Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors

Aouad, Mohamed Reda; Al-Mohammadi, Hannan Musallam; Al-blewi, Fawzia Faleh; Ihmaid, Saleh; Elbadawy, Hossein M.; Thagfan, Sultan S. Al; Rezki, Nadjet

doi:10.1016/j.bioorg.2019.103446

Cited by 28 publications

(11 citation statements)

References 48 publications

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“…The discovery of a single compound that has both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory capabilities was spurred by clinical evidence for the efficacy of tyrosine kinase inhibitors in combination with microtubule-targeting medicines in cancer therapy [62]. Several researches report this principle in designing dual EGFR/tubulin polymerization inhibitors [64][65][66][67].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, 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, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, 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, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…The derivative 26 f with the substitution of 4‐fluoro exhibited fair antiproliferative activity against breast cancer cells like MCF‐7 (1.21 μM). The hybrid 26 i with the substitution of 4‐nitro‐2‐chloro showed remarkable activity against breast cancer cells like MDA‐MB‐231 (1.65 μM) [44] …”

Section: Imidazole Hybridizes With Other Anticancer Pharmacophoresmentioning

confidence: 99%

Hybridization of Imidazole with Various Heterocycles in Targeting Cancer: A Decade's Work

Teli¹,

Chawla²

2021

ChemistrySelect

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Cancer is the world‘s biggest global health concern. The prevalence and mortality rates of cancer remain high despite significant progress in cancer therapy. The search for more effective, as well as less toxic treatment methods for cancer, is at the focus of current studies. Approximately 24.6 million people are suffering from cancer across the world as per the world health organization (WHO). In the year 2020, approximately 10 million deaths were reported due to cancer which has emerged as the second leading cause of mortality across the globe. Anticancer medicines have played a pivotal role in the medication of different types of cancers; however, they are associated with several side effects and relevance of drug resistance which evoke an immediate need for designing of new anticancer agents with multitargeted effect. Imidazole is a heterocyclic compound privileged with considerable anticancer activities and some imidazole derivatives have already got approval to treat cancer. Many hybrid molecules are available that play an important role in the treatment of cancer like chalcone, pyrazole, purine, triazine etc., and their pharmacophore provide the anticancer drug with low drug resistance and high efficacy, with low chances of toxicity and side effects. This review provides various approaches for the drug development of new safe and efficient antitumor agents imidazole hybrids with other heterocyclic moieties. An attempt has been made to advancement of the anticancer potential of the derivatives and hybrids of imidazole having intact or condensed imidazole moiety in the last decade along with the structure‐activity relationship studies, and mechanism of action.

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“…A literature survey discloses that there are few reports for the synthesis of triazolothiazines. Triazole fused with thiazine ring system possess anti‐inflammatory, [4a] cytotoxic, [4b] anti‐tumor, [4c] anti‐bacterial [4d] and anti‐fungal [4e] activities (Figure 1). Peter and co‐workers have reported [5] triazolo[5,1‐ b ]thiazinones in fair to good yield from the reaction of 1,2,4‐triazole‐3‐thiols and diethyl ethoxy‐methylenemalonate.…”

Section: Figurementioning

confidence: 99%

AlCl₃‐Catalyzed Synthesis of Triazolo[5,1‐b]thiazines

2021

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Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors

Cited by 28 publications

References 48 publications

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

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

Hybridization of Imidazole with Various Heterocycles in Targeting Cancer: A Decade's Work

AlCl₃‐Catalyzed Synthesis of Triazolo[5,1‐b]thiazines

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Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors

Cited by 28 publications

References 48 publications

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

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

Hybridization of Imidazole with Various Heterocycles in Targeting Cancer: A Decade's Work

AlCl3‐Catalyzed Synthesis of Triazolo[5,1‐b]thiazines

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AlCl₃‐Catalyzed Synthesis of Triazolo[5,1‐b]thiazines