molecules Article Article SynthesisSynthesis of of New New Derivatives Derivatives of of Benzofuran Benzofuran as as PotentialPotential Anticancer Anticancer Agents Agents Mariola Napiórkowska 1,*, Marcin Cieślak 2,*, Julia Kaźmierczak-Barańska 2, 1, 2, 2 MariolaKarolina Napi Królewska-Goliórkowska * ńska, Marcin 2 and Barbara Cie´slak Nawrot*, Julia 2 Ka´zmierczak-Bara´nska , Karolina Królewska-Goli ´nska 2 and Barbara Nawrot 2 1 Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, 1 ChairPoland and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland 2 Centre2 Centre of Molecularof Molecular and and Macromolecular Macromolecular Studies, Studies, Polish Polish Academy Academy of Sciences,of Sciences 112, 112 Sienkiewicza Sienkiewicza Str., Str., 90- 90-363363 Łó ódd´z,Poland;ź, Poland; [email protected]@cbmm.lodz.pl (J.K.-B.);(J.K.-B.); [email protected]@cbmm.lodz.pl (K.K.-G.);(K.K.-G.); [email protected] [email protected](B.N.) (B.N.) * Correspondence:* Correspondence: [email protected] [email protected] (M.N.);l (M.N.); [email protected] [email protected] (M.C.); (M.C.); Tel.: +48-22- Tel.:572-06-93+48-22-572-06-93 or +48-22-572-06-39 or +48-22-572-06-39 (M.N.); Tel.: (M.N.); +48-22-681-89-52+48-22-681-89-52 (M.C.); (M.C.); Fax: +48-22-572-06-79 (M.N.); Fax: +48- Fax:22-648-71-26+48-22-572-06-79 (M.C.) (M.N.); +48-22-648-71-26 (M.C.) AcademicAcademic Editor: Editor: Qiao-Hong Qiao-Hong Chen Chen Received:Received: 28 March 28 March 2019; 2019; Accepted: Accepted: 16 April 16 April 2019; 2019; Published: Publishe 18d: April 18 April 2019 2019 Abstract:Abstract:The The results results of ourof our previous previous research research indicated indicated that that some some derivatives derivatives of benzofurans,of benzofurans, particularlyparticularly halogeno-derivatives, halogeno-derivatives, are selectivelyare selectively toxic toxic towards towards human human leukemia leukemia cells. cells. Continuing Continuing our workour work with thiswith group this group of compounds of compounds we here reportwe here new report data onnew the data synthesis on the as wellsynthesis as regarding as well as the physico-chemicalregarding the physico-chemical and biological characterizationand biological ch ofaracterization fourteen new of derivatives fourteen new of benzofurans, derivatives of includingbenzofurans, six brominated including compounds. six brominated The structurescompound ofs. allThe new structures compounds of all were new establishedcompounds by were 1 13 spectroscopicestablished methods by spectroscopic ( H- and, methodsC-NMR, (1H- ESI and, MS), 13C-NMR, and elemental ESI MS), analyses. and elemental Their cytotoxicityanalyses. Their wascytotoxicity evaluated against was evaluated K562 (leukemia), against K562 MOLT-4 (leukemi (leukemia),a), MOLT-4 HeLa (leukemia), (cervix carcinoma), HeLa (cervix and carcinoma), normal cellsand (HUVEC). normal Fivecells compounds(HUVEC). Five (1c ,compounds1e, 2d, 3a, 3d (1c) showed, 1e, 2d, 3a significant, 3d) showed cytotoxic significant activity cytotoxic against activity all testedagainst cell lines all tested and selectivity cell lines forand cancer selectivity cell lines. for cancer The SAR cell analysislines. The (structure-activity SAR analysis (structure-activity relationship analysis)relationship indicated analysis) that the indicated presence that of the bromine presence introduced of bromine to aintroduced methyl or to acetyl a methyl group or thatacetyl was group attachedthat was to the attached benzofuran to the system benzofuran increased system their increased cytotoxicity their both cytotoxicity in normal both and in cancer normal cells. and cancer cells. Keywords: benzofurans; chemical synthesis; cytotoxic properties; HeLa; MOLT-4; K562 Keywords: benzofurans; chemical synthesis; cytotoxic properties; HeLa; MOLT-4; K562 1. Introduction 1.Benzofuran Introduction skeleton holds an important position in organic chemistry and it is considered to be oneBenzofuran of the most skeleton important holds heterocyclic an important systems position because in organic of itschemistry diverse and profile it is ofconsidered biological to be activity.one of This the structural most important unit is aheterocyclic central part systems of a variety beca ofuse biologically of its diverse active profile compounds. of biological Natural activity. andThis synthetic structural benzofuran unit is derivativesa central part have of beena variety reported of biologically to possess active wide therapeuticcompounds. properties, Natural and includingsynthetic antiviral, benzofuran immunosuppressive, derivatives have antioxidant, been reported antifungal, to possess anti-inflammatory, wide therapeutic