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  3. Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents

Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents

  • Eur J Med Chem. 2020 Feb 1;187:111962. doi: 10.1016/j.ejmech.2019.111962.
Saketh S Dinavahi 1,  Raghavendra Gowda 1,  Christopher G Bazewicz 2,  Madhu Babu Battu 3,  Jyh Ming Lin 4,  Robert J Chitren 5,  Manoj K Pandey 5,  Shantu Amin 6,  Gavin P Robertson 7,  Krishne Gowda 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
  • 2 Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; College of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
  • 3 Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad, 500039, India.
  • 4 Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
  • 5 Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, 08103, United States.
  • 6 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
  • 7 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
  • 8 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States. Electronic address: [email protected].
PMID: 31887569 DOI: 10.1016/j.ejmech.2019.111962
Abstract

The aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes that are overexpressed in various cancers. Increased expression of ALDH is associated with poor prognosis, stemness, and drug resistance. Because of the critical role of ALDH in Cancer Stem Cells, several ALDH inhibitors have been developed. Nonetheless, all these inhibitors either lack efficacy or are too toxic or have not been tested extensively. Thus, the continued development of ALDH inhibitors is warranted. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin backbone. The early molecular docking studies and enzymatic tests revealed that 3(a-l) and 4(a-l) are the potent ALDH1A1, ALDHA2, and ALDH3A1 inhibitors. ALDH inhibitory IC50s of 3(a-l) and 4(a-l) were 230 nM to >10,000 nM for ALDH1A1, 939 nM to >10,000 nM for ALDH2 and 193 nM to >10,000 nM for ALDH3A1. The most potent compounds 3(h-l) had IC50s for killing melanoma cells ranged from 2.1 to 5.7 μM, while for colon Cancer cells, it ranged from 2.5 to 5.8 μM and for multiple myeloma cells ranging from 0.3 to 4.7 μM. Toxicity studies of 3(h-l) revealed that 3h to be the least toxic multi-ALDH isoform inhibitor. Mechanistically, 3(h-l) caused increased ROS activity, lipid peroxidation, and toxic aldehyde accumulation, secondary to potent multi-ALDH isoform inhibition leading to increased Apoptosis and G2/M cell cycle arrest. Together, the study details the design, synthesis, and evaluation of potent, multi-isoform ALDH inhibitors to treat cancers.

Keywords

Aldehyde dehydrogenases; Cancer therapeutics; Colon cancer; Drug design; Drug development; Molecular docking; Multiple myeloma.

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