Expanding the Chemical Space of Arsenicin A-C Related Polyarsenicals and Evaluation of Some Analogs as Inhibitors of Glioblastoma Stem Cell Growth
Jacopo Vigna,
Denise Sighel,
Emanuele Filiberto Rosatti,
Andrea Defant,
Michael Pancher,
Viktoryia Sidarovich,
Alessandro Quattrone,
Ines Mancini
Affiliations
Jacopo Vigna
Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy
Denise Sighel
Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
Emanuele Filiberto Rosatti
Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
Andrea Defant
Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy
Michael Pancher
High Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
Viktoryia Sidarovich
High Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
Alessandro Quattrone
Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
Ines Mancini
Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy
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 Echinochalina bargibanti 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 GI50 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.
