Ultrasound-assisted Synthesis of 6-substituted indolo[2,3-b]quinolines: their Evaluation as Potential Cytotoxic Agents

Author(s): Nagaraju Marepu, Mahesh Gosi, Santhoshi Sumana Vedula, Sunandamma Yeturu*, Manojit Pal*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 7 , 2019


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Graphical Abstract:


Abstract:

Background: The indolo[2,3-b]quinoline framework is often found in various natural products displaying a range of pharmacological activities. This is an attractive template for the design and discovery of potential drugs especially for the identification of new anticancer agents.

Methods: The synthesis of 6-substituted indolo[2,3-b]quinolones was undertaken and carried out using a ultrasound assisted method involving two sequential C-N bond forming reactions between 3-(2- bromophenyl)-2-chloroquinoline and amines in a single pot in the presence of Pd(OAc)2 and a ligand (S)-BINAP. All the synthesized compounds were tested in vitro against two cancer cell lines e.g. MCF7 and HepG2 along with non-cancerous HEK293 cell lines.

Results: Two of these compounds showed promising and selective growth inhibition of MCF7 cell lines and one induced significant apoptosis in cancer (MCF7) cells.

Conclusion: Compounds based on indolo[2,3-b]quinolone framework may be useful for the identification of new cytotoxic agents thereby potential cure for breast cancer.

Keywords: Indolo[2, 3-b]quinoline, palladium, coupling, ultrasound, cytotoxicity, cancer cells.

