Efficient One-Pot Synthesis of Doxorubicin Conjugates Through Its Amino Group to Melanotransferrin P97

Abstract

The amino group of doxorubicin 1 is reacted with bis-NHS-ester linkers 6, or anhydrides 13 to offer in high yield modified doxorubicins 7–12 and 14–16, respectively. Compounds 7–12 are mono-NHS-esters, and can be directly coupled with melanotransferrin (p97), a useful vector with the ability to cross the blood-brain barrier, to yield the expected doxorubicin-p97 conjugates. Upon activating the carboxylic group with BTTU, compound 14–16 could be used in the same reaction. Structurally, the amino group of doxorubicin is covalently bonded to the amino groups of p97. The conjugates are potential candidates for treatment of brain tumors.

Keywords:

• Doxorubicin
• Bioconjugate
• Protein
• Cross-linking
• Blood-brain barrier
• Drug delivery
• Anticancer drug
• Brain tumor
• Amide bond linkage

Acknowledgments

We are grateful to Dr. Jim Zhang of Albany Molecular Research Inc for the preparation of some of the starting materials, Dr. Pascale Tiger, Dr. Malcolm Kennard, Dr. Gavin Arthur, Mr. Joseph Yang for help discussions and part of analytical work.