Function oriented synthesis: preparation and initial biological evaluation of new A-ring-modified bryologs

The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of complete...

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Bibliographic Details
Published inTetrahedron Vol. 67; no. 51; pp. 9998 - 10005
Main Authors Wender, Paul A., Reuber, Jenny
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 23.12.2011
Elsevier
Subjects
Affinity
Binding
Bioactivity
Biological
Bryostatin
Chemistry
Chemistry, Organic
Economics
Kinases
Macrocycle
Physical Sciences
PKC
Polarity
Science & Technology
Synthesis (chemistry)
Tuning
PKC
Bioactivity
Bryostatin
Macrocycle
TRANSLOCATION
PROTEIN-KINASE-C
ASYMMETRIC-SYNTHESIS
PHASE-II
ALDEHYDES
TERT-BUTYL
BRYOSTATIN ANALOGS
VINCRISTINE
CHEMISTRY
MODULATION
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Summary:The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7–2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A-ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function. [Display omitted]
Bibliography:NIH RePORTER
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ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2011.09.058