3,3-diaryl-1,3-dihydroindol-2-ones as antiproliferatives mediated by translation initiation inhibition.
A series of substituted 3,3-diphenyl-1,3-dihydro-indol-2-ones was synthesized from the corresponding isatins. The compounds were studied for cell growth inhibition mediated by partial depletion of intracellular Ca2+ stores that leads to phosphorylation of eIF2alpha. The diphenyloxindole (1) showed mechanism-specific antiproliferative activity that was comparable to known translation initiation inhibitors such as clotrimazole or troglitazone. SAR studies identified m'-tert-butyl and o-hydroxy substituted diphenyloxindole (25) as a lead compound for Ca2+-depletion-mediated inhibition of translation initiation.
Natarajan
Amarnath
A
Laboratory for Translational Research, Harvard Medical School, One Kendall Square, Building 600, 3rd Floor, Cambridge, MA 02139, USA.
Fan
Yun-Hua
YH
Chen
Han
H
Guo
Yuhong
Y
Iyasere
Julia
J
Harbinski
Frederick
F
Christ
William J
WJ
Aktas
Huseyin
H
Halperin
Jose A
JA
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D002118:Calcium