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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Letter Article

Design, Synthesis and Biological Evaluation of Camptothecin Conjugated with NSAIDs as Novel Dual-actin Antitumor Agents

Author(s): Xingchen Cai, Weiwei Huang, Yi Huang, Lihua Xia, Miao Liu, Mengke Wang, Wenchao Wang and Qingyong Li*

Volume 16, Issue 12, 2019

Page: [1378 - 1386] Pages: 9

DOI: 10.2174/1570180816666190221103257

Price: $65

Abstract

Background: The single-agent therapy was unable to provide an effective control of the malignant process, a well-established strategy to improve the efficacy of antitumor therapy is the rational design of drug combinations aimed at achieving synergistic effects.

Objective: The objective of this study is generating the new potential anticancer agents with synergistic activity. Owing to the unique mechanism of action of Camptothecin (CPT), it has shown abroad spectrum of anti-cancer activity against human malignancies, and growing evidence revealed that Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) reduce the risk of different kinds of cancers. So four CPT-NSAIDs conjugates were synthesized and evaluated.

Methods: In this study, a series of novel CPT - NSAIDs derivatives were synthesized by esterification. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines A549, Hela, HepG2, HCT116 by MTT assay. To probe the required stabilities as prodrugs, stability tests were studied in human plasma. To further evaluate the stability of Ketoprofen-CPT in vivo, the female SD rats were used to determine the pharmacokinetics following a single oral dose.

Results: In vitro results showed that Ketoprofen-CPT and Naproxen-CPT conjugates possessed nice efficacy. In a molecular docking model, the two conjugates interacted with Topo I-DNA through hydrogen bonds, - stacking and so on.In human plasma results showed that the prodrug was converted to ketoprofen and another compound. The female SD rats were used to determine the pharmacokinetics following a single oral dose, the half-life (t1/2) of Ketoprofen-CPT was approximately 12 h which was much longer than that of CPT.

Conclusion: Good activity was noted for some compounds will be helpful for the design of dualaction agents with most promising anti-cancer activity.

Keywords: Camptothecin-NSAIDs conjugate, antineoplastic, synthesis, dual-action, molecular docking, topoisomerase.

