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

Abstract

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.

A Comprehensive Computational NMR Analysis of Organic Polyarsenicals including the Marine Sponge-Derived Arsenicins A–D and Their Synthetic Analogs

“…Our interest has been focused on the computational analysis of NMR data of polyarsenicals, peculiar for the intriguing rigid cage of the structures of arsenicins A-D (Figures 1 and 2). In our study we have included also the dimethyl compound 5 as a representative example of alkyl analogs, but not the known diethyl and dipropyl arsenicals [10] which would have involved the evaluation of the possible conformations on the alkyl chain. Each structure's geometry was minimized by using B1B95/6-311+G(3df,2pd) as a combination of electronic correlation functional and basis set, in chloroform, via a Conductorlike Polarized Continuum Model (C-PCM), obtaining no vibrational imaginary wave number modes as indication of a reached minimum in the potential energy surface.…”

“…Drugs 2023, 21, x 10 of 13 [11]. The data for the S-series (6)(7)(8)(9)(10)(11)(12) are between 0.94 and 3.51 ppm, with the best value of 0.94 ppm for M06-L/aug-cc-p-VTZ/GIAO. They must be compared with the values in the range 4.77-5.56 reported in the case of S-polyarsenicals 6-8 [12] and 10-12 [10].…”

“…Very recently, the polyarsenical 5 and its diethyl and dipropyl analogs, made available via a selective synthesis starting from arsenic trioxide, the suitable carboxylic acid and the corresponding anhydride, have been evaluated as inhibitors of glioblastoma stem cells, and are recognized as a promising therapeutic target in glioblastoma treatment. By showing submicromolar GI 50 values and high selectivity toward non-tumor cell lines, these alkyl polyarsenicals are very promising for further biological evaluation [10].…”

“…The products 10-12 (Figure 3) have recently been obtained from the dimethyl analog 5 via a similar procedure, and characterized using NMR DFT calculations. However, their very poor water solubility, observed to be affected by replacing oxygen with sulfur atoms in the structural cages, prevented the biological evaluation of these polyarsenicals through in vitro screening [10]. Besides the compounds 6 and 8, the sulfur-containing polyarsenical 9 (Figure 3) was obtained by reacting arsenicin A with aqueous sodium sulfide, its structure confirmed by single-crystal X-ray diffraction data and evaluated as an acute PML inhibitor, proving to be more active than arsenicin A [13].…”

“…The products 10-12 (Figure 3) have recently been obtained from the dimethyl analog 5 via a similar procedure, and characterized using NMR DFT calculations. However, their very poor water solubility, observed to be affected by replacing oxygen with sulfur atoms in the structural cages, prevented the biological evaluation of these polyarsenicals through in vitro screening [10]. Fifteen years after the first NMR calculation was applied to arsenicin A's structure [11], we now report a comprehensive study on DFT-calculated NMR analysis of the whole series of arsenicin-like polyarsenicals, which in the meantime is enriched by natural and synthetic analogs of promising interest for their antitumor activities [14].…”