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

Di Lu, Michelle L. Coote, Junming Ho, Nathan L. Kilah, Ching Yeh Lin, Geoff Salem, Michelle L. Weir, Anthony C. Willis, S. Bruce Wild, Pierre J. Dilda

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22 Citations (Scopus)

Abstract

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% NEt 3/CH 2Cl 2). (S)-(-)-Arsenicin A, having an mp of 241-242 °C from dichloromethane, crystallizes in the space group P2 12 12 1 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A is reminiscent of arsenic(III) oxide (As 4O 6), but where three of the oxygen atoms in the inorganic oxide have been replaced by methylene groups in a chiral C 2 arrangement.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 P1̄: 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.

Original languageEnglish
Pages (from-to)1808-1816
Number of pages9
JournalOrganometallics
Volume31
Issue number5
DOIs
Publication statusPublished - 12 Mar 2012
Externally publishedYes

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