Medicinal Chemistry 105 (2015) 208e219 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Research paper The synthesis of indolo[2,3-b]quinoline derivatives with a guanidine group: Highly selective cytotoxic agents * Katarzyna Sidoryk a, , Marta Switalska b, Anna Jaromin c, Piotr Cmoch a, d, Iwona Bujak a, , _ Monika Kaczmarska a, Joanna Wietrzyk b e, Eddie G. Dominguez f, Robert Zarnowski f, David R. Andes f, Krzysztof Bankowski a, Marcin Cybulski a, Łukasz Kaczmarek a a Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland b Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla St., 53-114 Wroclaw, Poland c Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 14A Joliot-Curie St., 50-383 Wroclaw, Poland d Institute of Organic Chemistry, Polish Academy of Sciences, 44/52 Kasprzaka St., 01-224 Warsaw, Poland e Institute of Chemistry Environmental Protection and Biotechnology, Jan Długosz University, 13/15 Armii Krajowej Ave., 42-200 Cze˛stochowa, Poland f Department of Medicine, Section of Infectious Diseases, 4125 Microbial Sciences Building, 1550 Linden Dr., University of Wisconsin-Madison, Madison, WI 53706, USA article info abstract Article history: The synthesis of indolo[2,3-b]quinoline derivatives containing guanidine, amino acid or guanylamino Received 23 July 2015 acid substituents as well as their in vitro evaluation for the cytotoxic and antifungal activity are reported. Received in revised form The influence of the guanidine group on the selective cytotoxic and hemolytic properties of indolo[2,3-b] 5 October 2015 quinoline was investigated. Most of the compounds displayed a high cytotoxic activity in vitro and two of Accepted 10 October 2015 the most promising compounds (3 and 12) exhibited a high selectivity between normal and cancer cell- Available online xxx lines. The cytotoxic activity of compound 3 was about 600-fold lower against normal fibroblasts than against A549 and MCF-7 cancer cell lines. Novel entities acted as the DNA-intercalators when tested Keywords: e Neocryptolepine using a DNA methyl green assay but demonstrated zero or low hemolytic activity in comparison to their Antiproliferative activity unsubstituted analogs. The mechanism of action was studied for guanidine derivatives 3 and 12 and both Antifungal activity compounds were found to be very effective inducers of apoptosis. Biofilm © 2015 Elsevier Masson SAS. All rights reserved. Guanidine group Mechanism of action Apoptosis Hemolytic activity 1. Introduction activity and inhibits the proliferation of mouth cacinoma KB cells at a concentration of 1 mM. Moreover, its activity is similar to the Neocryptolepine is an alkaloid which displays a broad spectrum cytotoxic activity of doxorubicin (0.8 mM against KB cells) [7e9]. of biological activities including an antibacterial, antifungal, anti- Unfortunately, DiMIQ's high toxicity, lack of selectivity and very low inflammatory, cytotoxicity, and antimalarial activity [1e6] (Fig. 1). solubility in aqueous solutions, especially at neutral pH, seriously 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ, Fig. 1), the syn- limit the practical application of this compound in the treatment of thetic analog of neocryptolepine, demonstrates high cytotoxic cancer [10]. The high toxicity and low bioavailability of DiMIQ, prompted us to look for new analogs which would conform to the high requirements necessary for anticancer drugs: potent and se- lective activity and low side effects. Our recently published results 0 Abbreviations: Boc, tert-butyloxycarbonyl group; BSTU, N,N -bis-Boc-thiourea; reveal that this might be achieved by constructing conjugates DIPEA, N,N-diisopropylethylamine; DMF, dimethylformamide; DMSO, dime- composed of DiMIQ and amino acids or peptides [11e13]. As it has thylsulfoxide; DSS, 4,4-dimethyl-4-silapentane-1-sulfonic acid; HOBt, N-hydrox- ybenzotriazole monohydrate; HPLC, high performance liquid chromatography; been proved, the attachment of an amino acid moiety or a short TBTU, O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate; peptide chain to DiMIQ significantly improves its physicochemical TFA, trifluoroacetic acid. properties, resulting in the auspicious anticancer action in vivo with * Corresponding author. a relatively low hemolytic effect. Some of the recently reported E-mail address: [email protected] (K. Sidoryk). http://dx.doi.org/10.1016/j.ejmech.2015.10.022 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. K. Sidoryk et al. / European Journal of Medicinal Chemistry 105 (2015) 208e219 209 could be expected that the introduction of the guanyl substituents into novel conjugates would increase the DNA interaction and, as a result, advantageously affect the cytotoxic activity of the novel analogs. Besides stabilizing the drug-DNA complex, the guanidine group might also improve the delivery of the substances inside cancer cells by increasing their hydrophilicity and water solubility, while simultaneously decreasing their toxicity [25e28]. Herein we report the synthesis of new hybrid compounds with Fig. 1. Structures of neocryptolepine and DiMIQ. the indolo[2,3-b]quinoline core [(5,11-dimethyl-5H-indolo[2,3-b] quinoline e DIMIQ or 6-(2-dimethylaminoethyl)-11-methyl-6H- indolo[2,3-b]quinoline)] and a guanidine group, an amino acid neocryptolepine analogs showed promising antifungal and anti- residue or an N-guanylamino acid. All new conjugates were tested bacterial characteristics which could potentially aid future for their cytotoxic activity against cancer and normal cell lines and anticancer-antimicrobial treatment [13]. against fungal biofilms as well as for their DNA interactions. Most However, the cytotoxic activity in vitro of the above mentioned promising compounds were selected to establish their mechanism compounds and other known indolo[2,3-b]quinoline derivatives of action. Moreover, all novel conjugates were tested for their against cancer cells was comparable to their cytotoxic activity ability to induce the hemolysis of human erythrocytes, as this test is e against normal cell lines [14 17]. The lack of the selectivity of ac- one of the most important and most frequently studied biocom- tion of the indolo[2,3-b]quinoline derivatives obtained so far patibility measures. prompted us to search further for more selective antitumor com- pounds with high cytotoxic activity against cancer cells and low against normal cells. 2. Results and discussion After a detailed literature search, it was assumed that our goal could be accomplished by the introduction of a guanidine group 2.1. Synthesis into the indolo[2,3-b]qiunoline conjugates. The guanidine group widely exists in various natural products and pharmaceutically 5,11-dimethyl-5H-indolo[2.3-b]quinolin-9-yl-amine dihydro- active compounds [18,19]. This group has been found in metabolites chloride (1a) and 6-(2-dimethylaminoethyl)-11-methyl-6H-indolo of different living organisms and many naturally occurring sub- [2.3-b]quinolin-9-yl-amine trihydrochloride (10a) used for the SAR stances such as ptilomycalin A and bisguanidine. Ptilomycalin A, studies were prepared by treating the amino derivatives of 1 and 10 which exhibits an antimicrobial, antifungal, antiviral and also with HCl/MeOH. The synthesis of the N-guanidine- and N-guany- cytotoxic activity, was isolated from the sponges of the Red Sea and lamino acids conjugates of 1 is outlined in Scheme 1. The starting the Caribbean Sea [20e22]. Bisguanidine, TAN-1057, isolated from compound 1 is not commercially available and was synthesized as Flexibacter sp. PK-74 bacteria, possess a potent activity against b- described previously [14,29]. The guanidinylation of 1 with N,N0- lactam-resistant, Gram-positive bacteria [23]. The guanidine sub- bis-Boc-thiourea in the presence of DIPEA and HgCl2 gave the ex- structure is also present in the active pharmaceutical substances pected compound 2 with 77% yield. The treatment of the protected used to treat influenza A and B viral infections (Zanamivir), as well Boc-derivative (2) with the trifluoroacetic acid and then with HCl/ as bacterial infections (Chlorhexidine, Sulfaguanidine) (Fig. 2). MeOH gave N-guanyl-N-(5,11-dimethyl-5H-indolo[2,3-b]chinolin- Furthermore, it seems that the guanidine group plays an important 9-yl)-amine dihydrochloride 3 with an excellent 98% yield. The role in drug delivery to cancer cells due to its strong basic proper- guanidinylation of compounds 4 [12] and 7 [12] with BSTU under ties (pKa 12.5). Evidence has also been found for its possible strong standard conditions afforded 5 and 8 with a moderate 60% and a interaction with the phosphate residues of the minor groove of the good 80% yield, respectively. In the case of N -bis(tert-butylox- DNA helix [24]. Taking into consideration all the above facts, it ycarbonyl)guanyl-glycyl-N-(5,11-dimethyl-5H-indolo[2,3-b] Fig. 2. Guanidine-containing natural products and pharmaceuticals. 210 K. Sidoryk et al. / European Journal of Medicinal Chemistry 105 (2015) 208e219 Scheme 1. Reagents and conditions: (a) BSTU, HgCl2, DIPEA, DMF, 24 h, rt; (b) TFA, HCl/MeOH. chinolin-9-yl)-amide 5, the main product was obtained with a trifluoroacetates were converted into the appropriate hydrochlo- small amount of the impurity 5a. The Boc-removal of compounds 5 rides 14 and 16 by the HCl/MeOH treatment. and 8 with the trifluoroacetic acid and then the treatment
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