Trigonal scaffolds for multivalent targeting of melanocortin receptorsElectronic supplementary information (ESI) available: Copies of NMR spectra of all new compounds, analytical HPLC traces from analyses of compounds 14a-c, 16a-c, and 18, details of the protein assay and normalization of the fluorescence data from competition binding assays with binding curves and the resultant Ki values, and details of the molecular dynamics analysis of compounds 6, 14c, 16c and 18. See DOI: 10.1039/c4ob02094d

• Main Authors: Elshan, N. G. R. Dayan, Jayasundera, Thanuja, Anglin, Bobbi L, Weber, Craig S, Lynch, Ronald M, Mash, Eugene A
• Format: Article
• Language: English
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c4ob02094d

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 azidealkyne 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. Short, efficient syntheses of multivalent molecules targeted to the human melanocortin 4 receptor based on phloroglucinol, tripropargylamine, and 1,4,7-triazacyclononane are described.