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.