In this study, we report the synthesis, antibacterial and anticancer evaluation of 38 novel phenanthridines that were designed as analogs of the benzo[c]phenanthridine alkaloids. The prepared phenanthridines differ from the benzo[c]phenanthridines in the absence of a benzene A-ring. All novel compounds were prepared from 6-bromo-2-hydroxy-3-methoxybenzaldehyde in several synthetic steps through reduction of Schiff bases and accomplished by radical cyclization. Twelve derivatives showed high antibacterial activity against Bacillussubtilis, Micrococcusluteus and/or Mycobacteriumvaccae at single digit micromolar concentrations. Some compounds also displayed cytotoxicity against the K-562 and MCF-7 cancer cell lines at as low as single digit micromolar concentrations and were more potent than chelerythrine and sanguinarine. The active compounds caused cell-cycle arrest in cancer cells, increased levels of p53 protein and caused apoptosis-specific fragmentation of PARP-1. Biological activity was connected especially with the presence of the N-methyl quaternary nitrogen and 7-benzyloxy substitution (compounds 7i, 7j, 7k, and 7l) of phenanthridine.

Department of Organic Chemistry Faculty of Science Palacký University 17 Listopadu 1192 12 CZ 771 46 Olomouc Czech Republic

Institute of Molecular and Translation Medicine Faculty of Medicine Palacký University Hněvotínská 5 CZ 779 00 Olomouc Czech Republic

Laboratory of Growth Regulators Faculty of Science Palacký University and Institute of Experimental Botany ASCR Šlechtitelů 27 CZ 783 71 Olomouc Czech Republic

Zobrazit více v PubMed

Dvořák Z., Kubán V., Klejdus B., Vičar J., Ulrichová J., Hlaváč J., Šimánek V. Quaternary benzo[c]phenanthridines sanguinarine and chelerythrine: A review of investigations from chemical and biological studies. Heterocycles. 2006;68:2403. doi: 10.3987/REV-06-610. DOI

Ahsan H., Reagan-Shaw S., Breur J., Ahmad N. Sanguinarine induces apoptosis of human pancreatic carcinoma AsPC-1 and BxPC-3 cells via modulations in Bcl-2 family proteins. Cancer Lett. 2007;249:198–208. doi: 10.1016/j.canlet.2006.08.018. PubMed DOI

Jang B.-C., Park J.-G., Song D.-K., Baek W.-K., Yoo S.K., Jung K.-H., Park G.-Y., Lee T.-Y., Suh S.-I. Sanguinarine induces apoptosis in A549 human lung cancer cells primarily via cellular glutathione depletion. Toxicol. Vitro. 2009;23:281–287. doi: 10.1016/j.tiv.2008.12.013. PubMed DOI

Miao F., Yang X.-J., Zhou L., Hu H.-J., Zheng F., Ding X.-D., Sun D.-M., Zhou C.-D., Sun W. Structural modification of sanguinarine and chelerythrine and their antibacterial activity. Nat. Prod. Res. 2011;25:863–875. doi: 10.1080/14786419.2010.482055. PubMed DOI

Ishikawa T. Benzo[c]phenanthridine bases and their antituberculosis activity. Med. Res. Rev. 2001;21:61–72. doi: 10.1002/1098-1128(200101)21:1<61::AID-MED2>3.0.CO;2-F. PubMed DOI

Šimánek V. Benzophenanthridine alkaloids. In: Brossi A., editor. The Alkaloids. Volume 26. Academic Press; New York, NY, USA: 1985. pp. 185–240.

