An assembly concept for the consecutive introduction of unsymmetrical disulfide bonds: synthesis of a releasable multidrug conjugate of folic acid.
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.
Vlahov
Iontcho R
IR
Endocyte Inc., 3000 Kent Avenue, Suite A1-100, West Lafayette, IN 47906, USA. ivlahov@endocyte.com
Santhapuram
Hari Krishna R
HK
Wang
Yu
Y
Kleindl
Paul J
PJ
You
Fei
F
Howard
Stephen J
SJ
Westrick
Elaine
E
Reddy
Joseph A
JA
Leamon
Christopher P
CP
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
D002352:Carrier Proteins; D004220:Disulfides; D008024:Ligands; D010455:Peptides; D013438:Sulfhydryl Compounds; D005492:Folic Acid