Resolution and Improved Synthesis of (±)-Arsenicin A: A Natural Adamantane-Type Tetraarsenical Possessing Strong Anti-Acute Promelocytic Leukemia Cell Line Activity

• Published in: Organometallics Vol. 31; no. 5; pp. 1808 - 1816
• Main Authors: Lu, Di, Coote, Michelle L, Ho, Junming, Kilah, Nathan L, Lin, Ching-Yeh, Salem, Geoff, Weir, Michelle L, Willis, Anthony C, Wild, S. Bruce, Dilda, Pierre J
• Format: Journal Article
• Language: English
• Published: American Chemical Society 12.03.2012
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/om201180d

The resolution and improved synthesis of the naturally occurring, adamantane-type, tetraarsenical (±)-Arsenicin A is reported. The five-step synthesis of (±)-Arsenicin A from methylenebis(phenylarsinic acid) affords (±)-Arsenicin A as air-stable, colorless crystals having an mp of 182–184 °C after column chromatography and recrystallization from benzene (overall yield: 36%). The resolution of (±)-Arsenicin A was achieved by preparative HPLC on a Chiralpak IA column with the use of dichloromethane as eluent to give both enantiomers in >99% enantiomeric purity (HPLC); the isolated enantiomers had [α]589 20 = −60.2 and +62.3 (0.01% NEt3/CH2Cl2). (S)-(−)-Arsenicin A, having an mp of 241–242 °C from dichloromethane, crystallizes in the space group P212121 with one molecule having the (S As,S As,S As,S As) or overall S configuration in the asymmetric unit. The adamantane-type structure of (±)-Arsenicin A is reminiscent of arsenic(III) oxide (As4O6), but where three of the oxygen atoms in the inorganic oxide have been replaced by methylene groups in a chiral C 2 arrangement. ((±)-Arsenicin A, mp 182–184 °C, crystallizes from benzene in the centrosymmetrical space group P1̅: the unit cell of the crystal contains two independent pairs of molecules, the molecules in each pair being related by an inversion center.) The individual enantiomers of (±)-Arsenicin A racemize in the presence of traces of acid, and high-level ab initio calculations have been performed to examine the mechanism of the process. (±)-Arsenicin A exhibits a 21-fold greater inhibition of the induction of proliferation arrest and induces cell death at a 27-fold lower concentration in the acute promyelocytic leukemia cell line than the current “arsenical gold standard”, arsenic(III) oxide (Trisenox). (±)-Arsenicin A is also more potent than arsenic(III) oxide for the induction of proliferation arrest in two other cancers with particularly bad prognoses: pancreatic adenocarcinoma and glioblastoma.