Abstract
A series of 2-chloro N-substituted amino quinolines (2a–2j) were prepared and characterized by analytical and spectroscopic methods. As quinoline is an important pharmacophoric moiety, the prepared compounds were screened against a non-small cell lung cancer cell line, A549. One of the compounds, 2-chloro-8-methyl-N-(quinolin-5-yl)quinolin-4-amine (2b) is found to be active with inhibition concentration value of (IC50) 29.4 μM. The molecular docking studies with the predominant PI3K/AKT/mTOR pathway proteins also revealed the lesser binding energy with 2b. All the compounds are predicted to satisfy the ADME profile and the results let us to consider 2b as a lead compound for new generation of A549 cell line inhibitors and for further studies in this way.
Similar content being viewed by others
References
Afzal O, Kumar S, Haider MR et al. (2015) A review on anticancer potential of bioactive heterocycle quinoline. Eur J Med Chem 97:871–910
Bai X, Li P, Xie Y et al. (2016) Overexpression of 3-phosphoinositide-dependent protein kinase-1 is associated with prognosis of gastric carcinoma. Tumor Biol 37:2333–2339. https://doi.org/10.1007/s13277-015-4024-8
Bhat HR, Pandey PK, Ghosh SK, Singh UP (2013) Development of 4-aminoquinoline-1,3,5-triazine conjugates as potent antibacterial agent through facile synthetic route. Med Chem Res 22:5056–5065. https://doi.org/10.1007/s00044-013-0521-8
Bispo M, de LF, de Alcantara CC, de Moraes MO et al. (2015) A new and potent class of quinoline derivatives against cancer. Chem Mon 146:2041–2052. https://doi.org/10.1007/s00706-015-1570-0
Chan SH, Chui CH, Chan SW et al. (2013a) Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents. ACS Med Chem Lett 4:170–174. https://doi.org/10.1021/ml300238z
Chan SH, Chui CH, Chan SW et al. (2013b) Synthesis of 8-Hydroxyquinoline Derivatives as Novel Antitumor Agents. 4:170–174
Chattopadhyay S, Moran RG, Goldman ID (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther 6:404–417. https://doi.org/10.1158/1535-7163.MCT-06-0343
D’Mello SR, Borodezt K, Soltoff SP (1997) Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-1 signaling. J Neurosci 17:1548–1560
De La Nuez A, Rodríguez R (2008) Current methodology for the assessment of ADME-Tox properties on drug candidate molecules. Biotecnol Apl 25:97–110
Dienstmann R, Rodon J, Serra V, Tabernero J (2014) Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-13-0639
El-Sayed MA-A, El-Husseiny WM, Abdel-Aziz NI et al. (2018) Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study. J Enzyme Inhib Med Chem 33:199–209. https://doi.org/10.1080/14756366.2017.1407926
Eswaran S, Adhikari AV, Chowdhury IH et al. (2010) New quinoline derivatives: Synthesis and investigation of antibacterial and antituberculosis properties. Eur J Med Chem 45:3374–3383. https://doi.org/10.1016/j.ejmech.2010.04.022
Fang Y, Zhang C, Wu T, et al. (2017) Transcriptome sequencing reveals key pathways and genes associated with cisplatin resistance in lung adenocarcinoma A549 cells. PLoS One 12(1):1–17. https://doi.org/10.1371/journal.pone.0170609
Feldman RI, Wu JM, Polokoff MA et al. (2005) Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 280:19867–19874. https://doi.org/10.1074/jbc.M501367200
Forns P, Esteve C, Taboada L et al. (2012) Pyrazine-based Syk kinase inhibitors. Bioorganic Med Chem Lett 22:2784–2788. https://doi.org/10.1016/j.bmcl.2012.02.087
Friesner RA, Murphy RB, Repasky MP et al. (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49:6177–6196. https://doi.org/10.1021/jm051256o
