ABSTRACT
Zoanthamines are a family of marine alkaloids that have complex heptacyclic structures and are reported to be interleukin-6 modulators. While the structure of zoanthamines, especially the ABC-ring portion, is similar to that of steroids, the CDEFG-ring portion, composed of aminoacetal and lactone core, is a unique structural element. In this report, we designed and synthesized ABC-ring 6 and CDEFG-ring 7, which are truncated analogues of the northern and southern hemispheres of zoanthenol 5, respectively, and which incorporate all of the functionality of each hemisphere. A preliminary SAR study suggested that the hydrochloride of the CEFG-ring portion is an active pharmacophore for suppressing the growth of interleukin-6-dependent MH60 cells.
Subject(s)
Cnidaria/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , Alkaloids/chemical synthesis , Alkaloids/pharmacology , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Hybridomas , Interleukin-6/antagonists & inhibitors , Mice , Molecular Mimicry , Osteoporosis/drug therapy , Structure-Activity RelationshipABSTRACT
[reaction: see text]. Stereocontrolled synthesis of the ABC ring framework of zoanthenol has been achieved. Our studies show that a beta,beta-disubstituted enone can act as a good acceptor of arylpalladium intermediates in the formation of a congested benzylic quaternary carbon center through an intramoleculer Mizoroki-Heck reaction. The cis B/C ring system was stereoselectively converted to the trans-fused framework through a SmI2-promoted deoxygenation of the alpha-hydroxy ketone.
Subject(s)
Bridged-Ring Compounds/chemistry , Heterocyclic Compounds, Bridged-Ring/chemistry , Alkaloids/chemistry , Catalysis , Cyclization , Indicators and Reagents , Molecular Conformation , Palladium/chemistryABSTRACT
First total syntheses of (+)-secosyrins 1 and 2 and total syntheses of (+)-syributins 1 and 2 are described. The two chiral centers of diisopropyl tartrate were incorporated into target natural products. Stereoselective construction of the spiro skeleton of secosyrins could be realized by taking advantage of an alkyne-cobalt complex. The synthesis of these compounds established their relative and absolute stereochemistry unambiguously.
