Design and Synthesis of Indole Pyrimidine Scaffolds as Potential KSP Inhibitors and Anticancer Agents

Author(s): Radhika Chelamalla*, Ajitha Makula.

Journal Name: Current Enzyme Inhibition

Volume 15 , Issue 1 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Background: Several biological activities like anticancer, anti-inflammatory, analgesic, antitubercular activities are reported for pyrimidine scaffolds. Extensive work on pyrimidine indole scaffolds is required for antimitotic activity.

Objective: To synthesize a novel Indole Pyrimidine scaffold via an efficient synthetic method and to evaluate cytotoxic activity using various human cancer cell lines.

Methods: 4,4-(3-substituted phenyl)-6-methyl-N-[(Z)-(5-methyl-2-oxo-indolin-3-ylidene)amino]-2- oxo-3,4-dihydro-1H-pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated for cytotoxic activity. The structures were confirmed by IR, 1H NMR, C13NMR and Mass spectroscopy. The antiproliferative activities of the synthesized compounds were evaluated in vitro against human cancer cell lines including HeLa and MCF-7.

Results: The results revealed that most of the compounds possessed moderate to excellent potency. Three among 10 molecules, showed more than 70% growth inhibition against all tested cancer cells. The nature of the substituent group (R) on the indole ring affected significantly the anti-proliferative activity of the molecules. The IC50 values of the most promising compound 4h are 76.4µM and 88.2µM against HeLa and MCF-7 respectively, which are closer to the standard compound doxorubicin.

Conclusion: Molecular docking analysis demonstrated that 4b and 4d interact and bind efficiently with KSP binding site. The preliminary results made us investigate for further development of potent indole-pyrimidine scaffolds as cytotoxic agents.

Keywords: Cytotoxic activity, docking, indole, kinesin spindle protein, MTT assay, pyrimidine.

Jordan, M.A.; Wilson, L. Microtubules as target for anticancer drugs. Nature. Rev. Cancer, 2004, 4(4), 253-265.
Argyriou, A.A.; Bruna, J.; Marmiroli, P.; Cavaletti, G. Chemotherapy-induced peripheral neurotoxicity (CIPN): An update. Crit. Rev. Oncol. Hemat., 2012, 82(1), 51-77.
Cavalletti, G.; Cavalletti, E.; Montaguti, P.; Oggioni, N.; De Negri, O.; Tredici, G. Effect on the peripheral nervous system of the shortterm intravenous administration of paclitaxel in the rat. Neurotoxicology, 1997, 18, 137-145.
Lee, J.J.; Swain, S.M. Peripheral neuropathy induced by microtubule- stabilizing agents. J. Clin. Oncol., 2006, 24(10), 1633-1642.
Kavallaris, M.; Verrills, N.M.; Hill, B.T. Anticancer therapy with novel tubulin-interacting drugs. Drug Resist. Updates., 2001, 4(6), 392-401.
Yusuf, R.Z.; Duan, Z.; Lamendola, D.E.; Penson, R.T.; Seiden, M.V. Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr. Cancer Drug Targets, 2003, 3(1), 1-19.
Kavallaris, M.; Kuo, D.Y.S.; Burkhart, C.A.; Regl, D.L.; Norris, M.D.; Haber, M. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific -tubulin isotypes. J. Clin. Invest., 1997, 100, 1282-1293.
Wood, K.W.; Cornwell, W.D.; Jackson, J.R. Past and future of the mitotic spindle as an oncology target. Curr. Op. Pharmacol., 2009, 1(4), 370-377.
Rath, O.; Kozielski, F. Kinesins and cancer. Nature. Rev. Cancer, 2012, 12(8), 527-539.
Huszar, D.; Theoclitou, M.E.; Skolnik, J.; Herbst, R. Kinesin motor proteins as targets for cancer therapy. Cancer Metasta Rev., 2009, 28(1-2), 197-208.
Suvarna, G.K.; Vikas, G.; Sharada, P.; Revathi, R.; Muhammad, M. Protein kinases as drug targets in human and animal diseases. Curr. Enz. Inhib., 2017, 13(2), 99-106.
Yan, Y.; Sardana, V.; Xu, B.; Homnick, C.; Halczenko, W.; Buser, C.A.; Schaber, M.; Hartman, G.D.; Huber, H.E.; Kuo, L.C. Inhibition of a mitotic motor protein: where, how, and conformational consequences. J. Mol. Biol., 2004, 335(2), 547-554.
Luo, L.; Carson, J.D.; Dhana, D.; Jackson, J.R.; Huang, P.S.; Lee, Y.; Sakowicz, R.; Copeland, R.A. Mechanism of inhibition of human KSP by monastrol: insights from kinetic analysis and the effect of ionic strength on KSP inhibition. Biochemistry, 2004, 43(48), 15258-15266.
Gartner, M.; Plassmann, N.S.; Seiler, J.; Utz, M.; Vernos, I.; Surrey, T.; Giannis, A. Development and biological evaluation of potent and specific inhibitors of mitotic Kinesin Eg5. ChemBioChem, 2005, 6(7), 1173-1177.
Rodolfo do Couto, M.; Carlos Alberto, M.F. Discovery of dual chemotherapy drug candidates designed by molecular hybridization. Curr. Enz. Inhib., 2010, 6(4), 171-182.
Klein, E.; DeBonis, S.; Thiede, B.; Skoufias, D.A.; Kozielski, F.; Lebeau, L. New chemical tools for investigating human mitotic kinesin Eg5. Bioorg. Med. Chem., 2007, 15(19), 6474-6488.
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 1999, 19(14), 1639-1662.
Radhika, C.; Venkatesham, A. Anantha Krishna chaitanya, D. Synthesis and Biological activity of new 5-Methyl-3-Oxo-N2 [5′- Carbonyl-(4′-Aryl-6‘methyl)-1’,2′,3′,4′-Tetrahydropyrimidine-2′- One]Pyrazolidines. JAPER, 2014, 4(1), 1-4.
Larry, L.K.; Michael, D.T. Synthesis of Substituted Isatins. Tetrahedron Lett., 2013, 54(8), 1008-1011.
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A. Feasibility of high flux anti-cancer drug screen using diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83(11), 757-766.
Scudiero, D.A.; Shoemaker, R.H.; Paul, K.D. Evaluation of soluble tetrazolium/formazan assay for cell growth and drug sensitivity in cultures using human and other tumor cell lines. Cancer Res., 1988, 48(17), 4827-4833.
Alley, M.C.; Scudiero, D.A.; Monks, A. Feasibility of drug screening with panels of human tumor cell lines using microculture tetrazolium assay. Cancer Res., 1988, 48(3), 589-601.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [28 - 35]
Pages: 8
DOI: 10.2174/1573408014666181105144847
Price: $58

Article Metrics

PDF: 35