Synthesis, properties, and reactivity of cocaine benzoylthio ester possessing the cocaine absolute configuration.
One aspect of immunopharmacotherapy for cocaine abuse involves the use of a catalytic monoclonal antibody (mAb) to degrade cocaine via hydrolysis of the benzoate ester. A cocaine benzoylthio ester analogue provides a means to implement high-throughput selection strategies to potentially isolate mAbs with high activity. The required analogue was synthesized starting from (-)-cocaine hydrochloride and possessed the cocaine absolute configuration. Key points in the preparation were the introduction of the sulfur atom at C-3 via a bromomagnesium thiolate addition to the exo face of anhydroecgonine, separation of C-2 diastereomers, recycling of a C-2 thio ester byproduct, and formation of the necessary C-2 methyl and C-3 benzoylthio esters. Effects resulting from the lower electronegativity and greater hydrophobicity of sulfur compared to oxygen were observed. These characteristics could result in interesting drug properties. Furthermore, the analogue was found to be a substrate for catalytic mAbs that hydrolyze cocaine as monitored by HPLC and also spectrophotometry by coupling cleavage of the benzoylthio ester to the disulfide exchange with Ellman's reagent. Screening antibody libraries with the new cocaine analogue using the spectroscopic assay provides an avenue for the high-throughput identification of catalysts that efficiently breakdown cocaine.
Isomura
Shigeki
S
Department of Chemistry BCC-582, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Hoffman
Timothy Z
TZ
Wirsching
Peter
P
Janda
Kim D
KD
D017151:Antibodies, Catalytic / Q000737:chemistry / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000628:therapy; D006801:Humans; D008968:Molecular Conformation
D017151:Antibodies, Catalytic; D000911:Antibodies, Monoclonal; C114395:cocaine benzoyl thioester; D003042:Cocaine