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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

Citation

Lu, D and Coote, ML and Ho, J and Kilah, NL and Lin, CY and Salem, G and Weir, ML and Willis, AC and Wild, SB and Dilda, PJ, Resolution and improved synthesis of (±)-arsenicin A: A natural adamantane-type tetraarsenical possessing strong anti-acute promelocytic leukemia cell line activity, Organometallics, 31, (5) pp. 1808-1816. ISSN 0276-7333 (2012) [Refereed Article]

Copyright Statement

Copyright 2012 American Chemical Society

DOI: doi:10.1021/om201180d

Abstract

The 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A is reminiscent of arsenic(III) oxide (As4 O6 ), but where three of the oxygen atoms in the inorganic oxide have been replaced by methylene groups in a chiral C2 arrangement.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.

Item Details

Item Type:Refereed Article
Research Division:Chemical Sciences
Research Group:Inorganic Chemistry
Research Field:Bioinorganic Chemistry
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Chemical Sciences
Author:Kilah, NL (Dr Nathan Kilah)
ID Code:84231
Year Published:2012
Web of Science® Times Cited:14
Deposited By:Chemistry
Deposited On:2013-04-30
Last Modified:2017-10-25
Downloads:0

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