Abstract
The synthesis of all N-Me and N-H analogues of ent-verticilide is described, enabling a structure-activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The use of permeabilized cardiomyocytes allowed us to correlate the degree of N-methylation with activity without concern for changes in passive membrane permeability that these modifications can cause. A key hypothesis was that the minimal pharmacophore may be repeated in this cyclic oligomeric octadepsipeptide (a 24-membered macrocycle), opening the possibility that target engagement will not necessarily be lost with a single N-Me → N-H modification. The effect in the corresponding 18-membered ring oligomer (ent-verticilide B1) was also investigated. We report here that a high degree of N-methyl amide content is critical for activity in the ent-verticilide series but not entirely so for the ent-verticilide B1 series.
Original language | English (US) |
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Pages (from-to) | 1755-1762 |
Number of pages | 8 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 13 |
Issue number | 11 |
DOIs | |
State | Published - Nov 10 2022 |
Keywords
- arrhythmia
- calcium ion channel
- depsipeptide
- ring-size analogue
- ryanodine receptor
- tertiary amide
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry