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

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% 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A is reminiscent of arsenic(III) oxide (As4O6), but where three of the oxygen atoms in the inorganic oxide have been replaced by methylene groups in a chiral C 2 arrangement.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.

Sulfur Derivatives of the Natural Polyarsenical Arsenicin A: Biologically Active, Organometallic Arsenic–Sulfur Cages Related to the Minerals Realgar and Uzonite

“…The compounds (±)-1 and the hexaiodoarsine 5 were synthesized as previously described. 9 (R* As ,R* As ,S* As ,S* As )-2-Thia-1,3,5,7-tetraarsatricyclo-[3.3.0.0 3,7 ]octane, (±)-4. A solution of Na 2 S.9H 2 O (4.0 g, 16.7 mmol) in water (10 mL) was added to a solution of (±)-1 (0.20 g, 0.51 mmol) in benzene (20 mL) under nitrogen.…”

“…The enantiomers of (±)-1 are configurationally stable in dichloromethane containing a trace of triethylamine but are sensitive to acid-catalyzed racemization by a mechanism that is considered to involve the inversion of aquated arsenium ions. 9 It is noteworthy that the yeast Scopulariopsis brevicaulis, when growing on bread treated with aqueous ethyl(n-propyl)arsinic acid, synthesizes As-chiral (S)-ethylmethyl(n-propyl)arsine by reductive methylation with 60% enantioselectivity. 10 Nevertheless, (±)-1 is the first natural arsenical to be isolated that contains a chiral arsenic stereocenter.…”

“…11 In a recent investigation, we demonstrated that (±)-1 exhibits a 21-fold greater inhibition of the induction of proliferation arrest and induces cell death at a 27-fold lower concentration in the APL cell line (NB4) than the current "arsenical gold standard", arsenic(III) oxide as Trisenox. 9 We have now synthesized three sulfur derivatives of (±)-1 by reacting it with aqueous sodium sulfide in benzene. The heated mixture produces, by reductive desulfurization of the intermediate sulfur analog (±)-2, the chiral monosulfide (±)-4, which contains two As−As bonds and is structurally related to the mineral realgar (α-As 4 S 4 ), whereas the reaction at room temperature affords a separable mixture of diastereomeric chiral disulfides (±)-3a and (±)-3b, each of which contains a single As−As bond and is structurally related to the mineral uzonite (As 4 S 5 ).…”

“…The photoelectronic spectra reveal that each of the arsenic−sulfur cages absorbs UV radiation in the absence of an obvious chromophore, as is the case for the parent compound (±)-1. 9 The spectrum of the monosulfide (±)-4 contains peaks at λ max /nm [CH 2 Cl 2 (ε/ (dm 3 mol −1 cm −1 ))]: 322 (942), 278 (6017), 249 (17 527), and 236 (16 650). The spectra of the disulfides (±)-3a and (±)-3b contain peaks at 309 (2229), 280 (3942), 256 (6113), and 232 (10 405), and 315 (1680), 280 (2866), 248 (5228), and 231 (8110), respectively.…”

“…15 Biological Activity. We have shown previously that the parent arsenical (±)-1 (AsA) is more potent than arsenic(III) 9 We have now demonstrated that the monosulfide (±)-4 is an ca. 3-fold better inhibitor than the parent (±)-1 for these cells.…”