Facile Synthesis and Cytotoxicity of Phenazine-Chromene Hybrid Molecules Derived from Phenazine Natural Product

Author(s): Mei-Chen Zhang, Shu-Hui Gu, Guang-Pan Liu, Chen-Cheng Li, Han-Mei Xu*, Zhong-Xi Wu, Bo-Ping Ye, Yuan-Yuan Lu, De-Chun Huang, Zhi-Xiang Wang, Feng Jiang*.

Journal Name: Combinatorial Chemistry & High Throughput Screening

Volume 22 , Issue 1 , 2019

Become EABM
Become Reviewer

Abstract:

Aim and Objective: Small molecule targeted drugs can effectively reduce the toxicity and side effects of drugs, and improve the efficacy of drugs by their specific antitumor activity. Hence, the development of small molecular targeted drugs for cancer has important significance. This study was undertaken to design and synthesize novel phenazine-chromene hybrid molecules in order to optimize the structure and improve the efficacy of this kind of hybrids.

Materials and Methods: O-diaminobenzene was used as starting material to synthesize twentyfour heterocyclic compounds designed as hybrid molecules of phenazine and 4H-chromene pharmacophores by facile methods. The structures of the compound were confirmed by 1H NMR, 13C NMR and HRMS. Furthermore, the synthesized compounds were evaluated for in vitro activity against four human cancer cell lines and two non-cancer cell lines by MTT test.

Results: Some compounds showed strong cytotoxic activities against HepG2 and A549 cancer lines (IC50 = 5-10 µM). Comparing 2i with 2l, the introduction of hydrophilic groups on the phenazine core could not improve the antiproliferative activity significantly. Except 2d and 3c, compounds owning chlorine substituent on the 4H-chromene pharmacophore seemingly contribute to enhance the compounds’ antiproliferative activity. Specially, compound 3c showed highest cytotoxicity against A549 cells with IC50 values of 3.3±0.4 µM. Furthermore, all compounds showed low or no cytotoxicity against HUVEC and L02 non-cancer cells in vitro.

Conclusion: Compound 3c may be used as potential lead molecule against A549 cancer cells.

Keywords: Phenazine, 4H-chromene, hybrid molecules, antitumor activity, SAR, synthesis.