Galadari S., Rahman A., Pallichankandy S., Thayyullathil F. Molecular targets and anticancer potential of sanguinarine—A benzophenanthridine alkaloid. Phytomedicine. 2017;34:143–153. doi: 10.1016/j.phymed.2017.08.006. PubMed DOI

Slaninová I., Pěnčíková K., Urbanová J., Slanina J., Táborská E. Antitumour activities of sanguinarine and related alkaloids. Phytochem. Rev. 2014;13:51–68. doi: 10.1007/s11101-013-9290-8. DOI

Maiti M., Nandi R., Chaudhuri K. Sanguinarine: A monofunctional intercalating alkaloid. FEBS Lett. 1982;142:280–284. doi: 10.1016/0014-5793(82)80152-X. PubMed DOI

Wang X., Tanaka M., Krstin S., Peixoto H., Wink M. The interference of selected cytotoxic alkaloids with the cytoskeleton: An insight into their modes of action. Molecules. 2016;21:906. doi: 10.3390/molecules21070906. PubMed DOI PMC

Chan S.-L., Lee M.C., Tan K.O., Yang L.-K., Lee A.S.Y., Flotow H., Fu N.Y., Butler M.S., Soejarto D.D., Buss A.D., et al. Identification of chelerythrine as an inhibitor of BclXL function. J. Biol. Chem. 2003;278:20453–20456. doi: 10.1074/jbc.C300138200. PubMed DOI

Caolo M.A., Stermitz F.R. Benzophenanthridinium salt equilibria. Heterocycles. 1979;12:11. doi: 10.3987/R-1979-01-0011. DOI

Romo-Pérez A., Miranda L.D., Chávez-Blanco A.D., Dueñas-González A., del Rayo Camacho-Corona M., Acosta-Huerta A., García A. Mild C(sp3)–H functionalization of dihydrosanguinarine and dihydrochelerythrine for development of highly cytotoxic derivatives. Eur. J. Med. Chem. 2017;138:1–12. doi: 10.1016/j.ejmech.2017.06.021. PubMed DOI

Zee-Cheng R.K.Y., Yan S.-J., Cheng C.C. Antileukemic activity of ungeremine and related compounds. Preparation of analogs of ungeremine by a practical photochemical reaction. J. Med. Chem. 1978;21:199–203. doi: 10.1021/jm00200a011. PubMed DOI

Hatae N., Fujita E., Shigenobu S., Shimoyama S., Ishihara Y., Kurata Y., Choshi T., Nishiyama T., Okada C., Hibino S. Antiproliferative activity of O4-benzo[c]phenanthridine alkaloids against HCT-116 and HL-60 tumor cells. Bioorg. Med. Chem. Lett. 2015;25:2749–2752. doi: 10.1016/j.bmcl.2015.05.031. PubMed DOI

Nakanishi T., Suzuki M., Mashiba A., Ishikawa K., Yokotsuka T. Synthesis of NK109, an anticancer benzo[c]phenanthridine alkaloid. J. Org. Chem. 1998;63:4235–4239. doi: 10.1021/jo9718758. DOI

Kanzawa F., Nishio K., Ishida T., Fukuda M., Kurokawa H., Fukumoto H., Nomoto Y., Fukuoka K., Bojanowski K., Saijo N. Anti-tumour activities of a new benzo[c]phenanthridine agent, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium hydrogensulphate dihydrate (NK109), against several drug-resistant human tumour cell lines. Br. J. Cancer. 1997;76:571–581. doi: 10.1038/bjc.1997.428. PubMed DOI PMC

Nakanishi T., Masuda A., Suwa M., Akiyama Y., Hoshino-Abe N., Suzuki M. Synthesis of derivatives of NK109, 7-OH Benzo[c]phenanthridine alkaloid, and evaluation of their cytotoxicities and reduction-resistant properties. Bioorg. Med. Chem. Lett. 2000;10:2321–2323. doi: 10.1016/S0960-894X(00)00467-4. PubMed DOI

Fukuda M., Inomata M., Nishio K., Fukuoka K., Kanzawa F., Arioka H., Ishida T., Fukumoto H., Kurokawa H., Oka M., et al. A Topoisomerase II inhibitor, NK109, induces DNA single- and double-strand breaks and apoptosis. Jpn. J. Cancer Res. 1996;87:1086–1091. doi: 10.1111/j.1349-7006.1996.tb03114.x. PubMed DOI PMC

