Evaluation of Pyrano[3,2 C] Quinoline Analogues as Anticancer Agents

Author(s): Kuldip D. Upadhyay*, Anamik K. Shah.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 10 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents.

Objective: The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity.

Methods: A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model.

Results: The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model.

Conclusion: The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.

Keywords: Quinolines, cytotoxicity, immunogenic, kinase activity, in vivo efficacy, tumor growth inhibition.

[1]
Kulagowski, J.J.; Baker, R.; Curtis, N.R.; Leeson, P.D.; Mawer, I.M.; Moseley, A.M.; Ridgill, M.P.; Rowley, M.; Stansfield, I.; Foster, A.C.; Leeson, P.D. 3′-(Arylmethyl)- and 3′-(aryloxy)-3-phenyl-4-hydroxyquinolin-2(1H)-ones: Orally active antagonists of the glycine site on the NMDA receptor. J. Med. Chem., 1994, 37(10), 1402-1405.
[2]
Sharp, J. Antifungal methods employing certain carbostyrils., U.S. Patent 3,836,657. 1974.
[3]
Magedov, I.V.; Manpadi, M.; Ogasawara, M.A.; Dhawan, A.S.; Rogelj, S.; Van Slambrouck, S.; Steelant, W.F.; Evdokimov, N.M.; Uglinskii, P.Y.; Elias, E.M.; Knee, E.J.; Tongwa, P.; Antipin, M.Y.; Kornienko, A. Structural simplification of bioactive natural products with multicomponent synthesis. 2. antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones. J. Med. Chem., 2008, 51(8), 2561-2570.
[4]
McBrien, K.D.; Gao, Q.; Huang, S.; Klohr, S.E.; Wang, R.R.; Pirnik, D.M.; Neddermann, K.M.; Bursuker, I.; Kadow, K.F.; Leet, J.E. Fusaricide, a new cytotoxic N-hydroxypyridone from Fusarium sp. J. Nat. Prod., 1996, 59(12), 1151-1153.
[5]
Kamperdick, C.; Van, N.H.; Van Sung, T.; Adam, G. Bisquinolinone alkaloids from Melicope ptelefolia. Phytochemistry, 1999, 50(1), 177-181.
[6]
Chen, I-S.; Wu, S-J.; Tsai, I-L.; Wu, T-S.; Pezzuto, J.M.; Lu, M.C.; Chai, H.; Suh, N.; Teng, C-M. Chemical and bioactive constituents from Zanthoxylum simulans. J. Nat. Prod., 1994, 57(9), 1206-1211.
[7]
Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Barriault, N. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell-and caspase-based high-throughput screening assay. 2. Structure–activity relationships of the 7-and 5-, 6-, 8-positions. Bioorg. Med. Chem. Lett., 2005, 15(21), 4745-4751.
[8]
Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.; Dong, K.; Kianicka, I.; Custeau, D.; Boudreau, C.; Geerts, L.; Cai, S-X. Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4, 5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents. Mol. Cancer Ther., 2004, 3(11), 1375-1384.
[9]
Kasibhatla, S.; Gourdeau, H.; Meerovitch, K.; Drewe, J.; Reddy, S.; Qiu, L.; Zhang, H.; Bergeron, F.; Bouffard, D.; Yang, Q. Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity. Mol. Cancer Ther., 2004, 3(11), 1365-1374.
[10]
Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.; Herich, J.; Labreque, D.; Storer, R. Discovery of 4-Aryl-4 H-chromenes as a new series of apoptosis inducers using a cell-and caspase-based high-throughput screening assay. 1. structure-activity relationships of the 4-Aryl group. J. Med. Chem., 2004, 47(25), 6299-6310.
[11]
Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-Grundy, C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R. Discovery of 4-Aryl-4 H-chromenes as a New series of apoptosis inducers using a cell-and caspase-based high-throughput screening assay. 3. Structure-Activity relationships of fused rings at the 7, 8-positions. J. Med. Chem., 2007, 50(12), 2858-2864.
[12]
Cai, S.X.; Jiang, S.; Kemnitzer, W.E.; Zhang, H.; Attardo, G.; Denis, R. Substituted 4-aryl-4h-pyrrolo [2, 3-h] chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof. U.S. Patent 7,528,164. 2009.
[13]
Cai, S.X.; Jiang, S.; Attardo, G.; Denis, R.; Storer, R.; Rej, R. Substituted 4H-chromens, 2H-chromenes, chromans and analogs as activators of caspases and inducers of apoptosis and the use thereof. U.S. Patent 20,050,176,750. 2009.
[14]
Cai, S.X. Substituted 4H-chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof. U.S. Patent 7,053,117, 2006.
[15]
Cai, S.X.; Zhang, H.; Kemnitzer, W.E.; Jiang, S.; Drewe, J.; Storer, R. Substituted coumarins and quinolines and analogs as activators of caspases and inducers of apoptosis and the use thereof. U.S. Patent 7,235,674, 2006.
[16]
Drewe, J.A.; Cai, S.X.; Wang, Y. Substituted 4H-chromene and analogs as activators of caspases and inducers of apoptosis and the use thereof. WO Patent, 2,001,034,591, 2005.
[17]
Cai, S.X.; Xu, L.; Storer, R.; Attardo, G. 7, 8-fused 4H-chromene and analogs as activators of caspases and inducers of apoptosis and the use thereof. U.S. Patent 6,858,607, 2005.
[18]
Upadhyay, K.D.; Dodia, N.M.; Khunt, R.C.; Chaniara, R.S.; Shah, A.K. Synthesis and biological screening of pyrano[3,2-c]quinoline analogues as anti-inflammatory and anticancer agents. ACS Med. Chem. Lett., 2018, 9(3), 283-288.
[19]
Chaniyara, R.; Thakrar, S.; Kakadiya, R.; Marvania, B.; Detroja, D.; Vekariya, N.; Upadhyay, K.; Manvar, A.; Shah, A. DBU‐catalyzed multicomponent synthesis: Facile access of 4,5,6,9‐tetrahydro‐pyrido[3,2‐c]quinolines. J. Heterocycl. Chem., 2014, 51(2), 466-474.
[20]
Dengler, W.A.; Schulte, J.; Berger, D.P.; Mertelsmann, R.; Fiebig, H.H. Development of a propidium iodide fluorescence assay for proliferation and cytotoxicity assays. Anticancer Drugs, 1995, 6(4), 522-532.
[21]
Dengler, W.A.; Schulte, J.; Berger, D.P.; Mertelsmann, R.; Fiebig, H.H. Development of a propidium iodide fluorescence assay for proliferation and cytotoxicity assays. Anticancer Drugs, 1995, 6(4), 522-532.
[22]
Joshi, K.S.; Rathos, M.J.; Joshi, R.D.; Sivakumar, M.; Mascarenhas, M.; Kamble, S.; Lal, B.; Sharma, S. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther., 2007, 6(3), 918-925.
[23]
Losiewicz, M.D.; Carlson, B.A.; Kaur, G.; Sausville, E.A.; Worland, P.J. Potent inhibition of Cdc2 kinase activity by the flavonoid L86-8275. Biochem. Biophys. Res. Commun., 1994, 201(2), 589-595.
[24]
Joshi, K.S.; Wagh, V.; Sharma, S. Herbal composition and process for its preparation. U.S. Patent 8,137,708. 2012.
[25]
Kumar, S.; Vishwakarma, R.; Mundada, R.; Deore, V.; Kumar, P.; Sharma, S. Imidazo [4, 5-C] quinoline derivatives and their use in the treatment of tumors and/or inflammation. U.S. Patent 13/381,464, 2012.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 10
Year: 2019
Page: [1285 - 1292]
Pages: 8
DOI: 10.2174/1871520619666190308122734
Price: $58

Article Metrics

PDF: 32
HTML: 2