[1]
Ali, I.; Haque, A.; Saleem, K. Hsieh, Ming, F. Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: Synthesis, pharmacological and simulation studies. Bioorg. Med. Chem., 2013, 21(13), 3808-3820.
[2]
Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Al-Warthan, A.; Sanagi, M.M. Heterocyclic scaffolds: Centrality in anticancer drug development. Curr. Drug Targets, 2015, 16(7), 711-734.
[3]
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs. Future Med. Chem., 2013, 5(8), 961-978.
[4]
Ali, I.; Wani, W.A.; Saleem, K.; Haque, A. Platinum compounds: A hope for future cancer chemotherapy. Anticancer. Agents Med. Chem., 2013, 13(2), 296-306.
[5]
Ali, I.; Wani, W.A.; Saleem, K.; Haque, A. Thalidomide: A banned drug resurged into future anticancer drug. Curr. Drug Ther., 2012, 7(1), 13-23.
[6]
Basheer, A.A. Chemical chiral pollution: Impact on the society and science and need of the regulations in the 21st century. Chirality, 2018, 30(4), 402-406.
[7]
Ali, I. Nano anti-cancer drugs: Pros and cons and future perspectives. Curr. Cancer Drug Targets, 2011, 11(2), 131-134.
[8]
Ali, I.; Wani, W.A.; Saleem, K.; Wesselinova, D. Syntheses, DNA binding and anticancer profiles of L-glutamic acid ligand and its copper(II) and ruthenium(III) complexes. Med. Chem., 2013, 9(1), 11-21.
[9]
Ali, I.; Saleem, K.; Wesselinova, D.; Haque, A. Synthesis, DNA binding, hemolytic, and anti-cancer assays of curcumin I-based ligands and their ruthenium(III) complexes. Med. Chem. Res., 2013, 22(3), 1386-1398.
[10]
Ali, I.; Wani, W.A.; Saleem, K.; Hseih, M.F. Design and synthesis of thalidomide based dithiocarbamate Cu(II), Ni(II) and Ru(III) complexes as anticancer agents. Polyhedron, 2013, 56, 134-143.
[11]
Ali, I.; Wani, W.A.; Saleem, K.; Hsieh, M.F. Anticancer metallodrugs of glutamic acid sulphonamides: In silico, DNA binding, hemolysis and anticancer studies. RSC Advances, 2014, 4(56), 29629-29641.
[12]
Ali, I.; Lone, M.N.; Suhail, M.; Mukhtar, S.D.; Asnin, L. Advances in nanocarriers for anticancer drugs delivery. Curr. Med. Chem., 2016, 23(20), 2159-2187.
[13]
Ali, I.; Lone, M.N.; Alothman, Z.A.; Alwarthan, A. Insights into the pharmacology of new heterocycles embedded with oxopyrrolidine rings: DNA binding, molecular docking, and anticancer studies. J. Mol. Liq., 2017, 234, 391-402.
[14]
Ali, I.; Lone, M.N.; Hsieh, M.F. N-substituted (substituted-5-benzylidine) thiazolidine-2,4-diones: crystal structure, in silico, DNA binding and anticancer studies. Biointerface Res. Appl. Chem., 2016, 6(4), 1356-1379.
[15]
Decker, M. Hybrid molecules incorporating natural products: Applications in cancer therapy, neurodegenerative disorders and beyond. Curr. Med. Chem., 2011, 18(10), 1464-1475.
[16]
Laursen, J.B.; Nielsen, J. Phenazine natural products: Bios-ynthesis, synthetic analogues, and biological activity. Chem. Rev., 2004, 104(3), 1663-1685.
[17]
Gao, X.C.; Lu, Y.Y.; Xing, Y.Y.; Ma, Y.H.; Lu, J.S.; Bao, W.W.; Wang, Y.M.; Xi, T. A novel anticancer and antifungus phenazine derivative from a marine actinomycete BM-17. Microbiol. Res., 2012, 167(10), 616-622.
[18]
Sciabola, S.; Carosati, E.; Cucurull-Sanchez, L.; Baroni, M.; Mannhold, R. Novel TOPP descriptors in 3D-QSAR analysis of apoptosis inducing 4-aryl-4H-chromenes: Comparison versus other 2D- and 3D-descriptors. Bioorg. Med. Chem., 2007, 15(19), 6450-6462.
[19]
Fatemi, M.H.; Gharaghani, S. A novel QSAR model for prediction of apoptosis-inducing activity of 4-aryl-4-H-chromenes based on support vector machine. Bioorg. Med. Chem., 2007, 15(24), 7746-7754.
[20]
Afantitis, A.; Melagraki, G.; Sarimveis, H.; Koutentis, P.A.; Markopoulos, J.; Igglessi-Markopoulou, O. A novel QSAR model for predicting induction of apoptosis by 4-aryl-4H-chromenes. Bioorg. Med. Chem., 2006, 14(19), 6686-6694.
[21]
Gao, J.; Chen, M.; Tong, X.; Zhu, H.; Yan, H.B.; Liu, D.C.; Li, W.J.; Qi, S.Y.; Xiao, D.K.; Wang, Y.Z.; Lu, Y.Y.; Jiang, F. Synthesis, antitumor activity, and structure-activity relationship of some benzo[a]pyrano[2,3-c]phenazine derivatives. Comb. Chem. High Throughput Screen., 2015, 18(10), 960-974.
[22]
Lu, Y.Y.; Wang, L.L.; Wang, X.B.; Xi, T.; Liao, J.M.; Wang, Z.X.; Jiang, F. Design, combinatorial synthesis and biological evaluations of novel 3-amino-1′-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2′-oxospiro[benzo[a] pyrano[2,3-c]phenazine-1,3′-indoli-ne]-2-carbonitrile antitumor hybrid molecules. Eur. J. Med. Chem., 2017, 135, 125-141.
[23]
Lu, Y.Y.; Yan, Y.R.; Wang, L.L.; Wang, X.B.; Gao, J.; Xi, T.; Wang, Z.X.; Jiang, F. Design, facile synthesis and biological evaluations of novel pyrano[3,2-a]phenazine hybrid molecules as antitumor agents. Eur. J. Med. Chem., 2017, 127, 928-943.
[24]
Seillan, C.; Brisset, H.; Siri, O. Efficient synthesis of substituted dihydrotetraazapentacenes. Org. Lett., 2008, 10(18), 4013-4016.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 22
ISSUE: 1
Year: 2019
Page: [35 - 40]
Pages: 6
DOI: 10.2174/1386207322666190307125015
Price: $58

Article Metrics

PDF: 22
HTML: 3
EPUB: 1
PRC: 1