Trigonal scaffolds for multivalent targeting of melanocortin receptors

N. G.R.Dayan Elshan, Thanuja Jayasundera, Bobbi L. Anglin, Craig S. Weber, Ronald M. Lynch, Eugene A. Mash

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Melanocortin receptors can be used as biomarkers to detect and possibly treat melanoma. To these ends, molecules bearing one, two, or three copies of the weakly binding ligand MSH(4) were attached to scaffolds based on phloroglucinol, tripropargylamine, and 1,4,7-triazacyclononane by means of the copper-assisted azide-alkyne cyclization. This synthetic design allows rapid assembly of multivalent molecules. The bioactivities of these compounds were evaluated using a competitive binding assay that employed human embryonic kidney cells engineered to overexpress the melanocortin 4 receptor. The divalent molecules exhibited 10- to 30-fold higher levels of inhibition when compared to the corresponding monovalent molecules, consistent with divalent binding. The trivalent molecules were only statistically (∼2-fold) better than the divalent molecules, still consistent with divalent binding but inconsistent with trivalent binding. Possible reasons for these behaviors and planned refinements of the multivalent constructs targeting melanocortin receptors based on these scaffolds are discussed.

Original languageEnglish (US)
Pages (from-to)1778-1791
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number6
DOIs
StatePublished - Feb 14 2015

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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