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

Saketh S. Dinavahi, Raghavendra Gowda, Christopher G. Bazewicz, Madhu Babu Battu, Jyh Ming Lin, Robert J. Chitren, Manoj K. Pandey, Shantu Amin, Gavin P. Robertson, Krishne Gowda

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number111962
JournalEuropean Journal of Medicinal Chemistry
Volume187
DOIs
StatePublished - Feb 1 2020

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Aldehyde Dehydrogenase
Antineoplastic Agents
Protein Isoforms
Poisons
Cells
Isatin
G2 Phase Cell Cycle Checkpoints
Neoplastic Stem Cells
Stem cells
Multiple Myeloma
Drug Resistance
Aldehydes
Colonic Neoplasms
Lipid Peroxidation
Toxicity
Melanoma
Neoplasms
Apoptosis
Lipids

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Dinavahi, Saketh S. ; Gowda, Raghavendra ; Bazewicz, Christopher G. ; Battu, Madhu Babu ; Lin, Jyh Ming ; Chitren, Robert J. ; Pandey, Manoj K. ; Amin, Shantu ; Robertson, Gavin P. ; Gowda, Krishne. / Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents. In: European Journal of Medicinal Chemistry. 2020 ; Vol. 187.
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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.",
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Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents. / Dinavahi, Saketh S.; Gowda, Raghavendra; Bazewicz, Christopher G.; Battu, Madhu Babu; Lin, Jyh Ming; Chitren, Robert J.; Pandey, Manoj K.; Amin, Shantu; Robertson, Gavin P.; Gowda, Krishne.

In: European Journal of Medicinal Chemistry, Vol. 187, 111962, 01.02.2020.

Research output: Contribution to journalArticle

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T1 - Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents

AU - Dinavahi, Saketh S.

AU - Gowda, Raghavendra

AU - Bazewicz, Christopher G.

AU - Battu, Madhu Babu

AU - Lin, Jyh Ming

AU - Chitren, Robert J.

AU - Pandey, Manoj K.

AU - Amin, Shantu

AU - Robertson, Gavin P.

AU - Gowda, Krishne

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AB - 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.

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