Uji in silico Aktivitas Sitotoksik dan Toksisitas Senyawa Turunan N-(Benzoil)-N’- feniltiourea Sebagai Calon Obat Antikanker

Dini Kesuma, Siswandono Siswandono, Bambang Tri Purwanto, Suko Hardjono

Abstract


Senyawa N-(benzoil)-N’-feniltiourea mempunyai gugus farmakofor yang sama dengan turunan urea yang mempunyai aktivitas antikanker, sepertihidroksiurea, sehinggalayakdijadikansenyawaindukuntukdikembangkanlebihlanjutmelaluimodifikasistruktur.  Penelitianinibertujuanuntukmemprediksiaktivitas sitotoksik dan toksisitas dari duapuluh tiga senyawa turunanN-(benzoil)-N’-feniltiourea sebagaicalonobatantikanker. Salah satumekanismekerjaturunanN-(benzoil)-N’-feniltiourea sebagaiantikanker adalah menghambat VEGFR2,regulatorpentinguntuk proses angiogenesis, sertasangatberperanuntukpertumbuhan tumor dan metastasis. Aktivitas biologis dapat diprediksi melalui pemodelan molekul yang disebut uji in silico, menggunakan program MVD (Molegro Virtual Docker),sedang toksisitas dapat diprediksi menggunakan program pkCSMdanProtoxonline tool. Uji in silico dilakukan dengan melakukan docking senyawa yang akan diprediksi aktivitasnya dengan target reseptor, VEGFR2, PDB ID. 3WZE.Hasildockingberupaenergiikatandigambarkandengannilai Rerank Score (RS).Senyawa dengan nilai RS kecil berarti mempunyai ikatan ligan-reseptor yang stabil dan diprediksi mempunyai aktivitas yang besar. Dari hasilujiin silicodisimpulkanbahwasemuaturunanN-(benzoil)-N’-feniltiourea diprediksimenimbulkantoksisitas relatifrendah, danmempunyai aktivitas sitotoksik lebihbesardibandinghidroksiurea, tetapimasihlebihrendahdibandingsorafenib.N-(4-propoksibenzoil)-N’-feniltioureadanN-(3,5-di-trifluorometilbenzoil)-N’-feniltioureadiprediksi mempunyai aktivitas sitotoksik paling besar tetapi menimbulkan hepatotoksik, sehingga sebagai senyawa terpilih untuk disintesis dan dikembangkan lebih lanjut adalah N-(3,4-dimetilbenzoil)-N’-feniltiourea.

Keywords


Pemodelan molekul; N-(benzoil)-N’-feniltiourea; aktivitas sitotoksik; toksisitas

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References


Curtin, M.L., Frey, R.R.,Heyman, H.R., Soni, N.B., Marcotte, P.A., Pease, L.J.,Glaser, K.B., Magoc, T.J., Tapang, P., Albert, D.H., Osterling, D.J., Olson, A.M.,Bouska, J.J., Guan, Z., Preusser, L.C., Polakowski, J.S., Stewart, K.D., Tse, C.,Davidsen, S.K., Michaelides, M.R., 2012. Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinase families. Bioorganic & Medicinal Chemistry Letters, 22, pp. 3208-3212.

Dai, Y., Hartandi, K., Soni, N.B., Pease, L.J., Reuter, D.R., Olson, A.M., Osterling, D.J., Doktor, S.Z., Albert, D.H., Bouska, J.J., Glaser, K.B., Marcotte, P.A., Stewart, K.D., Davidsen, S.K., and Michaelides, M.R., 2008. Identification of aminopyrazolo-pyridine ureas as potent VEGFR-PDGFR multitargeted kinase inhibitors, Bioorganic & Medicinal Chemistry Letters, 18,pp. 386-390.

Hardjono, S., 2012. Modifikasi Struktur 1-(Benzoiloksi)urea dan Hubungan Kuantitatif Struktur-Aktivitas Sitotoksiknya, Universitas Airlangga, Disertasi, Surabaya.

Hardjono, S.,Siswandono, Purwanto, Darmanto, W., 2016. Quantitative Structure-Cytotoxic Activity Relationship 1-(Benzoyloxy)urea And Its Derivative, Current Drug Discovery Technollogy, Vol. 13, No.2, pp. 101-108.

Hassan, M., Abbas, Q., Ashraf, Z., Moustafa, A.A., Seo, S-Y, 2017. Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study, Computational Biology and Chemistry, 68, pp. 131-142.

Hinchliffe, A., 2008. Molecular Modeling for Beginners. 2nd ed., Chichester: John Wiley and Sons Ltd.

Hodge, H.C. and Sterner, J.H., 1949, Tabulation of Toxicity Classes, Journal American Industrial Hygiene Association Quarterly,Vol. 10, Issue 4, pp. 93-96. Published online: 09 Jan 2008.

Hoi, P.M.,Li, S, Vong, C.T.,Tseng, H.H.L., Kwan, Y.W., Lee, S.M-Y., 2015. Recent advances in structure-based drug design and virtual screening of VEGFR tyrosine kinase inhibitors. Methods,71, pp. 85-91.

Jensen, F., 2007. Introduction to Computational Chemistry, 2nd Ed, Chichester: John Wiley & Sons Ltd.

Li K and Luo J, 2010. The role of SIRT1 in tumorigenesis, North American Journal of Medical Sciences (Boston), 4(2), pp.104–106.

Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, F.J., 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews, 23, 3-25.

Nasyanka, A.L., 2017, Hubungan Kuantitatif Struktur Aktivitas Sitotoksik dari Senyawa Induk N-Benzoil-N’-(4-fluorofenil)tiourea dan Turunannya Terhadap Cell Line MCF7, Universitas Airlangga, Tesis, Surabaya.

Okamoto K., Kawada, M.I., Jestel A., Konig K., Funahashi Y., Matsushima T., Tsuruoka A., Inaoue A., and Matsui J., 2015. Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealedby Biochemical Characterization, ACS Medicinal Chemistry Letters, 6, pp. 89 -94.

Pires, D.E.V., Blundell, T.L., and Ascher, D.B., 2015. pkCSM Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures, Journal of Medicinal Chemistry, 58, pp.4066−4072.

Ruswanto, Siswandono, Richa,M., Tita, N., Tresna, L.,2017. Molecular Docking of 1-Benzoyl-3-methylthiourea as Anti Cancer Candidate and Its Absorption, Distribution, and Toxicity Prediction, Journal of Pharmaceutical Science and Research, Vol. 9(5), pp. 680-684.

Saeed, A., Rehman, S., Channar, P.A., Larik, F.A., Abbas, Q., Hassan, M., Raza, H., Flörke, U., Seo, S-Y., 2017. Long chain 1-acyl-3-arylthioureas as jack bean urease inhibitors, synthesis, kinetic mechanism and molecular docking studies, Journal of the Taiwan Institute of Chemical Engineers, Vol. 77, pp. 54-63.

Schlick, T., 2010. Molecular Modeling and Simulation, An Interdisciplinary Guide. 2nd ed., New York: Springer Science+Business Media.

Siswandono, 2014. Pengembangan Obat Baru, Edisi Pertama, Surabaya: Airlangga University Press.

Siswandono (ed.), 2016. Kimia Medisinal I, Edisi Kedua, Surabaya: Airlangga University Press.

Usui, T., Ban, H.S., Kawada, J., Hirokawa, T., and Nakamura, H., 2008. Discovery of indenopyrazoles as EGFR and VEGFR-2 tyrosine kinase inhibitors by in silico high-throughput screening. Bioorganic & Medicinal Chemistry Letters, 18, pp. 285-288.

World Health Organization and International Agency for Research on Cancer (IARC), 2012, GLOBOCAN 2012: Estimated cancer incidence, mortality, and prevalence worldwide in 2012.Diakses melalui http://globocan.iarc.fr/Pages/fact_sheets_ population.aspx pada tanggal 1 Mei 2017.




DOI: http://dx.doi.org/10.20961/jpscr.v3i1.16266

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