Gopalsamy A, Shi M, Boschelli DH et al. (2007) Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors. J Med Chem 50:5547–5549. https://doi.org/10.1021/jm070851i
Joerger M, Omlin a, Cerny T, Früh M (2010) The role of pemetrexed in advanced non small-cell lung cancer: special focus on pharmacology and mechanism of action. Curr Drug Targets 11:37–47. https://doi.org/10.2174/138945010790030974
Johnson MC, Hu Q, Lingardo L et al. (2011) Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery. J Comput Aided Mol Des 25:689–698. https://doi.org/10.1007/s10822-011-9456-7
Kawade VS (2018) Therapeutic Potential of PI3K/Akt/mTOR Signalling Pathway: Effective Combination Therapy for Cancer. Indian J Pharma Sci 80:702–708
Korrodi-Gregório L, Soto-Cerrato V, Vitorino R et al. (2016) From proteomic analysis to potential therapeutic targets: Functional profile of two lung cancer cell lines, A549 and SW900, widely studied in pre-clinical research. PLoS ONE 11:1–27. https://doi.org/10.1371/journal.pone.0165973
Mandewale MC, Patil UC, Shedge SV et al. (2017) A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ J Basic Appl Sci 6:354–361. https://doi.org/10.1016/j.bjbas.2017.07.005
Manohar S, Pepe A, Vélez Gerena CE et al. (2014) Anticancer activity of 4-aminoquinoline-triazine based molecular hybrids. RSC Adv 4:7062–7067. https://doi.org/10.1039/c3ra45333b
Medina JR, Blackledge CW, Heerding DA et al. (2010) Aminoindazole PDK1 inhibitors: A case study in fragment-based drug discovery. ACS Med Chem Lett 1:439–442. https://doi.org/10.1021/ml100136n
Mondal SK, Mondal NB, Banerjee S, Mazumder UK (2009) Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies. Indian J Pharmacol 41:176–181. https://doi.org/10.4103/0253-7613.56075
Mora A, Komander D, Van Aalten DMF, Alessi DR (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15:161–170
Mostafa M. Ghorab, Mansour S, Al said RKA (2014) Design, synthesis and potential anti-proliferative activity of some novel 4-aminoquinoline derivatives Acta Pharm 64:285–297. https://doi.org/10.2478/acph-2014-0030
Murphy ST, Alton G, Bailey S et al. (2011) Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1). J Med Chem 54:8490–8500. https://doi.org/10.1021/jm201019k
O’Brien NJ, Brzozowski M, Buskes MJ et al. (2014a) Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors. Bioorg Med Chem 22:3879–3886. https://doi.org/10.1016/j.bmc.2014.06.018
O’Brien NJ, Brzozowski M, Wilson DJD et al. (2014b) Synthesis and biological evaluation of substituted 2-anilino-7H-pyrrolopyrimidines as PDK1 inhibitors. Tetrahedron 70:4947–4956. https://doi.org/10.1016/j.tet.2014.05.033
O’Neill PM, Ward Sa, Berry NG et al. (2006) A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs. Curr Top Med Chem 6:479–507. https://doi.org/10.2174/156802606776743147
Oyallon B, Brachet-Botineau M, Logé C et al. (2018) Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors. Eur J Med Chem 154:101–109. https://doi.org/10.1016/j.ejmech.2018.04.056
Prabha K, Prasad KJR (2014) Synthesis and spectroscopic distinction of benzonaphthonaphthyridine and its isomer. Synth Commun 1441–1452. https://doi.org/10.1080/00397911.2013.831104
Rabal O, Sánchez-Arias JA, San José-Enériz E, et al. (2018) Detailed Exploration around 4-Aminoquinolines Chemical Space to Navigate the Lysine Methyltransferase G9a and DNA Methyltransferase (DNMT) Biological Spaces. J Med Chem https://doi.org/10.1021/acs.jmedchem.7b01925
Rehan M, Bajouh OS (2018) Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer-signaling PI3K/AKT/mTOR pathway. J Cell Biol 1–12. https://doi.org/10.1002/jcb.27100
Ren J, Zhao J, Zhou Y-S et al. (2013) Synthesis and antitumor activity of novel 4-aminoquinoline derivatives. Med Chem Res 22:2855–2861. https://doi.org/10.1007/s00044-012-0283-8
Rudrapal M, Chetia D, Prakash A (2013) Synthesis, antimalarial-, and antibacterial activity evaluation of some new 4-aminoquinoline derivatives. Med Chem Res 22:3703–3711. https://doi.org/10.1007/s00044-012-0371-9
Sáenz FE, Mutka T, Udenze K et al. (2012) Novel 4-aminoquinoline analogs highly active against the blood and sexual stages of Plasmodium in vivo and in vitro. Antimicrob Agents Chemother 56:4685–4692. https://doi.org/10.1128/AAC.01061-12
Schrödinger Release 2018-2: QikProp, Schrödinger, LLC, New York, NY 2018. schrodinger.pdf
Sestito S, Nesi G, Daniele S et al. (2015) Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme. Eur J Med Chem 105:274–288. https://doi.org/10.1016/j.ejmech.2015.10.020
Shaikh SKJ, Kamble RR, Somagond SM et al. (2017) Tetrazolylmethyl quinolines: design, docking studies, synthesis, anticancer and antifungal analyses. Eur J Med Chem 128:258–273. https://doi.org/10.1016/j.ejmech.2017.01.043
Shivakumar D, Williams J, Wu Y et al. (2010) Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 6:1509–1519. https://doi.org/10.1021/ct900587b
Singh P, Bast F (2014) Multitargeted molecular docking study of plant-derived natural products on phosphoinositide-3 kinase pathway components. Med Chem Res. https://doi.org/10.1007/s00044-013-0774-2
Thomas KD, Adhikari AV, Telkar S et al. (2011) Design, synthesis and docking studies of new quinoline-3-carbohydrazide derivatives as antitubercular agents. Eur J Med Chem 46:5283–5292. https://doi.org/10.1016/j.ejmech.2011.07.033
Solomon VR (2011) Quinoline as a privileged scaffold in drug discovery. Curr Med Chem 18:1488–1508. HL
Vennila KN, Prabha K, Manoj M, et al. (2010) 2-Chloro-7-methyl-12-phenyldibenzo[b, g][1,8]naphthyridin-11(6 H)-one. Acta Crystallogr Sect E Struct Reports Online 66:o1823–o1823. https://doi.org/10.1107/S160053681002430X
Verbanac D, Malik R, Chand M et al. (2016) Synthesis and evaluation of antibacterial and antioxidant activity of novel 2-phenyl-quinoline analogs derivatized at position 4 with aromatically substituted 4H-1,2,4-triazoles. J Enzyme Inhib Med Chem 31:104–110. https://doi.org/10.1080/14756366.2016.1190714
Wang J, Li J, Lu A, et al. (2014) Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho‑p38 expression. Oncol Lett 1159–1164. https://doi.org/10.3892/ol.2014.1863
Yasmin S, Mhlongo NN, Soliman ME et al. (2017) Comparative Design, In Silico Dockingand Predictive ADME/ TOX Properties of Some Novel 2, 4-hydroxy Derivatives of Thiazolidine-2, 4-diones as PPARγ Modulator. J Pharm Chem 4:11. https://doi.org/10.14805/jphchem.2017.art74
Zhao H, Chen G, Ye L, et al. (2018) DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways. Int J Oncol 381–389. https://doi.org/10.3892/ijo.2018.4624
Acknowledgements
The authors are highly thankful to the Department of Science and Technology, New Delhi for financial support under WOS-A Scheme (SR/WOS-A/CS-1084/2014). KNV acknowledges the computational facility and Schrodinger access offered by Prof. D. Velmurugan, BSR Faculty, Center for crystallography and Biophysics, University of Madras, Chennai.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Vennila, K.N., Prabha, K., Sunny, D. et al. Preparation and biological evaluation of quinoline amines as anticancer agents and its molecular docking. Med Chem Res 28, 1298–1307 (2019). https://doi.org/10.1007/s00044-019-02374-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-019-02374-w