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[1]
Verbeke, H.; Geboes, K.; Van Damme, J.; Struyf, S. The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer. Biochim. Biophys. Acta, 2012, 1825(1), 117-129.
[PMID: 22079531]
[2]
Tang, F.; Wang, Y.; Hemmings, B.A.; Rüegg, C.; Xue, G. PKB/Akt-dependent regulation of inflammation in cancer. Semin. Cancer Biol., 2018, 48, 62-69.
[http://dx.doi.org/10.1016/j.semcancer.2017.04.018] [PMID: 28476657]
[3]
Sahin, I.H.; Hassan, M.M.; Garrett, C.R. Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: Current state-of-the science. Cancer Lett., 2014, 345(2), 249-257.
[http://dx.doi.org/10.1016/j.canlet.2013.09.001] [PMID: 24021750]
[4]
Raghav, D.; Maniyadath, B.; Mohan, A. In silico Designing of novel camptothecin analogues as potent inhibitors of topoisomerase I: A Molecular Docking, QSAR, and ADME-T Study. Lett. Drug Des. Discov., 2016, 13(9), 859-868.
[http://dx.doi.org/10.2174/1570180813666160518123550]
[5]
Riva, E.; Comi, D.; Borrelli, S.; Colombo, F.; Danieli, B.; Borlak, J.; Evensen, L.; Lorens, J.B.; Fontana, G.; Gia, O.M.; Via, L.D.; Passarella, D. Synthesis and biological evaluation of new camptothecin derivatives obtained by modification of position 20. Bioorg. Med. Chem., 2010, 18(24), 8660-8668.
[http://dx.doi.org/10.1016/j.bmc.2010.09.069] [PMID: 21071230]
[6]
Martino, E.; Della Volpe, S.; Terribile, E.; Benetti, E.; Sakaj, M.; Centamore, A.; Sala, A.; Collina, S. The long story of camptothecin: From traditional medicine to drugs. Bioorg. Med. Chem. Lett., 2017, 27(4), 701-707.
[http://dx.doi.org/10.1016/j.bmcl.2016.12.085] [PMID: 28073672]
[7]
Li, D.Z.; Zhang, Q.Z.; Wang, C.Y.; Zhang, Y.L.; Li, X.Y.; Huang, J.T.; Liu, H.Y.; Fu, Z.D.; Song, H.X.; Lin, J.P.; Ji, T.F.; Pan, X.D. Synthesis and antitumor activity of novel substituted uracil-1′(N)-acetic acid ester derivatives of 20(S)-camptothecins. Eur. J. Med. Chem., 2017, 125, 1235-1246.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.013] [PMID: 27871039]
[8]
Song, Z.L.; Wang, M.J.; Li, L.; Wu, D.; Wang, Y.H.; Yan, L.T.; Morris-Natschke, S.L.; Liu, Y.Q.; Zhao, Y.L.; Wang, C.Y.; Liu, H.; Goto, M.; Liu, H.; Zhu, G.X.; Lee, K.H. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives. Eur. J. Med. Chem., 2016, 115, 109-120.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.070] [PMID: 26994847]
[9]
Li, Q.; Wang, W.; Liu, Y.; Lian, B.; Zhu, Q.; Yao, L.; Liu, T. The biological characteristics of a novel camptothecin-artesunate conjugate. Bioorg. Med. Chem. Lett., 2015, 25(1), 148-152.
[http://dx.doi.org/10.1016/j.bmcl.2014.10.048] [PMID: 25453788]
[10]
Ranjan, C.; Kumar, J.; Sharma, K. 1, 2, 4-Oxadiazole incorporated ketoprofen analogues in search of safer non-steroidal anti-inflammatory agents: Design, syntheses, biological evaluation and molecular docking studies. Lett. Drug Des. Discov., 2018, 15(6), 590-601.
[http://dx.doi.org/10.2174/1570180814666170810115134]
[11]
Verdoodt, F.; Kjaer, S.K.; Friis, S. Influence of aspirin and non-aspirin NSAID use on ovarian and endometrial cancer: Summary of epidemiologic evidence of cancer risk and prognosis. Maturitas, 2017, 100, 1-7.
[http://dx.doi.org/10.1016/j.maturitas.2017.03.001] [PMID: 28539172]
[12]
Sakinala, P.; Chikhale, R.; Tajne, M. Design, synthesis and pharmacological evaluation of some novel tetrahydrocarbazoles as potential COX-2 inhibitors. Lett. Drug Des. Discov., 2018, 15(4), 437-449.
[http://dx.doi.org/10.2174/1570180814666170602084037]
[13]
Stolfi, C.; De Simone, V.; Pallone, F.; Monteleone, G. Mechanisms of action of non-steroidal anti-inflammatory drugs (NSAIDs) and mesalazine in the chemoprevention of colorectal cancer. Int. J. Mol. Sci., 2013, 14(9), 17972-17985.
