title: An assembly concept for the consecutive introduction of unsymmetrical disulfide bonds: synthesis of a releasable multidrug conjugate of folic acid.
abstract: We describe the development of methodology which allows for the introduction of a second disulfide bond into a molecular framework with a pre-existing disulfide linker system. Compounds which contain an S-9-fluorenylmethyl-protected thiol and an additional disulfide linkage are deprotected in situ and trapped with an activated thiophile. This methodology allowed for the synthesis of the first molecule possessing two different biologically active agents covalently attached to a folate receptor targeting ligand unit via two disulfide-based release systems.
authors.affiliation: Endocyte Inc., 3000 Kent Avenue, Suite A1-100, West Lafayette, IN 47906, USA. ivlahov@endocyte.com
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: Hari Krishna R
authors.initials: HK
authors.lastname: Santhapuram
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kleindl
authors.forename: Fei
authors.initials: F
authors.lastname: You
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Howard
authors.forename: Elaine
authors.initials: E
authors.lastname: Westrick
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Reddy
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004220:Disulfides / Q000737:chemistry; D016503:Drug Delivery Systems; D015195:Drug Design; D005492:Folic Acid / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D013438:Sulfhydryl Compounds
chemical_list: D002352:Carrier Proteins; D004220:Disulfides; D008024:Ligands; D010455:Peptides; D013438:Sulfhydryl Compounds; D005492:Folic Acid