Login Register Cart 0
Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Anticancer Evaluation of Sulfur Containing 9-anilinoacridines

Author(s): Pranav Gupta, Radhika V. Kumar, Chul-Hoon Kwon* and Zhe-Sheng Chen*

Volume 17, Issue 1, 2022

Published on: 28 July, 2021

Page: [102 - 119] Pages: 18

DOI: 10.2174/1574892816666210728122910

Price: $65

Abstract

Background: DNA topoisomerases are a class of enzymes that play a critical role in fundamental biological processes of replication, transcription, recombination, repair and chromatin remodeling. Amsacrine (m-AMSA), the best-known compound of 9-anilinoacridines series, was one of the first DNA-intercalating agents to be considered a Topoisomerase II inhibitor.

Objectives: A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer activity.

Methods: Cell viability was assessed by the MTT assay. The topoisomerase II inhibitory assay was performed using the Human topoisomerase II Assay kit, and flow cytometry was used to evaluate the effects on the cell cycle of K562 cells. Molecular docking was performed using the Schrödinger Maestro program.

Results: Compound 36 was found to be the most cytotoxic of the sulfide series against SW620, K562, and MCF-7. The limited SAR suggested the importance of the methansulfonamidoacetamide side chain functionality, the lipophilicity, and the relative metabolic stability of 36 in contributing to the cytotoxicity. Topoisomerase II α inhibitory activity appeared to be involved in the cytotoxicity of 36 through the inhibition of decatenation of kinetoplast DNA (kDNA) in a concentration- dependent manner. Cell cycle analysis further showed Topo II inhibition through the accumulation of K562 cells in the G2/M phase of the cell cycle. The docking of 36 into the Topo II α-DNA complex suggested that it may be an allosteric inhibitor of Topo II α.

Conclusion: Compound 36 exhibits anticancer activity by inhibiting topoisomerase II, and it could further be evaluated in in vivo models.

Keywords: Amsacrine, Topoisomerase, 9-anilinoacridines, anti-cancer, DNA, cell cycle.

