Synthesis and caspase-3 inhibitory activity of 8-sulfonyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines.
A convenient synthesis of novel 8-sulfonyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines is described. As key steps to assemble the target molecular scaffold, our method features (a) Pfitzinger reaction of isatin-5-sulfonate 1 with methyl 3-oxo-3-phenylpropanoate, (b) formation of 1-(1H-pyrazol-4-yl)-1H-pyrrole-2,5-dione intermediate 5, and (c) reaction of sulfinic acid 9 with acrylate or methylacrylate leading to the corresponding sulfonyl propionates. Two compounds, ester 11 and morpholide 13, have been identified as potent inhibitors of caspase-3 with IC50 = 6 nM. Our primary data suggest noncompetitive and reversible character of caspase-3 inhibition.
Kravchenko
Dmitri V
DV
Department of Organic Chemistry, Chemical Diversity Research Institute, Khimki, Moscow Region, Russia. dk@chemdiv.com
Kysil
Volodymyr M
VM
Tkachenko
Sergey E
SE
Maliarchouk
Sergey
S
Okun
Ilya M
IM
Ivachtchenko
Alexandre V
AV
D053148:Caspase 3; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011804:Quinolines; D053148:Caspase 3