A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer

被引：2

作者：

Shamsudin, Nur Farisya ^{[1
]}

Leong, Sze-Wei ^{[2
]}

Koeberle, Andreas ^{[3
,4
]}

Suriya, Utid ^{[5
]}

Rungrotmongkol, Thanyada ^{[5
]}

Chia, Suet Lin ^{[6
]}

Taher, Muhammad ^{[7
]}

Haris, Muhammad Salahuddin ^{[7
]}

Alshwyeh, Hussah Abdullah ^{[8
,9
]}

Alosaimi, Areej A. ^{[9
]}

Mediani, Ahmed ^{[10
]}

Ilowefah, Muna Abdulsalam ^{[11
]}

Islami, Deri ^{[12
]}

Faudzi, Siti Munirah Mohd ^{[12
]}

Aluwi, Mohd Fadhlizil Fasihi Mohd ^{[13
]}

Wai, Lam Kok ^{[14
]}

Rullah, Kamal ^{[1
]}

机构：

[1] Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kulliyyah Pharm, Drug Discovery & Synthet Chem Res Grp, Kuantan 25200, Pahang, Malaysia

[2] Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia

[3] Univ Innsbruck, Michael Popp Inst, Innsbruck, Austria

[4] Univ Innsbruck, Ctr Mol Biosci Innsbruck CMBI, A-6020 Innsbruck, Austria

[5] Chulalongkorn Univ, Fac Sci, Dept Biochem, Struct & Computat Biol Res Unit, Bangkok 10330, Thailand

[6] Univ Putra Malaysia, Inst Biosci, UPM MAKNA Canc Res Lab, Serdang 43400, Selangor, Malaysia

[7] Int Islamic Univ Malaysia, Dept Pharmaceut Technol, Kulliyyah Pharm, Jalan Sultan Ahmad Shah, Kuantan 25200, Pahang, Malaysia

[8] Imam Abdulrahman Bin Faisal Univ, Basic & Appl Sci Res Ctr, Dammam 31441, Saudi Arabia

[9] Imam Abdulrahman Bin Faisal Univ, Coll Sci, Dept Biol, Dammam 31441, Saudi Arabia

[10] Univ Kebangsaan Malaysia, Inst Syst Biol, Bangi 43600, Malaysia

[11] Wadi Alshatti Univ, Fac Food Sci, Dept Food Technol, Tripoli, Libya

[12] Univ Abdurrab, Fac Pharm & Hlth Sci, Jalan Riau Ujung, Pekanbaru 28292, Riau, Indonesia

[13] Univ Putra Malaysia, Inst Biosci, Lab Nat Prod, Serdang 43400, Selangor, Malaysia

[14] Univ Kebangsaan Malaysia, Fac Pharm, Drugs & Herbal Res Ctr, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia

来源：

FUTURE MEDICINAL CHEMISTRY | 2024年 / 16卷 / 15期

关键词：

apoptosis; autophagy; chromone; colon cancer; ULK1; inhibitor; NF-KAPPA-B; MOLECULAR-DYNAMICS; MEMBRANE PERMEABILIZATION; ISOFLAVONOIDS; PATHWAY; DISCOVERY; PI3K/AKT; SCAFFOLD; COMPLEX; STRESS;

D O I：

10.1080/17568919.2024.2363668

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aim: Chromones are promising for anticancer drug development. Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC50 3.2 mu M) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 mu M). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1. Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs. [GRAPHICS] .

引用

页码：1499 / 1517

页数：19

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