Expanding the Chemical Space of Arsenicin A-C Related Polyarsenicals and Evaluation of Some Analogs as Inhibitors of Glioblastoma Stem Cell Growth

The marine polyarsenical metabolite arsenicin A is the landmark of a series of natural and synthetic molecules characterized by an adamantane-like tetraarsenic cage. Arsenicin A and related polyarsenicals have been evaluated for their antitumor effects in vitro and have been proven more potent than...

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Bibliographic Details
Published in:Marine drugs 2023-03, Vol.21 (3), p.186
Main Authors: Vigna, Jacopo, Sighel, Denise, Rosatti, Emanuele Filiberto, Defant, Andrea, Pancher, Michael, Sidarovich, Viktoryia, Quattrone, Alessandro, Mancini, Ines
Format: Article
Language:English
Subjects:
Acids
Adamantane - therapeutic use
Analogs
Anticancer properties
antitumor
Antitumor activity
Antitumour agents
Arsenic
Arsenic trioxide
Arsenic Trioxide - pharmacology
Arsenic Trioxide - therapeutic use
As-S cage
Brain cancer
Brain Neoplasms - drug therapy
Cages
calculated NMR spectrum
Cancer therapies
Cell Line, Tumor
Cell lines
Chemical properties
Drug therapy
FDA approval
Glioblastoma
Glioblastoma - drug therapy
Glioblastoma - pathology
Glioblastoma multiforme
Health aspects
Humans
Hypoxia
Leukemia
marine metabolite
Metabolites
NMR
Nuclear magnetic resonance
polyarsenical
Stem Cells
Structural analysis
Therapeutic targets
Tumor cell lines
Tumors
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Summary:The marine polyarsenical metabolite arsenicin A is the landmark of a series of natural and synthetic molecules characterized by an adamantane-like tetraarsenic cage. Arsenicin A and related polyarsenicals have been evaluated for their antitumor effects in vitro and have been proven more potent than the FDA-approved arsenic trioxide. In this context, we have expanded the chemical space of polyarsenicals related to arsenicin A by synthesizing dialkyl and dimethyl thio-analogs, the latter characterized with the support of simulated NMR spectra. In addition, the new natural arsenicin D, the scarcity of which in the extract had previously limited its full structural characterization, has been identified by synthesis. The dialkyl analogs, which present the adamantane-like arsenicin A cage substituted with either two methyl, ethyl, or propyl chains, were efficiently and selectively produced and evaluated for their activity on glioblastoma stem cells (GSCs), a promising therapeutic target in glioblastoma treatment. These compounds inhibited the growth of nine GSC lines more potently than arsenic trioxide, with GI values in the submicromolar range, both under normoxic and hypoxic conditions, and presented high selectivity toward non-tumor cell lines. The diethyl and dipropyl analogs, which present favorable physical-chemical and ADME parameters, had the most promising results.
ISSN:1660-3397
1660-3397
DOI:10.3390/md21030186