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

Shamsudin NF 1 , Leong SW 2 , Koeberle A 3 , Suriya U 4 , Rungrotmongkol T 4 , Chia SL 5 Show all authors , Taher M 6 , Haris MS 6 , Alshwyeh HA 7 , Alosaimi AA 8 , Mediani A 9 , Ilowefah MA 10 , Islami D 11 , Mohd Faudzi SM 12 , Fasihi Mohd Aluwi MF 13 , Wai LK 14 , Rullah K 1

Affiliations 

  • 1 Drug Discovery & Synthetic Chemistry Research Group, Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, Bandar Indera Mahkota, Kuantan 25200, Pahang, Malaysia
  • 2 Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
  • 3 Michael Popp Institute & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria
  • 4 Structural & Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
  • 5 UPM - MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
  • 6 Department of Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan 25200, Pahang, Malaysia
  • 7 Basic & Applied Scientific Research Centre, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
  • 8 Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
  • 9 Institute of Systems Biology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Malaysia
  • 10 Department of Food Technology, Faculty of Food Science, Wadi Alshatti University, Libya
  • 11 Faculty of Pharmacy & Health Sciences, Universitas Abdurrab, Jalan Riau Ujung, Pekanbaru 28292, Riau, Indonesia
  • 12 Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia
  • 13 Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, Gambang 26300, Pahang, Malaysia
  • 14 Drugs & Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia
Future Med Chem, 2024 Aug 02;16(15):1499-1517.
PMID: 38949858 DOI: 10.1080/17568919.2024.2363668

Abstract

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 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 μM). 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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