[1]
Sidoryk, K.; Jaromin, A.; Edward, J.A.; Świtalska, M.; Stefańska, J.; Cmoch, P.; Zagrodzka, J.; Szczepek, W.; Peczyńska-Czoch, W.; Wietrzyk, J.; Kozubek, A.; Zarnowski, R.; Andes, D.R.; Kaczmarek, Ł. Searching for new derivatives of neocryptolepine: Synthesis, antiproliferative, antimicrobial and antifungal activities. Eur. J. Med. Chem., 2014, 78, 304-313.
[2]
Bracca, A.B.J.; Heredia, D.A.; Larghi, E.L.; Kaufman, T.S. Neocryptolepine (Cryprotackieine), A unique bioactive natural product: isolation, synthesis, and profile of its biological activity. Eur. J. Org. Chem., 2014, 2014, 7979-8003.
[3]
Kumar, S.; Bawa, S.; Gupta, H. Biological activities of quinoline derivatives. Mini Rev. Med. Chem., 2009, 9, 1648-1654.
[4]
Lavrado, L.; Moreira, R.; Paulo, A. Indoloquinolines as scaffolds for drug discovery. Curr. Med. Chem., 2010, 17, 2348-2370.
[5]
Cimanga, K.; de Bruyne, T.; Lasure, A.; Poel, B.V.; Pieters, L.; Claeys, M.D.; Berghe, V.; Kambu, K.; Tona, L.; Vlietinck, A.J. In vitro biological activities of alkaloids from Cryptolepis sanguinolenta. Planta Med., 1996, 62, 22-27.
[6]
Garbett, N.C.; Graves, D.E. Extending nature’s leads: The anticancer agent ellipticine. Curr. Med. Chem. Anticancer Agents, 2004, 4, 149-172.
[7]
Peczynska-Czoch, W.; Pognan, F.; Kaezmarek, L.; Boratynski, J. Synthesis and structure-activity relationship of methyl-substituted Indolo[2,3-b]quinolines: Novel cytotoxic, DNA topoisomerase II inhibitors. J. Med. Chem., 1994, 37, 3503-3510.
[8]
Sunke, R.; Kumar, V.; Ashfaq, M.A.; Yellanki, S.; Medisetti, R.; Kulkarni, P.; Ramarao, E.V.V.S.; Ehtesham, N.Z.; Pal, M.A. Pd(II)-catalyzed C–H activation approach to densely functionalized N-heteroaromatics related to neocryptolepine and their evaluation as potential inducers of apoptosis. RSC Advances, 2015, 5, 44722-44727.
[9]
Kaczmarek, L.; Luniewski, W.; Zagrodzki, B.; Godlewska, J.; Osiadacz, J.; Wietrzyk, J.; Opolski, A.; Peczyńska-Czoch, W. Synthesis of 6-substituted 6H-indolo[2,3-b]quinolines as novel cytotoxic agents and topoisomerase II inhibitors. Acta Pol. Pharm., 2002, 59, 199-207.
[10]
James, K.M.; Willetts, N.; Procter, D.J. Samarium(II)−Mediated Linker Cleavage-Cyclization in Fluorous Synthesis: Reactions of samarium enolates. Org. Lett., 2008, 10, 12031206.
[11]
Liu, B.; Gao, H.; Yu, Y.; Wu, W.; Jiang, H. Palladium-Catalyzed intermolecular aerobic oxidative cyclization of 2-Ethynylanilines with Isocyanides: Regioselective synthesis of 4-Halo-2-aminoquinolines. J. Org. Chem., 2013, 78, 10319-10328.
[12]
Nallapati, S.B.; Prasad, B.; Sreenivas, B.Y.; Sunke, R.; Poornachandra, Y.; Kumar, C.G.; Sridhar, B.; Shivashankar, S.; Mukkanti, K.; Pal, M. Apparent carbon monoxide insertion via double isocyanide incorporation during Palladium-Catalyzed construction of indoloquinoline ring in a single pot: Synthesis of new cytotoxic agents. Adv. Synth. Catal., 2016, 358, 3387-3393.
[13]
Prasad, B.; Nallapati, S.B.; Kolli, S.K.; Sharma, A.K.; Yellanki, S.; Medisetti, R.; Kulkarni, P.; Sripelly, S.; Mukkanti, K.; Pal, M. Pd-catalyzed isocyanide insertion / nucleophilic attack by indole C-3 / desulfonylation in the same pot: A direct access to indoloquinolines of pharmaceutical interest. RSC Advances, 2015, 5, 62966-62970.
[14]
Luniewski, W.; Wietrzyk, J.; Godlewska, J.; Switalska, M.; Piskozub, M.; Peczynska-Czoch, W.; Kaczmarek, L. New derivatives of 11-methyl-6-[2-(dimethylamino)ethyl]-6H-indolo[2,3-b]quinoline as cytotoxic DNA topoisomerase II inhibitors. Bioorg. Med. Chem. Lett., 2012, 22, 6103-6107.
[15]
Godlewska, J.; Luniewski, W.; Zagrodzki, B.; Kaczmarek, L.; Bielawska-Pohl, A.; Dus, D.; Wietrzyk, J.; Opolski, A.; Siwko, M.; Jaromin, A.; Jakubiak, A.; Kozubek, A.; Peczynska-Czoch, W. Biological evaluation of omega-(dialkylamino)alkyl derivatives of 6H-indolo[2,3-b]quinoline--novel cytotoxic DNA topoisomerase II inhibitors. Anticancer Res., 2005, 25, 2857-2868.
[16]
