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Identification of Novel Isatin Derivative Bearing a Nitrofuran Moiety as Potent Multi-Isoform Aldehyde Dehydrogenase Inhibitor.
Gowda, Krishne; Raza, Asif; Vangala, Venugopal; Lone, Nazir Ahmad; Lin, Jyh Ming; Singh, Jaikee Kumar; Srivastava, Sandeep Kumar; Schell, Todd D; Robertson, Gavin P; Amin, Shantu; Sharma, Arun K.
Afiliação
  • Gowda K; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
  • Raza A; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
  • Vangala V; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
  • Lone NA; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
  • Lin JM; Department of Biochemistry and Molecular Biology, Penn State Cancer Institute, Penn State College of Medicine Hershey, Hershey, PA 17033, USA.
  • Singh JK; Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India.
  • Srivastava SK; Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India.
  • Schell TD; Department of Microbiology and Immunology, Penn State Cancer Institute, Penn State College of Medicine Hershey, Hershey, PA 17033, USA.
  • Robertson GP; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
  • Amin S; Departments of Pathology, Dermatology, Surgery, Melanoma Skin Cancer Center, Penn State Cancer Institute, Penn State College of Medicine Hershey, Hershey, PA 17033, USA.
  • Sharma AK; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
Molecules ; 29(13)2024 Jun 29.
Article em En | MEDLINE | ID: mdl-38999066
ABSTRACT
Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aldeído Desidrogenase / Inibidores Enzimáticos / Simulação de Acoplamento Molecular / Isatina Limite: Humans Idioma: En Revista: Molecules Assunto da revista: BIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: CH / SUIZA / SUÍÇA / SWITZERLAND

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aldeído Desidrogenase / Inibidores Enzimáticos / Simulação de Acoplamento Molecular / Isatina Limite: Humans Idioma: En Revista: Molecules Assunto da revista: BIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: CH / SUIZA / SUÍÇA / SWITZERLAND