A Solanesol-Derived Scaffold for Multimerization of Bioactive Peptides

Abstract

A flexible molecular scaffold bearing varying numbers of terminal alkyne groups was synthesized in five steps from solanesol. R(CO)-MSH(4)-NH 2 ligands, which have a relatively low affinity for binding at the human melanocortin 4 receptor (hMC4R), were prepared by solid phase synthesis and were N-terminally acylated using 6-azidohexanoic acid. Multiple copies of the azide N 3 (CH 2 ) 5 (CO)-MSH(4)-NH 2 were attached to the alkyne-bearing, solanesol-derived molecular scaffold via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Control studies showed that the binding affinity of the triazole-containing ligand, CH 3 (CH 2 ) 3 (C 2 N 3 )(CH 2 ) 5 (CO)-MSH(4)-NH 2 , was not significantly diminished relative to the corresponding parental ligand, CH 3 (CO)-MSH(4)-NH 2 . In a competitive binding assay using a Eu-labeled probe based on the superpotent ligand NDP-α-MSH, the monovalent and multivalent constructs appear to bind to hMC4R as monovalent species. In a similar assay using a Eu-labeled probe based on MSH(4), modest increases in binding potency with increased MSH(4) content per scaffold were observed.

Trigonal scaffolds for multivalent targeting of melanocortin receptors

“…Volatiles were removed under vacuum and the resultant slurry subjected to flash column chromatography using a mobile phase of 10% MeOH/CHCl 3 . Product-containing fractions were combined and solvents removed in vacuo to give 11 as a white solid, mp 94–96 °C (lit 24 mp 94–96 °C). Yield 3.81 g (15.7 mmol, 75%); R f 0.38 (10% MeOH/CHCl 3 , visualization KMnO 4 ); 1 H NMR (500 MHz, methanol- d 4 ) δ 4.47 (t, J = 5.3 Hz, 1H, CH), 3.96–3.70 (m, 2H, O-CH 2 ), 3.33 (t, J = 6.9 Hz, 2H, N 3 -CH 2 ), 2.34 (t, J = 7.5 Hz, 2H, CH 2 ), 1.67 (m, 4H, overlapped CH 2 ), 1.56–1.35 (m, 2H, CH 2 ); 13 C NMR (125 MHz, methanol- d 4 ) δ 175.98 (CO), 175.09 (CO), 63.11, 56.43, 52.27, 36.62, 29.61, 27.35, 26.21.…”

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…Solanesol-derived and sucrose-derived scaffolds were utilized to make both bivalent and tetravalent ligands attached to the His-DPhe-Arg-Trp tetrapeptide sequence [270, 271]. Moderate improvement in binding affinity at the hMC4R was observed, likely due to proximity effects and increasing the moles of pharmacophore present, but not indicative of cooperative or multivalent binding.…”

“…Moderate improvement in binding affinity at the hMC4R was observed, likely due to proximity effects and increasing the moles of pharmacophore present, but not indicative of cooperative or multivalent binding. The authors hypothesized their ligands may not possess the correct linker length or improperly presented the pharmacophores for cooperative binding [270, 271]. …”

Solanesol: a review of its resources, derivatives, bioactivities, medicinal applications, and biosynthesis

“…Wang et al (2003aWang et al ( , b, 2005) synthesised a number of solanesol derivatives and found several compounds with good antitumour activities. Alleti et al (2010) synthesised a solanesol-derived scaffold bearing varying numbers of terminal alkyne groups for multimerisation of bioactive peptides. Recently, Xiao et al (2012) synthesised 12 diacid solanesyl tegafur esters by the reaction of solanesol with four acid anhydrides and N-alkoxy-tegafur; the preliminary bioassay results showed that these target compounds possess antitumour activities to some extent.…”