[http://dx.doi.org/10.3390/ijms140917972] [PMID: 24005861]
[14]
Ghanghas, P.; Jain, S.; Rana, C.; Sanyal, S.N. Chemopreventive action of non-steroidal anti-inflammatory drugs on the inflammatory pathways in colon cancer. Biomed. Pharmacother., 2016, 78, 239-247.
[http://dx.doi.org/10.1016/j.biopha.2016.01.024] [PMID: 26898448]
[15]
Peesa, J.P.; Yalavarthi, P.R.; Rasheed, A. A perspective review on role of novel NSAID prodruds in the management of acute inflammation. J. Acute Dis., 2016, 5(5), 364-381.
[http://dx.doi.org/10.1016/j.joad.2016.08.002]
[16]
Cincinelli, R.; Musso, L.; Artali, R.; Guglielmi, M.; Bianchino, E.; Cardile, F.; Colelli, F.; Pisano, C.; Dallavalle, S. Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors. Eur. J. Med. Chem., 2018, 143, 2005-2014.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.021] [PMID: 29150335]
[17]
Yu, C.C.; Pan, S.L.; Chao, S.W.; Liu, S.P.; Hsu, J.L.; Yang, Y.C.; Li, T.K.; Huang, W.J.; Guh, J.H. A novel small molecule hybrid of vorinostat and DACA displays anticancer activity against human hormone-refractory metastatic prostate cancer through dual inhibition of histone deacetylase and topoisomerase I. Biochem. Pharmacol., 2014, 90(3), 320-330.
[http://dx.doi.org/10.1016/j.bcp.2014.06.001] [PMID: 24915421]
[18]
Tanaka, Y.; Aikawa, K.; Nishida, G.; Homma, M.; Sogabe, S.; Igaki, S.; Hayano, Y.; Sameshima, T.; Miyahisa, I.; Kawamoto, T.; Tawada, M.; Imai, Y.; Inazuka, M.; Cho, N.; Imaeda, Y.; Ishikawa, T. Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins. J. Med. Chem., 2013, 56(23), 9635-9645.
[http://dx.doi.org/10.1021/jm401170c] [PMID: 24215352]
[19]
Li, Q.; Lv, H.; Zu, Y.; Qu, Z.; Yao, L.; Su, L.; Liu, C.; Wang, L. Synthesis and antitumor activity of novel 20s-camptothecin analogues. Bioorg. Med. Chem. Lett., 2009, 19(2), 513-515.
[http://dx.doi.org/10.1016/j.bmcl.2008.11.031] [PMID: 19056266]
[20]
Dong, G.; Fang, Y.; Liu, Y.; Liu, N.; Wu, S.; Zhang, W.; Sheng, C. Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(9), 1929-1933.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.039] [PMID: 28351590]
[21]
Dos Santos, C.B.R.; da Silva Ramos, R.; Ortiz, B.L.S.; da Silva, G.M.; Giuliatti, S.; Balderas-Lopez, J.L.; Navarrete, A.; Carvalho, J.C.T. Oil from the fruits of Pterodon emarginatus Vog.: A traditional anti-inflammatory. Study combining in vivo and in silico. J. Ethnopharmacol., 2018, 222, 107-120.
[http://dx.doi.org/10.1016/j.jep.2018.04.041] [PMID: 29723629]
[22]
Jin, F.; Gao, D.; Zhang, C.; Liu, F.; Chu, B.; Chen, Y.; Chen, Y.Z.; Tan, C.; Jiang, Y. Exploration of 1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylurea derivatives as selective dual inhibitors of Raf1 and JNK1 kinases for anti-tumor treatment. Bioorg. Med. Chem., 2013, 21(3), 824-831.
[http://dx.doi.org/10.1016/j.bmc.2012.04.006] [PMID: 23260578]
[23]
Feng, K.; Ren, Y.; Li, R. Combined pharmacophore-guided 3D-QSAR, molecular docking and molecular dynamics studies for evodiamine analogs as DNA topoisomerase I inhibitors. J. Taiwan Inst. Chem. E., 2017, 78, 81-95.
[http://dx.doi.org/10.1016/j.jtice.2017.06.027]
[24]
Huarte, J.; Espuelas, S.; Lai, Y.; He, B.; Tang, J.; Irache, J.M. Oral delivery of camptothecin using cyclodextrin/poly(anhydride) nanoparticles. Int. J. Pharm., 2016, 506(1-2), 116-128.
[http://dx.doi.org/10.1016/j.ijpharm.2016.04.045] [PMID: 27102993]
[25]
Bailly, C. DNA relaxation and cleavage assays to study topoisomerase I inhibitors. Methods Enzymol., 2001, 340, 610-623.
[http://dx.doi.org/10.1016/S0076-6879(01)40445-9] [PMID: 11494873]

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