« Previous Next »
[1]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70(1): 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Gupta P, Zhang GN, Barbuti AM, et al. Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia. Cancer Lett 2020; 472: 132-41.
[http://dx.doi.org/10.1016/j.canlet.2019.11.040] [PMID: 31837444]
[3]
Chen SH, Chan NL, Hsieh TS. New mechanistic and functional insights into DNA topoisomerases. Annu Rev Biochem 2013; 82: 139-70.
[http://dx.doi.org/10.1146/annurev-biochem-061809-100002] [PMID: 23495937]
[4]
Barnum KJ, O’Connell MJ. Cell cycle regulation by checkpoints. Methods Mol Biol 2014; 1170: 29-40.
[http://dx.doi.org/10.1007/978-1-4939-0888-2_2] [PMID: 24906307]
[5]
Singh A, Kaur N, Singh G, et al. Topoisomerase I and II inhibitors: A patent review. Recent Patents Anticancer Drug Discov 2016; 11(4): 401-23.
[http://dx.doi.org/10.2174/0929866523666160720095940] [PMID: 27450102]
[6]
Danks MK, Schmidt CA, Cirtain MC, Suttle DP, Beck WT. Altered catalytic activity of and DNA cleavage by DNA topoisomerase II from human leukemic cells selected for resistance to VM-26. Biochemistry 1988; 27(24): 8861-9.
[http://dx.doi.org/10.1021/bi00424a026] [PMID: 2853972]
[7]
Selas A, Martin-Encinas E, Fuertes M, et al. A patent review of topoisomerase I inhibitors (2016-present). Expert Opin Ther Pat 2021; 31(6): 473-508.
[http://dx.doi.org/10.1080/13543776.2021.1879051] [PMID: 33475439]
[8]
Janockova J, Plšíkováa J, Kašpárková J, et al. Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds Eur J Pharm Sci 2015; 76: 192-202.
[http://dx.doi.org/10.1016/j.ejps.2015.04.023]
[9]
Kalirajan R, Kulshrestha V, Sankar S, Jubie S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their antioxidant and anticancer activities as topoisomerase II inhibitors. Eur J Med Chem 2012; 56: 217-24.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.025] [PMID: 22982526]
[10]
Khadka DB, Cho WJ. Topoisomerase inhibitors as anticancer agents: A patent update. Expert Opin Ther Pat 2013; 23(8): 1033-56.
[http://dx.doi.org/10.1517/13543776.2013.790958] [PMID: 23611704]
[11]
Rene B, Fosse P, Khelifa T, Jacquemin-Sablon A, Bailly C. The 1′-substituent on the anilino ring of the antitumor drug amsacrine is a critical element for topoisomerase II inhibition and cytotoxicity. Mol Pharmacol 1996; 49(2): 343-50.
[PMID: 8632768]
[12]
Fosse P, et al. Stimulation of site-specific topoisomerase II-mediated DNA cleavage by an n-methylpyrrolecarboxamide-anilinoacridine conjugate: Relation to DNA binding . Biochemistry 1994; 33(33): 9865-74.
[http://dx.doi.org/10.1021/bi00199a007]
[13]
Yu L, Ma J, Han J, et al. Licochalcone B arrests cell cycle progression and induces apoptosis in human breast cancer MCF-7 Cells. Recent Pat Anticancer Drug Discov 2016; 11(4): 444-52.
[http://dx.doi.org/10.2174/1574892811666160906091405] [PMID: 27719653]
[14]
Pommier Y, Covey J, Kerrigan D, Mattes W, Markovits J, Kohn K W. Role of DNA intercalation in the inhibition of purified mouse leukemia (L1210) DNA topoisomerase II by 9-aminoacridines. Biochem Pharmacol 1987; 36(20): 3477-86.
[http://dx.doi.org/10.1016/0006-2952(87)90329-7]
[15]
Kwon C H, Blanco D R, Baturay N. p-(Methylsulfinyl)phenyl nitrogen mustard as a novel bioreductive prodrug selective against hypoxic tumors. J Med Chem 1992; 35(11): 2137-9.
[http://dx.doi.org/10.1021/jm00089a027]
[16]
Jain M, Fan J, Baturay N Z, Kwon C-H. Sulfonyl-containing aldophosphamide analogues as novel anticancer prodrugs targeted against cyclophosphamide-resistant tumor cell lines. J Med Chem 2004; 47(15): 3843-52.
[http://dx.doi.org/10.1021/jm0304764]
[17]
Chen K-M, Sun Y-W, Tang Y-W, Sun Z-Y, Kwon C-H. Synthesis and antitumor activity of sulfur-containing 9-anilinoacridines. Mol Pharm 2005; 2(2): 118-28.
[http://dx.doi.org/10.1021/mp049913g]
[18]
Pauwels R, Balzarini J, Baba M, et al. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 1988; 20(4): 309-21.
[http://dx.doi.org/10.1016/0166-0934(88)90134-6] [PMID: 2460479]
[19]
Zhang J, Chai S, Ruan X. SOX4 serves an oncogenic role in the tumourigenesis of human breast adenocarcinoma by promoting cell proliferation, migration and inhibiting apoptosis. Recent Pat Anticancer Drug Discov 2020; 15(1): 49-58.
[http://dx.doi.org/10.2174/1574892815666200212112119] [PMID: 32048979]
[20]
Amini E, Nabiuni M, Behzad SB, et al. Anticancer potential of Aguerin B, a sesquiterpene lactone isolated from Centaurea behen in metastatic breast cancer cells. Recent Pat Anticancer Drug Discov 2020; 15(2): 165-73.
[21]
Xiao L, Xu J, Weng Q, et al. Mechanism of a novel camptothecin-deoxycholic acid derivate induced apoptosis against human liver cancer HepG2 cells and human colon cancer HCT116 cells. Recent Pat Anticancer Drug Discov 2019; 14(4): 370-82.
