Sulfur Derivatives of the Natural Polyarsenical Arsenicin A: Biologically Active, Organometallic Arsenic–Sulfur Cages Related to the Minerals Realgar and Uzonite

• Published in: Organometallics 2015-03, Vol.34 (5), p.829-840
• Main Authors: Lu, Di, Arulmozhiraja, Sundaram, Coote, Michelle L, Rae, A. David, Salem, Geoff, Willis, Anthony C, Wild, S. Bruce, Benhenda, Shirine, Breitenbach, Valerie Lallemand, de Thé, Hugues, Zhai, Xiaoyi, Hogg, Philip J, Dilda, Pierre J
• Format: Article
• Language: English
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/om500829y

(±)-Arsenicin A (AsA), (±)-1, the first natural polyarsenical to be isolated, has the adamantane-type structure of the mineral arsenolite (As4O6), in which three of the oxygen atoms have been replaced by methylene groups to give an organometallic, arsenic–oxygen cage of C 2 symmetry. Heating of a benzene solution of AsA with aqueous sodium sulfide produces, by reductive desulfurization of the intermediate sulfur analog (±)-2, the monosulfide cage (±)-4, which contains two As–As bonds and which has a C 2-chiral cage structure related to the mineral realgar (α-As4S4). At room temperature the reaction affords a chiral disulfide derivative that exists as a pair of separable diastereomers, (±)-3a and (±)-3b, each of which contains a single As–As bond and is structurally related to the mineral uzonite (As4S5). The crystal structures of the monosulfide (±)-4 and the diastereomeric disulfides (±)-3a and (±)-3b have been determined. As for AsA, the sulfur derivatives exhibit strong UV absorptions and can be resolved on a Chiralpak IA column. The monosulfur cage (±)-4 is considerably more potent and more selective than AsA and the current “arsenical gold standard”, arsenic(III) oxide as Trisenox, against the acute promelocytic leukemia cells (NB4) and certain solid cancer cell lines.