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

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]58920 = −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 (SAs,SAs,SAs,SAs) 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of the oxygen atoms in the inorganic oxide have been replaced by methylene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 C2 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.