[http://dx.doi.org/10.2174/1574892814666191016162346] [PMID: 31644410]
[22]
Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM. The structure of DNA-bound human topoisomerase II alpha: Conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J Mol Biol 2012; 424(3-4): 109-24.
[http://dx.doi.org/10.1016/j.jmb.2012.07.014] [PMID: 22841979]
[23]
Moorthy NS, Cerqueira NM, Ramos MJ, Fernandes PA. Aryl- and heteroaryl-thiosemicarbazone derivatives and their metal complexes: A pharmacological template. Recent Pat Anticancer Drug Discov 2013; 8(2): 168-82.
[http://dx.doi.org/10.2174/1574892811308020005] [PMID: 22963201]
[24]
Staudinger H, Meyer J. Über neue organische phosphorverbindungen III. Phosphinmethylenderivate und phosphinimine. Helv Chim Acta 1919; 2(1): 635-46.
[http://dx.doi.org/10.1002/hlca.19190020164]
[25]
Malik G, Ferry A, Guinchard X, Crich D. Synthesis of β-Hydroxy O-alkyl hydroxylamines from epoxides using a convenient and versatile two-step procedure. Synthesis 2013; 45: 0065-74.
[26]
Su TL, Lin YW, Chou TC, et al. Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: Synthesis and biological activity. J Med Chem 2006; 49(12): 3710-8.
[http://dx.doi.org/10.1021/jm060197r] [PMID: 16759114]
[27]
Gupta P, Jani KA, Yang DH, Sadoqi M, Squillante E, Chen ZS. Revisiting the role of nanoparticles as modulators of drug resistance and metabolism in cancer. Expert Opin Drug Metab Toxicol 2016; 12(3): 281-9.
[http://dx.doi.org/10.1517/17425255.2016.1145655] [PMID: 26799671]
[28]
Gupta P, Xie M, Narayanan S, et al. GSK1904529A, a potent IGF-IR inhibitor, reverses MRP1-mediated multidrug resistance. J Cell Biochem 2017; 118(10): 3260-7.
[http://dx.doi.org/10.1002/jcb.25975] [PMID: 28266043]
[29]
Kathawala RJ, Gupta P, Ashby CR Jr, Chen ZS. The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist Updat 2015; 18: 1-17.
[http://dx.doi.org/10.1016/j.drup.2014.11.002] [PMID: 25554624]
[30]
Anreddy N, Gupta P, Kathawala RJ, Patel A, Wurpel JN, Chen ZS. Tyrosine kinase inhibitors as reversal agents for ABC transporter mediated drug resistance. Molecules 2014; 19(9): 13848-77.
[http://dx.doi.org/10.3390/molecules190913848] [PMID: 25191874]
[31]
Wen Y, Zhao RQ, Zhang YK, et al. Effect of Y6, an epigallocatechin gallate derivative, on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells. Oncotarget 2017; 8(18): 29760-70.
[http://dx.doi.org/10.18632/oncotarget.15964] [PMID: 28423656]
[32]
Guo C, Gasparian AV, Zhuang Z, et al. 9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-kappaB and p53 pathways. Oncogene 2009; 28(8): 1151-61.
[http://dx.doi.org/10.1038/onc.2008.460] [PMID: 19137016]
[33]
Kumar R, Kaur M, Kumari M. Acridine: A versatile heterocyclic nucleus. Acta Pol Pharm 2012; 69(1): 3-9.
[34]
Yamamoto K, Kokubun T, Sato K, et al. The DNA topoisomerase II inhibitor amsacrine as a novel candidate adjuvant in a model of glaucoma filtration surgery. Sci Rep 2019; 9(1): 19288.
[http://dx.doi.org/10.1038/s41598-019-55365-7]
[35]
Gupta P, Kathawala RJ, Wei L, et al. PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia. Cancer Lett 2016; 383(2): 220-9.
[http://dx.doi.org/10.1016/j.canlet.2016.09.025] [PMID: 27720778]
[36]
Cortés F, Pastor N, Mateos S, Domínguez I. Roles of DNA topoisomerases in chromosome segregation and mitosis. Mutat Res 2003; 543(1): 59-66.
[http://dx.doi.org/10.1016/S1383-5742(02)00070-4] [PMID: 12510017]
[37]
Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol 2008; 9(11): 910-6.
[http://dx.doi.org/10.1038/nrm2510]
[38]
Ross DT, Scherf U, Eisen MB, et al. Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 2000; 24(3): 227-35.
[http://dx.doi.org/10.1038/73432] [PMID: 10700174]
[39]
Xiao FY, Jiang ZP, Yuan F, et al. Down-regulating NQO1 promotes cellular proliferation in K562 cells via elevating DNA synthesis. Life Sci 2020; 248: 117467.
[http://dx.doi.org/10.1016/j.lfs.2020.117467] [PMID: 32105706]
[40]
Huang YB, Wang XF, Wang HY, Liu Y, Chen Y. Studies on mechanism of action of anticancer peptides by modulation of hydrophobicity within a defined structural framework. Mol Cancer Ther 2011; 10(3): 416-26.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0811] [PMID: 21252288]
[41]
Chiangjong W, Chutipongtanate S, Hongeng S. Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review). Int J Oncol 2020; 57(3): 678-96.
[http://dx.doi.org/10.3892/ijo.2020.5099] [PMID: 32705178]
[42]
Yang Y, Zhang H, Wanyan Y, et al. Effect of hydrophobicity on the anticancer activity of fatty-acyl-conjugated CM4 in breast cancer cells. ACS Omega 2020; 5(34): 21513-23.
[http://dx.doi.org/10.1021/acsomega.0c02093] [PMID: 32905373]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy