Arsenicin A : synthesis, derivatisation and biological activity
Creators: name: Lu, Di
Publisher: name: Canberra, ACT : The Australian National University
Year: 2012
Subjects: subject: QD412.A7 L8 2012
subject: Organoarsenic compounds
subject: Organoarsenic compounds Synthesis
subject: Structure-activity relationships (Biochemistry)

description: The improved synthesis and resolution of the first naturally occurring polyarsenical, Arsenicin A [As₄0₃(CH₂)₃] has been achieved. The putative structure of Arsenicin A resembled that of arsenic(III) oxide (As40 6) , but where three of the oxygen atoms in the inorganic oxide had been replaced by methylene groups in a chiral C2 arrangement. The five-step synthesis involves reduction of methylenebis(phenylarsinic acid) to the bis( secondary arsine) (RAs * ,RAs *)-( ± )/(RAs * ,S As *)-CH2[ AsHPh h followed by deprotonation and reaction of the resulting diarsenide with ( chloromethyl)diphenylarsine to give the tetra( tertiary arsine) (RAs * ,RAs *)-( ± )l(RAs * ,S As *)-CH2[ AsPh(CH2AsPh2) )i. Replacement of the six phenyl groups in the tetra(tertiary arsine) with iodine was accomplished by reaction with anhydrous hydrogen iodide to give the hexaiodoarsine ( RAs *, RAs *)-( ± )/ ( RAs * ,S As *)-CH2 [ Asl(CH2Ash) ]i, crystals of the (RAs * ,S As*) diastereomer being characterised by X-ray crystallography. Hydrolysis of the hexaiodoarsine with aqueous ammonia gives (±)-Arsenicin A as colourless air- and moisture-stable crystals in an overall yield of 36% after column chromatography and recrystallisation from benzene. (±)-Arsenicin A exhibits strong absorptions in the UV region, even though the molecule contains no obvious chromophore. A theoretical investigation revealed that the absorption was facilitated by through-space and through-bond interactions between lone pairs on the arsenic and oxygen atoms and the organometallic framework of the molecule. (±)Arsenicin A was resolved with &gt;99% efficiency by preparative chiral HPLC on a Chiralpak IA column with use of dichloromethane as eluent and the structure and absolute configuration of(S)-(- )-Arsenicin A were established by X-ray crystallography. The individual enantiomers of (±)-Arsenicin A racernise in solution in the presence of traces of acid and high-level ab initio calculations have been carried out 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 (APL) cell line than the current "arsenical gold standard", arsenic(III) oxide (Trisenox®). Treatment of a benzene solution of (±)-Arsenicin A with aqueous sodium sulfide produces first the trisulfur analogue (±)-Arsenicin A-S3 (AsA-83) (not isolated), which undergoes reductive desulfurisation with excess sulfide to give the disulfide (±)Arsenicin A-S2 and then the monosulfide (±)-Arsenicin A-S1 (AsA-81). The derivative (±)-Arsenicin A-S2 exists as a pair of separable diastereomers, (±)-Arsenicin A-a-S2 (AsA-a-82) and (±)-Arsenicin A-{3-S2 (AsA-iS-82). The crystal structures of AsA-a-82, AsA-Jj-82 and AsA-81 have been determined. The disulfides have the cage-like structure of the mineral uzonite (As4Ss) in which there is a single As-As bond; the disulfide diastereomers each contain four chiral arsenic stereocentres. The monosulfide cage AsA- 81 contains two As- As bonds and has a structure related to the mineral realgar (a-As4S4) in which three of the sulfur atoms have been replaced by methylene groups in a Ci-chiral arrangement. As found for (±)-Arsenicin A, the sulfur derivatives exhibit strong UV absorptions and can be resolved on a Chiralpak IA column. The selenium derivatives(±)Arsenicin A-Se1 (AsA-8e1), (±)-Arsenicin A-a-Se2 (AsA-a-8e2) and (±)-Arsenicin A-{3- Se2 (AsA-Jj-8e2) have been synthesised by the reaction of a benzene solution of(±)Arsenicin A with sodium hydrogen selenide. The crystal structure of the monoselenide AsA-8e1 was determined and shown to have the realgar-type, cage structure. Preliminary results indicate that AsA-81 and AsA-8e1 are considerably more potent against the acute promelocytic leukemia cell line than arsenic(III) oxide and all histotypes of ovarian cancer cell lines tested than the standard chemotherapeutic drugs, cisplatin and carboplatin.