Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement. Synthesis and biological evaluation of ring and conformational analogues of the Hsp90 molecular chaperone inhibitor geldanamycin.
A series of ansa-quinones has been prepared by chemical synthesis, and evaluated by biological techniques. Thus, 19-membered ansa-lactams, simplified analogues of the naturally occurring Hsp90 molecular chaperone inhibitor geldanamycin, were obtained by concise routes, the key steps being the combination of a ring-closing metathesis to give a 17-membered ring followed by Claisen rearrangement to effect ring expansion. The methodology was also used to prepare an "unnatural" 18-membered ring analogue. In ATPase enzyme assays, the synthetic ansa-quinones were weak inhibitors of Hsp90.
McErlean
Christopher S P
CS
School of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD.
Proisy
Nicolas
N
Davis
Christopher J
CJ
Boland
Nicola A
NA
Sharp
Swee Y
SY
Boxall
Kathy
K
Slawin
Alexandra M Z
AM
Workman
Paul
P
Moody
Christopher J
CJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology; D003500:Cyclization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases; C001277:geldanamycin