New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound <b>IC261</b>, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The...

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Autores principales:	Momen R. Fareed, Mai E. Shoman, Mohammed I. A. Hamed, Mohamed Badr, Hanin A. Bogari, Sameh S. Elhady, Tarek S. Ibrahim, Gamal El-Din A. Abuo-Rahma, Taha F. S. Ali
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	oindoles antiproliferative tubulin polymerization inhibitors EGFR kinase inhibitors casein kinase Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/1fa090297e6e4a839f74fdf924fcba24
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spelling	oai:doaj.org-article:1fa090297e6e4a839f74fdf924fcba242021-11-25T18:39:27ZNew Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors10.3390/ph141111141424-8247https://doaj.org/article/1fa090297e6e4a839f74fdf924fcba242021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1114https://doaj.org/toc/1424-8247A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound <b>IC261</b>, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, <b>4b,</b> and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, <b>4e,</b> showed potent activity against the colon cancer COLO-205 cell line with an IC<sub>50</sub> value of 0.2 and 0.3 μM. A mechanistic study demonstrated <b>4b</b>’s efficacy in inhibiting microtubule assembly (IC<sub>50</sub> = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC<sub>50</sub> of 1.92 ± 0.09 μg/mL, <b>4b</b> inhibited CK1 almost as well as <b>IC261</b>. Additionally, <b>4b</b> and <b>4e</b> were effective inhibitors of EGFR-TK with IC<sub>50</sub>s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC<sub>50</sub> = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with <b>4b,</b> with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, <b>4b</b> and <b>4e</b> are considered promising potent multitarget agents against colon cancer that require optimization.Momen R. FareedMai E. ShomanMohammed I. A. HamedMohamed BadrHanin A. BogariSameh S. ElhadyTarek S. IbrahimGamal El-Din A. Abuo-RahmaTaha F. S. AliMDPI AGarticleoindolesantiproliferativetubulin polymerization inhibitorsEGFR kinase inhibitorscasein kinaseMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1114, p 1114 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	oindoles antiproliferative tubulin polymerization inhibitors EGFR kinase inhibitors casein kinase Medicine R Pharmacy and materia medica RS1-441
spellingShingle	oindoles antiproliferative tubulin polymerization inhibitors EGFR kinase inhibitors casein kinase Medicine R Pharmacy and materia medica RS1-441 Momen R. Fareed Mai E. Shoman Mohammed I. A. Hamed Mohamed Badr Hanin A. Bogari Sameh S. Elhady Tarek S. Ibrahim Gamal El-Din A. Abuo-Rahma Taha F. S. Ali New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
description	A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound <b>IC261</b>, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, <b>4b,</b> and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, <b>4e,</b> showed potent activity against the colon cancer COLO-205 cell line with an IC<sub>50</sub> value of 0.2 and 0.3 μM. A mechanistic study demonstrated <b>4b</b>’s efficacy in inhibiting microtubule assembly (IC<sub>50</sub> = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC<sub>50</sub> of 1.92 ± 0.09 μg/mL, <b>4b</b> inhibited CK1 almost as well as <b>IC261</b>. Additionally, <b>4b</b> and <b>4e</b> were effective inhibitors of EGFR-TK with IC<sub>50</sub>s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC<sub>50</sub> = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with <b>4b,</b> with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, <b>4b</b> and <b>4e</b> are considered promising potent multitarget agents against colon cancer that require optimization.
format	article
author	Momen R. Fareed Mai E. Shoman Mohammed I. A. Hamed Mohamed Badr Hanin A. Bogari Sameh S. Elhady Tarek S. Ibrahim Gamal El-Din A. Abuo-Rahma Taha F. S. Ali
author_facet	Momen R. Fareed Mai E. Shoman Mohammed I. A. Hamed Mohamed Badr Hanin A. Bogari Sameh S. Elhady Tarek S. Ibrahim Gamal El-Din A. Abuo-Rahma Taha F. S. Ali
author_sort	Momen R. Fareed
title	New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
title_short	New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
title_full	New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
title_fullStr	New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
title_full_unstemmed	New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
title_sort	new multi-targeted antiproliferative agents: design and synthesis of ic261-based oxindoles as potential tubulin, ck1 and egfr inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1fa090297e6e4a839f74fdf924fcba24
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New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

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