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Resolution and improved synthesis of (±)-arsenicin A: A natural adamantane-type tetraarsenical possessing strong anti-acute promelocytic leukemia cell line activity
journal contribution
posted on 2023-05-17, 17:15 authored by Lu, D, Coote, ML, Ho, J, Nathan KilahNathan Kilah, Lin, CY, Salem, G, Weir, ML, Willis, AC, Wild, SB, Dilda, PJThe resolution and improved synthesis of the naturally occurring, adamantanetype, 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 /CH2 Cl2 ). (S)-(−)-Arsenicin A, having an mp of 241−242 °C from dichloromethane, crystallizes in the space group P21 21 21 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A is reminiscent of arsenic(III) oxide (As4 O6 ), but where three of the oxygen atoms in the inorganic oxide have been replaced by methylene groups in a chiral C2 arrangement.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 P1 ̅: 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.
History
Publication title
OrganometallicsVolume
31Issue
5Pagination
1808-1816ISSN
0276-7333Department/School
School of Natural SciencesPublisher
Amer Chemical SocPlace of publication
1155 16Th St, Nw, Washington, USA, Dc, 20036Rights statement
Copyright 2012 American Chemical SocietyRepository Status
- Restricted