Synthesis of IB-01212 by multiple N-methylations of peptide bonds.

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Abstract

There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI-Ag[2]O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure-activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212.

Journal

  • Bioorganic & medicinal chemistry

    Bioorganic & medicinal chemistry 22(21), 6156-6162, 2014-09-08

    Elsevier Ltd.

Codes

  • NII Article ID (NAID)
    120005512275
  • NII NACSIS-CAT ID (NCID)
    AA10938083
  • Text Lang
    ENG
  • Article Type
    journal article
  • ISSN
    0968-0896
  • Data Source
    IR 
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