Hisatomi T., Sueoka-Aragane N., Sato A., Tomimasu R., Ide M., Kurimasa A., Okamoto K., Kimura S., Sueoka E. NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase II and DNA-dependent protein kinase. Blood. 2011;117:3575–3584. doi: 10.1182/blood-2010-02-270439. PubMed DOI

Toyoda E., Kagaya S., Cowell I.G., Kurosawa A., Kamoshita K., Nishikawa K., Iiizumi S., Koyama H., Austin C.A., Adachi N. NK314, a topoisomerase II inhibitor that specifically targets the α isoform. J. Biol. Chem. 2008;283:23711–23720. doi: 10.1074/jbc.M803936200. PubMed DOI PMC

Guo L., Liu X., Nishikawa K., Plunkett W. Inhibition of topoisomerase II and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials. Mol. Cancer Ther. 2007;6:1501–1508. doi: 10.1158/1535-7163.MCT-06-0780. PubMed DOI

Wang L.K., Johnson R.K., Hecht S.M. Inhibition of topoisomerase I function by nitidine and fagaronine. Chem. Res. Toxicol. 1993;6:813–818. doi: 10.1021/tx00036a010. PubMed DOI

Janin Y.L., Bisagni E., Carrez D. Synthesis of some benzo[h]quinoline derivatives. J. Heterocycl. Chem. 1993;30:1129–1131. doi: 10.1002/jhet.5570300452. DOI

Bernardo P.H., Wan K.-F., Sivaraman T., Xu J., Moore F.K., Hung A.W., Mok H.Y.K., Yu V.C., Chai C.L.L. Structure−activity relationship studies of phenanthridine-based Bcl-X L inhibitors. J. Med. Chem. 2008;51:6699–6710. doi: 10.1021/jm8005433. PubMed DOI

Yu Y., Singh S.K., Liu A., Li T.-K., Liu L.F., LaVoie E.J. Substituted dibenzo[c,h]cinnolines: Topoisomerase I-targeting anticancer agents. Bioorg. Med. Chem. 2003;11:1475–1491. doi: 10.1016/S0968-0896(02)00604-1. PubMed DOI

Yapi A.-D., Desbois N., Chezal J.-M., Chavignon O., Teulade J.-C., Valentin A., Blache Y. Design and preparation of aza-analogues of benzo[c]phenanthridine framework with cytotoxic and antiplasmodial activities. Eur. J. Med. Chem. 2010;45:2854–2859. doi: 10.1016/j.ejmech.2010.03.006. PubMed DOI

Steinhauer T.N., Girreser U., Meier C., Cushman M., Clement B. One-step synthetic access to isosteric and potent anticancer nitrogen heterocycles with the benzo[c]phenanthridine scaffold. Chem. A Eur. J. 2016;22:8301–8308. doi: 10.1002/chem.201600308. PubMed DOI

Hou Z., Yang R., Zhang C., Zhu L.-F., Miao F., Yang X.-J., Zhou L. 2-(Substituted phenyl)-3,4-dihydroisoquinolin-2-iums as novel antifungal lead compounds: Biological evaluation and structure-activity relationships. Molecules. 2013;18:10413–10424. doi: 10.3390/molecules180910413. PubMed DOI PMC

Yang X., Yao Y., Qin Y., Hou Z., Yang R., Miao F., Zhou L. Synthesis and in vitro antifungal activities of new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides. Chem. Pharm. Bull. 2013;61:731–739. doi: 10.1248/cpb.c13-00221. PubMed DOI

Ishikawa T., Ishii H. Recent advances on antitumor-active benzo[c]phenanthridine alkaloids. Heterocycles. 1999;50:627. doi: 10.3987/REV-98-SR(H)9. DOI

Mackay S.P., Meth-Cohn O., Waigh R.D. Synthesis of quaternary benzo[c]phenanthridine alkaloids and their analogues. Adv. Heterocycl. Chem. 1996;67:345–389. doi: 10.1016/S0065-2725(08)60073-2. DOI

Stýskala J., Cankař P., Soural M., Hradil P., Vičar J., Šimánek V., Hlaváč J. Synthesis of isodecarine. Heterocycles. 2007;73:769. doi: 10.3987/COM-07-S(U)57. DOI

Stýskala J., Hlaváč J., Cankař P. Synthesis of oxidative dihydroxy metabolites of benzo[c]phenanthridines. Tetrahedron. 2013;69:4670–4678. doi: 10.1016/j.tet.2013.03.105. DOI

Larghi E.L., Obrist B.V., Kaufman T.S. A formal total synthesis of the marine alkaloid aaptamine. Tetrahedron. 2008;64:5236–5245. doi: 10.1016/j.tet.2008.03.036. DOI

Meisels A., Sondheimer F. The constituents of casimiroa edulis llave et lex. III. 1 The structure of casimiroin 2. J. Am. Chem. Soc. 1957;79:6328–6333. doi: 10.1021/ja01580a056. DOI

Majumdar K., Taher A., Debnath P. palladium-catalyzed intramolecular biaryl coupling: A highly efficient avenue for benzannulated pyranoquinolines and julolidine derivatives. Synthesis. 2009;2009:793–800. doi: 10.1055/s-0028-1083363. DOI

Harayama T., Aktyama T., Kawano K. A convenient synthesis of benzo[c]phenanthridine alkaloid, chelerythrine, by the palladium-assisted internal biaryl coupling reaction. Chem. Pharm. Bull. 1996;44:1634–1636. doi: 10.1248/cpb.44.1634. DOI

Campeau L.-C., Parisien M., Leblanc M., Fagnou K. Biaryl synthesis via direct arylation: Establishment of an efficient catalyst for intramolecular processes. J. Am. Chem. Soc. 2004;126:9186–9187. doi: 10.1021/ja049017y. PubMed DOI

Harayama T., Akiyama T., Akamatsu H., Kawano K., Abe H., Takeuchi Y. Total synthesis of benzo[c]phenanthridine alkaloids, chelerythrine and 12-methoxydihydrochelerythrine, by a palladium-assisted internal biaryl coupling reaction. Synthesis. 2001;2001:0444–0450. doi: 10.1055/s-2001-11424. DOI

Ackermann L. Carboxylate-assisted transition-metal-catalyzed C−H bond functionalizations: Mechanism and scope. Chem. Rev. 2011;111:1315–1345. doi: 10.1021/cr100412j. PubMed DOI

De S., Mishra S., Kakde B.N., Dey D., Bisai A. Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[c]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert -butoxide. J. Org. Chem. 2013;78:7823–7844. doi: 10.1021/jo400890k. PubMed DOI

Dewanji A., Murarka S., Curran D.P., Studer A. Phenyl hydrazine as initiator for direct arene C–H arylation via base promoted homolytic aromatic substitution. Org. Lett. 2013;15:6102–6105. doi: 10.1021/ol402995e. PubMed DOI PMC

Carpino L.A. Simple preparation of active manganese dioxide from activated carbon. J. Org. Chem. 1970;35:3971–3972. doi: 10.1021/jo00836a091. DOI

Murray P.R., Baron E.J., Pfaller M.A., Tenover F.C., Yolken R.H. Manual of Clinical Microbiology. 7th ed. American Society for Microbiology; Washington, DC, USA: 1999.

Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 8th ed. Clinical and Laboratory Standards Institute (CLSI); Villanova, PA, USA: 2009. Approved Standard Document M07-A7.

Williams A.B., Schumacher B. p53 in the DNA-damage-repair process. Cold Spring Harb. Perspect. Med. 2016;6:a026070. doi: 10.1101/cshperspect.a026070. PubMed DOI PMC

Zatloukal M., Jorda R., Gucký T., Řezníčková E., Voller J., Pospíšil T., Malínková V., Adamcová H., Kryštof V., Strnad M. Synthesis and in vitro biological evaluation of 2,6,9-trisubstituted purines targeting multiple cyclin-dependent kinases. Eur. J. Med. Chem. 2013;61:61–72. doi: 10.1016/j.ejmech.2012.06.036. PubMed DOI

Heterocycles in Medicinal Chemistry