2. Academic Validation
  3. Optimization of a Stable Linker Involved DEVD Peptide-Doxorubicin Conjugate That Is Activated upon Radiation-Induced Caspase-3-Mediated Apoptosis

Optimization of a Stable Linker Involved DEVD Peptide-Doxorubicin Conjugate That Is Activated upon Radiation-Induced Caspase-3-Mediated Apoptosis

  • J Med Chem. 2015 Aug 27;58(16):6435-47. doi: 10.1021/acs.jmedchem.5b00420.
Seung Woo Chung 1,  Beom Suk Lee 2 3,  Jeong uk Choi 1,  Seong Who Kim 4,  In-San Kim 3,  Sang Yoon Kim 2 3,  Youngro Byun 1 5
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , 151-742 Seoul, South Korea.
  • 2 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , 138-736 Seoul, South Korea.
  • 3 Biomedical Research Institute, Korea Institute of Science and Technology , 136-791 Seoul, South Korea.
  • 4 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , 138-736 Seoul, South Korea.
  • 5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University , 151-742 Seoul, South Korea.
PMID: 26263187 DOI: 10.1021/acs.jmedchem.5b00420
Abstract

The current study demonstrates the process of selecting an optimal structure for a caspase-3-cleavable doxorubicin prodrug that could be synthesized by simple chemistry in high yields. The prodrug was intended to activate in the presence of Caspase-3, whose expression can be exogenously regulated by inducing Apoptosis with radiation therapy at a specific site of interest. For this purpose, doxorubicin was conjugated with a DEVD peptide via a heterobifunctional linker. Since the active form of the prodrug comprises the linker besides doxorubicin, we tested several different linkers and selected EMCS based on the examination of its in vitro biological activities. Consequently, DEVD-cysteamide-EMCS-doxorubicin was synthesized as the final compound. According to the various in vitro and in vivo studies, the synthesized prodrug was highly selective for tumors when coupled with radiation therapy, with the added benefit of ease of production.

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