Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex

Makoto N. Masuno, Isaac N Pessah, Marilyn M. Olmstead, Tadeusz F. Molinski

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Bastadin-5, a brominated macrodilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and nonmuscle cells by modulating RyR1/FKBP12 complex. Analogues of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogues of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient SNAr macroetherification, and evaluated in an assay that measures [3H]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analogue (±)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 μM), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 μM) under the same conditions. Structure-activity relationships of both families of cyclic analogues showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogues were those that conserved the dibromocatechol ether moiety that corresponds to the 'western edge' of the bastadin-5 structure. These data suggest that cyclic analogues of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity.

Original languageEnglish (US)
Pages (from-to)4497-4511
Number of pages15
JournalJournal of Medicinal Chemistry
Volume49
Issue number15
DOIs
StatePublished - Jul 27 2006
Externally publishedYes

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Tacrolimus Binding Protein 1A
Ryanodine Receptor Calcium Release Channel
Structure-Activity Relationship
Modulation
Ryanodine
Assays
Benzaldehydes
Sarcoplasmic Reticulum
Porifera
bastadin 5
Ether
Muscle Cells
Functional groups
Inhibitory Concentration 50
Muscle
Substitution reactions
Membranes
Atoms

ASJC Scopus subject areas

  • Organic Chemistry

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Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex. / Masuno, Makoto N.; Pessah, Isaac N; Olmstead, Marilyn M.; Molinski, Tadeusz F.

In: Journal of Medicinal Chemistry, Vol. 49, No. 15, 27.07.2006, p. 4497-4511.

Research output: Contribution to journalArticle

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