Inhibition and reversal of myogenic differentiation by purine-based microtubule assembly inhibitors.
Using a muscle cell differentiation screen, we have identified myoseverin from a 2,6,9-trisubsituted purine library as a purine-based microtubule binding molecule [1]. Structure-activity relation studies of myoseverin identify positions N2 and N6 to be critical for inhibiting muscle differentiation. Inhibition of microtubule polymerization induced the reversion of terminally differentiated myotubes to mononucleated cells that were responsive to both growth and differentiation conditions, without any observable cytotoxicity. Comparison of myoseverin derivatives to taxol, vinblastine, nocodazole, and colchicine identify myoseverin's effect as being selectively reversible in addition to lacking the cytotoxic effects of these non-purine-based microtubule-disrupting molecules. Myoseverin, as a purine-based microtubule inhibitor, reverted terminal muscle-differentiated cells to a state that was responsive to environmental cues. These results suggest that myoseverin may have applications in muscle regeneration and stem cell differentiation.
Perez
Omar D
OD
Department of Chemistry, University of California, Berkeley 94720, USA. operez@stanford.edu
Chang
Young-Tae
YT
Rosania
Gustavo
G
Sutherlin
Dan
D
Schultz
Peter G
PG
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D009132:Muscles / Q000166:cytology* / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D012038:Regeneration; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011687:Purines; C407365:myoseverin