Synthesis and Biological Evaluation of RGD and isoDGR-Monomethyl Auristatin Conjugates Targeting Integrin α V β 3

ChemMedChem. 2019 May 6;14(9):938-942. doi: 10.1002/cmdc.201900049. Epub 2019 Mar 22.


This work reports the synthesis of a series of small-molecule-drug conjugates containing the αV β3 -integrin ligand cyclo[DKP-RGD] or cyclo[DKP-isoDGR], a lysosomally cleavable Val-Ala (VA) linker or an "uncleavable" version devoid of this sequence, and monomethyl auristatin E (MMAE) or F (MMAF) as the cytotoxic agent. The conjugates were obtained via a straightforward synthetic scheme taking advantage of a copper-catalyzed azide-alkyne cycloaddition as the key step. The conjugates were tested for their binding affinity for the isolated αv β3 receptor and were shown to retain nanomolar IC50 values, in the same range as those of the free ligands. The cytotoxic activity of the conjugates was evaluated in cell viability assays with αv β3 integrin overexpressing human glioblastoma (U87) and human melanoma (M21) cells. The conjugates possess markedly lower cytotoxic activity than the free drugs, which is consistent with inefficient integrin-mediated internalization. In almost all cases the conjugates featuring isoDGR as integrin ligand exhibited higher potency than their RGD counterparts. In particular, the cyclo[DKP-isoDGR]-VA-MMAE conjugate has low nanomolar IC50 values in cell viability assays with both cancer cell lines tested (U87: 11.50±0.13 nm; M21: 6.94±0.09 nm) and is therefore a promising candidate for in vivo experiments.

Keywords: antitumor agents; auristatins; drug delivery; integrins; peptidomimetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Binding, Competitive
  • Cell Line, Tumor
  • Cycloaddition Reaction
  • Drug Evaluation, Preclinical
  • Humans
  • Integrin alphaVbeta3 / drug effects*
  • Integrin alphaVbeta3 / metabolism
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology*


  • Antineoplastic Agents
  • Integrin alphaVbeta3
  • Oligopeptides
  • arginyl-glycyl-aspartic acid
  • monomethyl auristatin E