title: Enantiomeric resolution of albendazole sulfoxide by semipreparative HPLC and in vitro study of growth inhibitory effects on human cancer cell lines.
abstract: Analytical and semipreparative high performance liquid chromatography methods using polysaccharide-based chiral stationary phases were developed for the enantiomeric resolution of albendazol sulfoxide. The enantioseparation of this compound was evaluated with four chiral stationary phases: cellulose and amylose tris(3,5-dimethylphenylcarbamate), amylose tris[(S)-1-phenylethylcarbamate] and amylose tris(3,5-dimethoxyphenylcarbamate), under three elution conditions: normal, reversed-phase and polar organic mode. The influences of the mobile phase and of the structure of the chiral stationary phase on the enantiomeric separation are discussed. The best chiral performances were achieved on an amylose tris(3,5-dimethylphenylcarbamate) phase under normal (R(s)=4.96) and polar organic mode (R(s)=2.60 and 3.09). A polar organic condition using methanol as mobile phase offered shorter retention factors (k(1)=0.34) and was scaled up to semipreparative HPLC to obtain milligram quantities of both albendazole sulfoxide enantiomers for further in vitro studies. Optical rotation and circular dichroism of both enantiomers of albendazole sulfoxide was determined. The compounds ABZ, ABZ-SO, (R)-(+)-ABZ-SO and (S)-(-)-ABZ-SO were all evaluated regarding their capacity to inhibit the in vitro growth of three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma). In addition, the effect of the (R)-(+)-ABZ-SO compound in the cell cycle profile and apoptosis of MCF-7 cells were also studied. Results indicated that compound ABZ was the most potent regarding cell growth inhibition and that the (+)-(R)-ABZ was a more potent inhibitor of cell growth than the (S)-(-)-ABZ-SO, particularly in the MCF-7 cell line. In addition, the (R)-(+)-ABZ-SO significantly increased the levels of apoptosis of the MCF-7 cells.
authors.affiliation: Chemistry Department, Federal University of São Carlos, São Carlos, SP, Brazil.
authors.forename: Kátia Roberta A
authors.initials: KR
authors.lastname: Belaz
authors.forename: Marina
authors.initials: M
authors.lastname: Denadai
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Almeida
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
authors.forename: M Madalena
authors.initials: MM
authors.lastname: Pinto
authors.forename: Quezia B
authors.initials: QB
authors.lastname: Cass
authors.forename: Regina V
authors.initials: RV
authors.lastname: Oliveira
mesh_terms: D015766:Albendazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000871:Anthelmintics / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D002942:Circular Dichroism / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009904:Optical Rotation; D013237:Stereoisomerism
chemical_list: D000871:Anthelmintics; D000970:Antineoplastic Agents; D015766:Albendazole; C027186:albendazole sulfoxide