Myriaporone 3/4 structure--activity relationship studies define a pharmacophore targeting eukaryotic protein synthesis.
Myriaporones are naturally occurring compounds which structurally resemble the southern hemisphere of the tedanolide family of macrolide antitumor agents. Despite the fact that myriaporone 3/4 represents only a portion of tedanolide, it nonetheless retains much of its biological activity. We show here that like tedanolide, myriaporone 3/4 inhibits protein synthesis and proliferation of mammalian cells with low nanomolar potencies but displays no prokaryotic growth inhibitory effect. Moreover, myriaporone 3/4 displays a very rapid, reversible and p21-independent activity to block S phase progression in mammalian cells. Structure-activity relationship studies revealed that the C18-C19 epoxide and the C14 hydroxymethyl group (tedanolide numbering) of myriaporone 3/4 are required for cell cycle inhibition. These constitute previously unidentified and/or novel pharmacophores for myriaporone 3/4. Our results show that the important biological activities associated with the structurally complex tedanolides are present and can be harnessed in the chemically much simpler myriaporones. This greatly increases the value of the latter as investigative tools for biochemical research as well as for development of potential therapeutics.
Hines
John
J
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520-8103, USA.
Roy
Myriam
M
Cheng
Hua
H
Agapakis
Christina M
CM
Taylor
Richard
R
Crews
Craig M
CM
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004852:Epoxy Compounds / Q000819:agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D008322:Mammals; D008954:Models, Biological; D014176:Protein Biosynthesis / Q000187:drug effects*; D011714:Pyrans / Q000819:agonists / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000187:drug effects
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D011714:Pyrans; C505858:myriaporone 3; C505860:myriaporone 4