Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

I. Ciftci, Halil; O. Radwan, Mohamed; E. Ozturk, Safiye; Ulusoy, N. Gokce; Sozer, Ece; E. Ellakwa, Doha; Ocak, Zeynep; Can, Mustafa; F.S. Ali, Taha; I. Abd-Alla, Howaida; Yayli, Nurettin; Tateishi, Hiroshi; Otsuka, Masami; Fujita, Mikako

doi:10.3390/molecules24193535

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Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

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Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-ku, Kumamoto 862-0976, Japan

Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan

Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki 12622, Cairo, Egypt

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Chemistry Department, Faculty of Science, Ege University, Erzene Mahallesi, Genclik Caddesi, Bornova/Izmir 35040, Turkey

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Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City 11651, Cairo, Egypt

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Department of Microbiology, Kocaeli State Hospital, Cedit Mahallesi Gunes Cad, Hastane Yolu Sk, Kocaeli 41300, Turkey

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Department of Engineering Sciences, Faculty of Engineering and Architecture, Izmir Katip Celebi University, Havaalani Sosesi Caddesi No:25, Cigli/Izmir 35620, Turkey

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Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt

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Faculty of Pharmacy, Karadeniz Technical University, Trabzon 61080, Turkey

Authors to whom correspondence should be addressed.

Academic Editors: Nazim Sekeroglu, Anake Kijjoa and Sevgi Gezici

Molecules 2019, 24(19), 3535; https://doi.org/10.3390/molecules24193535

Received: 26 July 2019 / Revised: 25 September 2019 / Accepted: 26 September 2019 / Published: 30 September 2019

(This article belongs to the Special Issue Selected Papers from the Joint Symposia of MESMAP-5 & ISPBS-5)

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Abstract

Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1–PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1–GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC₅₀ 5.46, 4.78 and 3.19 μM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC₅₀ = 1.44 μM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells. View Full-Text

Keywords: leukemia; chronic myelogenous leukemia; ABL kinase; pentacyclic triterpenes; gypsogenin; apoptosis

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I. Ciftci, H.; O. Radwan, M.; E. Ozturk, S.; Ulusoy, N.G.; Sozer, E.; E. Ellakwa, D.; Ocak, Z.; Can, M.; F.S. Ali, T.; I. Abd-Alla, H.; Yayli, N.; Tateishi, H.; Otsuka, M.; Fujita, M. Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity. Molecules 2019, 24, 3535. https://doi.org/10.3390/molecules24193535

AMA Style

I. Ciftci H, O. Radwan M, E. Ozturk S, Ulusoy NG, Sozer E, E. Ellakwa D, Ocak Z, Can M, F.S. Ali T, I. Abd-Alla H, Yayli N, Tateishi H, Otsuka M, Fujita M. Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity. Molecules. 2019; 24(19):3535. https://doi.org/10.3390/molecules24193535

Chicago/Turabian Style

I. Ciftci, Halil, Mohamed O. Radwan, Safiye E. Ozturk, N. G. Ulusoy, Ece Sozer, Doha E. Ellakwa, Zeynep Ocak, Mustafa Can, Taha F.S. Ali, Howaida I. Abd-Alla, Nurettin Yayli, Hiroshi Tateishi, Masami Otsuka, and Mikako Fujita. 2019. "Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity" Molecules 24, no. 19: 3535. https://doi.org/10.3390/molecules24193535

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Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

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