Ali, S.; Li, Y.; Anwar, S.; Yang, F.; Chen, Z.; Liang, Y. One-Pot Access to Indolo[2,3-b]quinolines by electrophile-triggered cross-amination/friedel-crafts alkylation of indoles with 1-(2-tosylaminophenyl)ketones. J. Org. Chem., 2012, 77, 424-431.
[17]
Yan, Z.; Wan, C.; Wan, J.; Wang, Z. An efficient iron-promoted synthesis of 6H-indolo[2,3-b]quinolines and neocryptolepine derivatives. Org. Biomol. Chem., 2016, 14, 4405-4408.
[18]
Shi, L.; Wang, B. Tandem Rh(III)-Catalyzed C–H amination/ annulation Reactions: Synthesis of indoloquinoline derivatives in water. Org. Lett., 2016, 18, 2820-2823.
[19]
Yu, S.; Li, Y.; Zhou, X.; Wang, H.; Kong, L.; Li, X. Access to structurally diverse quinoline-fused heterocycles via rhodium(iii)-catalyzed c–c/c–n coupling of bifunctional substrates. Org. Lett., 2016, 18, 2812-2815.
[20]
Fan, L.; Liu, M.; Ye, Y.; Yin, G. Synthesis of 6-Substituted 6H-Indolo[2,3-b]quinolines from Isoindigos. Org. Lett., 2017, 19, 186-189.
[21]
Haritha, M.; Rani, C.S.; Rao, M.V.B.; Pal, M. Pd/C-catalyzed synthesis of 4-biaryl substituted 2-amino benzo[h]chromene derivatives as potential cytotoxic agents. Lett. Drug Des. Discov., 2017. in the press.
[22]
Balicki, R.; Kozlowska, M.; Sobotka, W. Novel Pyrethroid Insecticides. II. Synthesis of α-Cyano Substituted 3-Quinolylmethyl Esters. Bul. Pol. Acad. Sci. Chem., 1986, 34, 281-287.
[23]
Boganyi, B.; Kaman, J. A concise synthesis of indoloquinoline skeletons applying two consecutive Pd-catalyzed reactions. Tetrahedron, 2013, 69, 9512-9519.
[24]
Nikumbh, S.P.; Raghunadh, A.; Murthy, V.N.; Jinkala, R.; Joseph, S.C.; Murthy, Y.L.N.; Prasad, B.; Pal, M. A greener approach towards double heteroarylation of N, O and S nucleophiles: Synthesis of bioactive polynuclear fused N-heteroarenes. RSC Advances, 2015, 5, 74570-74574.
[25]
Driver, M.S.; Hartwig, J.F. Carbon-Nitrogen-Bond-Forming reductive elimination of arylamines from palladium(II) phosphine complexes. J. Am. Chem. Soc., 1997, 119, 8232-8245.
[26]
Hartwig, J.F.; Richards, S.; Barañano, D.; Paul, F. Influences on the relative rates for C−N Bond-Forming reductive elimination and β-hydrogen elimination of amides. A case study on the origins of competing reduction in the palladium-catalyzed amination of aryl halides. J. Am. Chem. Soc., 1996, 118, 3626-3633.
[27]
Driver, M.S.; Hartwig, J.F. A rare, low-valent alkylamido complex, a diphenylamido complex, and their reductive elimination of amines by three-coordinate intermediates. J. Am. Chem. Soc., 1995, 117, 4708-4709.
[28]
Widenhoefer, R.A.; Buchwald, S.L. Halide and amine influence in the equilibrium formation of palladium tris(o-tolyl)phosphine mono(amine) complexes from palladium aryl halide dimers. Organometallics, 1996, 15, 2755-2763.
[29]
Mason, T.J.; Peters, D. Practical sonochemistry; Ellis Horwood: New York, NY, USA, 1991.
[30]
Mason, T.J. Sonochemistry and the environment - providing a “green” link between chemistry, physics and engineering. Ultrason. Sonochem., 2007, 14, 476-483.
[31]
Beslija, S. The Role of Anthracyclines/Anthraquinones in metastatic breast cancer. Breast Cancer Res. Treat., 2003, 81, 25-32.
[32]
Lown, J.W. Anthracycline and anthraquinone anticancer agents: Current status and recent developments. Pharmacol. Ther., 1993, 60, 185-214.
[33]
Zou, Y.; Yan, C.; Knaus, E.E.; Zhang, H.; Zhang, Y.; Huang, Z. Discovery of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates with potent anticancer activity. RSC Advances, 2017, 7, 18893-18899.
[34]
Nakhi, A.; Adepu, R.; Rambabu, D.; Kishore, R.; Vanaja, G.R.; Kalle, A.M.; Pal, M. Thieno[3,2-c]pyran-4-one based novel small molecules: Their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents. Bioorg. Med. Chem. Lett., 2012, 22, 4418-4427.


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Article Details

VOLUME: 19
ISSUE: 7
Year: 2019
Published on: 28 March, 2019
Page: [599 - 608]
Pages: 10
DOI: 10.2174/1389557518666180727170055
Price: $65

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