Discovery of quinolinediones exhibiting a heat shock response and angiogenesis inhibition.
A series of substituted quinoline-5,8-diones were synthesized and evaluated as inhibitors of the chaperone protein Hsp90 using two assays: competition for binding to C-terminal ATP-binding site and competition for binding to N-terminal ATP-binding site. In addition, the ability of the compounds to induce the heat shock response was determined using a reporter fibroblast cell line. Of all the compounds assayed, only 6-aziridinyl-2-biphenylquinoline-5,8-dione induced a heat shock response and did so without interacting at the ATP binding sites of Hsp90. COMPARE analysis was carried out on quinoline-5,8-diones active in the National Cancer Institute's 60-cell line screen with the goal of discovering quinoline-5,8-dione structures that interact with other cellular targets (molecular targets) important for cancer chemotherapy. COMPARE analysis led to the discovery of a combretastatin-like quinoline-5,8-dione structure that, in fact, inhibited angiogenesis.
Hargreaves
Robert H J
RH
Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
David
Cynthia L
CL
Whitesell
Luke J
LJ
Labarbera
Daniel V
DV
Jamil
Akmal
A
Chapuis
Jean C
JC
Skibo
Edward B
EB
D000255:Adenosine Triphosphate / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011804:Quinolines; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate