Synthetic Optimization of Ellipticine and Antitumor Activity of Novel Hexacyclic Derivatives of Ellipticine

Author(s): Jingjing Lin, Mei Tang, Ru Zhao, Qianqian Du, Longying Shen, Guohua Du, Yafen Zhang, Yan Li*, Xiandao Pan*.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 33 , 2019


Abstract:

Background: For decades, a great deal of research work has been done to synthesize ellipticine and its derivatives because of their potential antitumor properties and anti-HIV activities. However, the resonance structures in different media, a low level of solubility at physiological pH and systemic toxicity have prevented the use of ellipticine as a therapeutic agent. Besides, the low yield and complex steps of ellipticine synthesis limit its application.

Methods: A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated.

Results: The synthesis process of ellipticine was optimized, and the total yield of the synthetic route was increased to 50% through several operation steps optimization. Fourteen ellipticine hexacyclic derivatives were synthesized. The synthetic compounds were screened for anti-tumor activity in vivo and in vitro, and some of the derivatives had good anti-tumor activity.

Conclusion: Compared with ellipticine, the compound 1l showed higher antitumor activity and better tolerance to tumor models. The compound 1l treatment increased the percentage of late apoptotic cells from 3.1% (DMSO) to 21.6% (20.0 μM) in NCI-H460 cells. It also was observed the effect of 1l on G2 phase arrest was similar as that of ellipticine. The mechanism of action indicated compound 1l could be a topoisomerase IIα poison. These studies provided the basis for the pharmacodynamics and toxicology of ellipticine, and further clarifies the structureactivity relationship of antitumor activity of ellipticine.

Keywords: Ellipticine, hexacyclic derivatives, synthesis, antitumor activity, topoisomerase IIα inhibitor, xenograft model.

[1]
Roviello GN, Iannitti R, Roviello V, Palumbo R, Simonyan H, Vicidomini C. Synthesis and biological evaluation of a novel Amadori compound. Amino Acids 2017; 49(2): 327-35.
[http://dx.doi.org/10.1007/s00726-016-2363-4] [PMID: 27864693]
[2]
Roviello GN, Iannitti R, Palumbo R, Simonyan H, Vicidomini C, Roviello V. Lac-L-TTA, a novel lactose-based amino acid-sugar conjugate for anti-metastatic applications. Amino Acids 2017; 49(8): 1347-53.
[http://dx.doi.org/10.1007/s00726-017-2433-2] [PMID: 28478584]
[3]
Carella A, Roviello V, Iannitti R, et al. Evaluating the biological properties of synthetic 4-nitrophenyl functionalized benzofuran derivatives with telomeric DNA binding and antiproliferative activities. Int J Biol Macromol 2019; 121: 77-88.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.09.153] [PMID: 30261256]
[4]
Musumeci D, Roviello GN, Rigione G, et al. Benzodifuran derivatives as potential antiproliferative agents: possible correlation between their bioactivity and aggregation properties. ChemPlusChem 2017; 82: 251-60.
[http://dx.doi.org/10.1002/cplu.201600547]
[5]
Platellaa C, Guidab S, Bonmassar L, et al. Antitumour activity of resveratrol on human melanoma cells: A possible mechanism related to its interaction with malignant cell telomerase. Biochim Biophys Acta Gen Subj 2017; 1861(11PtA): 2843-51.
[http://dx.doi.org/10.1016/j.bbagen.2017.08.001]
[6]
Dalton LK, Demerac S, Elmes BC, et al. Synthesis of the tumour-inhibitory alkaloids, ellipticine, 9-methoxyellipticine, and related pyrido [4,3-b] carbazoles. Aust J Chem 1967; 20: 2715-7.
[http://dx.doi.org/10.1071/CH9672715]
[7]
Knölker HJ, Reddy KR. Isolation and synthesis of biologically active carbazole alkaloids. Chem Rev 2002; 102(11): 4303-427.
[http://dx.doi.org/10.1021/cr020059j] [PMID: 12428991]
[8]
Schmidt AW, Reddy KR, Knölker HJ. Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem Rev 2012; 112(6): 3193-328.
[http://dx.doi.org/10.1021/cr200447s] [PMID: 22480243]
[9]
Gribble GW. Synthesis and antitumor activity of ellipticine alkaloids and related compounds. Alkaloids 1990; 39: 239-352.
[http://dx.doi.org/10.1016/S0099-9598(08)60169-8]
[10]
Sappati S, Hassanali A, Gebauer R, Ghosh P. Nuclear quantum effects in a HIV/cancer inhibitor: The case of ellipticine. J Chem Phys 2016; 145(20): 205102-12.
[http://dx.doi.org/10.1063/1.4968046] [PMID: 27908111]
[11]
Auclair C, Multimodal R. Multimodal action of antitumor agents on DNA: the ellipticine series. Arch Biochem Biophys 1987; 259(1): 1-14.
[http://dx.doi.org/10.1016/0003-9861(87)90463-2] [PMID: 3318697]
[12]
Fung SY, Duhamel J, Chen P. Solvent effect on the photophysical properties of the anticancer agent ellipticine. J Phys Chem A 2006; 110(40): 11446-54.
[http://dx.doi.org/10.1021/jp062778y] [PMID: 17020255]
[13]
Kim JY, Lee SG, Chung JY, et al. Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases. Toxicology 2011; 289(2-3): 91-102.
[http://dx.doi.org/10.1016/j.tox.2011.07.014] [PMID: 21843585]
[14]
Vann KR, Ergün Y, Zencir S, Oncuoglu S, Osheroff N, Topcu Z. Inhibition of human DNA topoisomerase IIα by two novel ellipticine derivatives. Bioorg Med Chem Lett 2016; 26(7): 1809-12.
[http://dx.doi.org/10.1016/j.bmcl.2016.02.034] [PMID: 26906637]
[15]
Kotrbová V, Mrázová B, Moserová M, et al. Cytochrome b(5) shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy. Biochem Pharmacol 2011; 82(6): 669-80.
[http://dx.doi.org/10.1016/j.bcp.2011.06.003] [PMID: 21683692]
[16]
Banerjee A, Sanyal S, Majumder P, et al. Recognition of chromatin by the plant alkaloid, ellipticine as a dual binder. Biochem Biophys Res Commun 2015; 462(4): 352-7.
[http://dx.doi.org/10.1016/j.bbrc.2015.04.140] [PMID: 25960297]
[17]
Zsila F. The anticancer agent ellipticine binds to glycosaminoglycans at mildly acidic pH characteristic of the extracellular matrix of tumor tissues. RSC Adv 2016; 6: 810-4.
[http://dx.doi.org/10.1039/C5RA23437A]
[18]
Mamgain S, Sharma P, Pathak RK, et al. Computer aided screening of natural comppunds targeting the E6 protein of HPV using molecular docking. Biomed Informatics 2015; 115: 236-42.
[19]
Deane FM, O’Sullivan EC, Maguire AR, et al. Synthesis and evaluation of novel ellipticines as potential anti-cancer agents. Org Biomol Chem 2013; 11(8): 1334-44.
[http://dx.doi.org/10.1039/c2ob27186a] [PMID: 23314103]
[20]
Lin JJ, Yang YJ, Shen LY, et al. Recent progress in synthesis and pharmacological effects of ellipticine and its derivatives. Yao Xue Xue Bao 2017; 52: 1387-96.
[21]
Reddy NB, Burra VR, Ravindranath LK, et al. Synthesis and biological evaluation of benzimidazole fused ellipticine derivatives as anticancer agent. Monatshefte für Chemie-Chemical Monthly 2016; 147: 599-604.
[http://dx.doi.org/10.1007/s00706-016-1684-z]
[22]
Devraj R, Barrett JF, Fernandez JA, Katzenellenbogen JA, Cushman M. Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates. J Med Chem 1996; 39(17): 3367-74.
[http://dx.doi.org/10.1021/jm9602930] [PMID: 8765520]
[23]
Banerjee S, Pabbathi A, Sekhar MC, Samanta A. Dual fluorescence of ellipticine: excited state proton transfer from solvent versus solvent mediated intramolecular proton transfer. J Phys Chem A 2011; 115(33): 9217-25.
[http://dx.doi.org/10.1021/jp206232b] [PMID: 21812494]
[24]
Honda T, Kato M, Inoue M, et al. Synthesis and antitumor activity of quaternary ellipticine glycosides, a series of novel and highly active antitumor agents. J Med Chem 1988; 31(7): 1295-305.
[http://dx.doi.org/10.1021/jm00402a007] [PMID: 3385725]
[25]
Prudent R, Moucadel V, Nguyen CH, et al. Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. Cancer Res 2010; 70(23): 9865-74.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0917] [PMID: 21118972]
[26]
Russell EG, O’Sullivan EC, Miller CM, Stanicka J, McCarthy FO, Cotter TG. Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells. Invest New Drugs 2014; 32(6): 1113-22.
[http://dx.doi.org/10.1007/s10637-014-0140-3] [PMID: 25107543]
[27]
Russell EG, Guo J, O’Sullivan EC, O’Driscoll CM, McCarthy FO, Cotter TG. 7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice. Invest New Drugs 2016; 34(1): 15-23.
[http://dx.doi.org/10.1007/s10637-015-0302-y] [PMID: 26559431]
[28]
Yang Y, Zhu C, Zhang M, et al. Condensation of anthranilic acids with pyridines to furnish pyridoquinazolones via pyridine dearomatization. Chem Commun (Camb) 2016; 52(87): 12869-72.
[http://dx.doi.org/10.1039/C6CC07365D] [PMID: 27735960]
[29]
Li DZ, Zhang QZ, Wang CY, et al. Synthesis and antitumor activity of novel substituted uracil-1′(N)-acetic acid ester derivatives of 20(S)-camptothecins. Eur J Med Chem 2017; 125: 1235-46.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.013] [PMID: 27871039]
[30]
Sordet O, Khan QA, Kohn KW, Pommier Y. Apoptosis induced by topoisomerase inhibitors. Curr Med Chem Anticancer Agents 2003; 3(4): 271-90.
[http://dx.doi.org/10.2174/1568011033482378] [PMID: 12769773]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 25
ISSUE: 33
Year: 2019
Page: [3578 - 3589]
Pages: 12
DOI: 10.2174/1381612825666190404122650
Price: $58

Article Metrics

PDF: 22
HTML: 2

Special-new-year-discount