antimicrobial, properties, analgesic,including antihyperglycemic, antiviral, immunosuppressive, and antitumor activitiesantioxidant, [1–6 antifungal,]. Cicerfuran, anti-inflammatory, Conocarpan, and Ailanthoidol antimicrobial, are theanalgesic, best known antihyperglycemic, biologically active and antitumor natural benzofurans activities [1–6]. (Figure Cicerfuran,1). Specifically, Conocarpan the, andCicerfuran Ailanthoidol showsare antifungalthe best known activity, biologicallyConocarpan activehas beennatural reported benzofurans as an (Figure antifungal 1). Specifically, and antitrypanosomal the Cicerfuran agent,shows and Ailanthoidolantifungal activity,exhibits anticancer,Conocarpan antiviral, has been immunosuppressive, reported as an antifungal antioxidant, and andantitrypanosomal antifungal activityagent, [1, 2,and7]. TheAilanthoidol synthetic benzofuranexhibits anticancer, derivatives antiviral, are represented immunosuppressive, by Amiodarone (Figure antioxidant,1), being and usedantifungal in the treatment activity of [1,2,7]. ventricular The andsynthetic supraventricular benzofuran arrhythmias,derivatives are and represented by Bufuralol ,by which Amiodarone is a non-specific(Figure 1),β-adrenergic being used blocker in the withtreatment an affi nityof ventri for βcular1 and andβ2-adrenergic supraventricular receptors arrhythmias, [3,4,7]. and by BufuralolNowadays,, which when is cancer,a non-specific after cardiovascular β-adrenergic diseases,blocker with is the an second affinity most for β common1 and β2-adrenergic cause of deathreceptors and still [3,4,7]. constitutes an unresolved problem of clinical medicine and pharmacology, extensive research regarding new anticancer compounds is especially important. These new drugs should possess improved pharmacokinetics and specifically destroy cancer cells, without causing negative Molecules 2019, 24, x; doi: www.mdpi.com/journal/molecules Molecules 2019, 24, 1529; doi:10.3390/molecules24081529 www.mdpi.com/journal/molecules Molecules 2019, 24, 1529 2 of 16 side effects. Research in the group of benzofuran derivatives is justified, especially by the fact that one can find many examples of data in the literature on benzofurans with anticancer activity. In many cases,Molecules the benzofuran 2019, 24, x skeleton is fused with other heterocyclic or aromatic moieties (Figure2 ).of 17 H CO 3 CH3 H3C O OH O HO O O Conocarpan Cicerfuran OH HO OH O NH O CH3 CH2CH3 OCH3 H3C OCH3 CH Bufuralol 3 Ailanthoidol CH3 CH3 N I O O O H3C I Amiodarone MoleculesFigure 2019, 1. 24, x 3 of 17 FigureStructures 1. Structures of naturalof natural and and synthetic synthetic benzofuranbenzofuran derivatives derivatives with with biological biological activity. activity. Nowadays, when cancer, Rafter cardiovascular diseases, is the second most common cause of N death and still constitutes an unresolved problem of clinical medicine and pharmacology,R extensive O N research regarding new anticancerN compounds is especiallyH3CO important. These new drugs should O possess improved pharmacokinetics and specifically destroy cancer cells,II without causingN negative H C I side effects.2 Research in the group of benzofuran derivatives is justified, especially by the fact that R= H, -CH , -CH CH one can find many examples of data in the literature3 on2 benzofurans3 with anticancer activity. In many cases, the benzofuran skeleton is fused with other heterocyclic or aromatic moietiesCOOH (Figure 2).OCH 3 S HOOC NH OH N Br O O O III IV OCH3 N N SR N 1 O R V 1 R = -C6H5; -CH2CH=CH2 R= -CH C H ; CH COOH; -CH CONH 2 6 5 2 2 2 FigureFigure 2. Structures 2. Structures of of synthetic synthetic benofuran benofuran derivatives I–IV–V withwith anticancer anticancer activity activity [7]. [7]. There are several benzofuranyl imidazole derivatives among them (I and II), which were found to be cytotoxic towards an ovarian carcinoma cell line (Skov-3). The study of N-(5-(2- bromobenzyl)thiazole-2-yl) benzofuran-2-carboxamide (III) showed that this compound inhibited the growth of HCC (human hepatocellular carcinoma) cells and induced their apoptosis. The synthetic derivative IV was found to have antitumor activity and it was an effective chemopreventive and chemotherapeutic agent against malignant T cells. Moreover, a series of triazole derivatives V showed moderate antitumor activity. Recent data reported this type of benzofuran derivatives as potential therapeutic agents for breast cancer [7]. These are only a few examples from a large group of benzofurans with anticancer activity. Moreover, examples of compounds with cytotoxic activity were found among the simple derivatives of benzofuran like 2- and 3-benzofuranocarboxylic acid derivatives VI–VII (Figure