The Hybrid Pyrroloisoindolone-Dehydropyrrolizine Alkaloid (-)-Chlorizidine A Targets Proteins within the Glycolytic Pathway.
The cytotoxic activity of (-)-chlorizidine A, a marine alkaloid containing a unique fusion between a pyrroloisoindolone and dehydropyrrolizine, was explored by using a combination of cellular and molecular methods. Our studies began by applying preliminary SAR evidence gathered from semisynthetic bioactivity evaluations to prepare an active immunoaffinity fluorescent (IAF) probe. This probe was then used to identify two cytosolic proteins, GAPDH and hENO1, as the targets of (-)-chlorizidine A.
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093-0204, USA.
Xavier
X
Álvarez-Micó
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.
Danilo D
DD
Rocha
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.
Larissa A
LA
Guimarães
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, AZ, 85721, USA.
Andrew
A
Ambrose
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, AZ, 85721, USA.
Eli
E
Chapman
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.|Departamento de Farmacologia, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.
Leticia V
LV
Costa-Lotufo
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093-0358, USA. jlaclair@ucsd.edu.
James J
JJ
La Clair
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093-0204, USA. wfenical@ucsd.edu.
William
W
Fenical
D000595:Amino Acid Sequence; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010751:Phosphopyruvate Hydratase / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D001688:Biological Products; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D026121:Indole Alkaloids; D011506:Proteins; D025521:Tumor Suppressor Proteins; C581611:chlorizidine; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase
drug discovery; enolase; glycolysis; mode of action; natural products