Efficient Synthesis of Doxorubicin Melanotransferrin p97 Conjugates Through SMCC Linker

Abstract

Doxorubicin–succinimidyl 4‐[N‐maleimidomethyl]cyclohexane‐1‐carboxylate (SMCC) 3, prepared by treating doxorubicin (1) with SMCC 2, is treated with 2‐mercaptoacetic acid to give doxorubicin–SMCC–sulfo‐acetic acid 5. Treating with benzotriazol‐1‐yl‐N,N,N′,N‐tetramethyluronium tetrafluoroborate (BTTU), the carboxy group of 5 is activated, and reacts efficiently with the amino group of melanotransferrin p97 to afford the expected doxorubicin‐p97 conjugate 6, which is a potential agent capable to cross the blood–brain barrier (BBB) to treat brain tumors.

Keywords:

• Doxorubicin
• Blood–brain barrier
• Melanotransferrin
• Vector‐mediated approach
• SMCC linker
• Bioconjugate

Acknowledgments

We are grateful to Albany Molecular Research Inc for the preparation of some of the starting materials, Ms. Grace Laliberte, Dr. Pascale Tiger, Dr. Malcolm Kennard, Dr. Gavin Arthur for help discussions and part of analytic work.