Synthesis and Structure−Activity Relationship of 4-Substituted 2-(2-Acetyloxyethyl)-8-(morpholine- 4-sulfonyl)pyrrolo[3,4-c]quinoline- 1,3-diones as Potent Caspase-3 Inhibitors

Abstract

Synthesis, biological evaluation, and SAR dependencies for a series of novel 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline inhibitors of caspase-3 are described. The inhibitory activity of the synthesized compounds is highly dependent on the nature of 4-substituents on the core scaffold. 4-methyl-and 4-phenyl-substituted derivatives, which were the most active compounds within this series, inhibited caspase-3 with IC50 of 23 and 27 nM, respectively.

Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species

“…Our results demonstrate that in the presence of isoquinoline-1,3,4-trione derivatives, dihydrolipoic acid has a high tendency to react with oxygen to generate ROS, which could specifically oxidize the catalytic cysteine of caspase-3. This implies that DTT could be replaced with a high level of dihydrolipoic acid to take part in the redox cycle in vivo, which may explain partially the ability of these chemicals to attenuate cell apoptosis (19,22), taking into account that dihydrolipoic acid exists in mitochondria of various cells. This suggestion does not exclude the possibility that other molecules in vivo could catalyze isoquinoline-1,3,4-trione derivatives to generate ROS, thereby changing the cellular redox state and the activity of thiol-enzymes besides caspases.…”

“…Ongoing endeavors of many pharmaceutical companies and academic institutions have led to the identification of a series of small-molecule inhibitors of caspase-3, including N-nitrosoanilines (13), dithiocarbamate (14), anilinoquinazolines (15), isatin sulfonamide analogues (16 -18), 1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c]quinolines (19), 2-(2,4-dichlorophenoxy)-N-(2-mercaptoethyl)-acetamide, and 5-fluoro-1H-indole-2-carboxylic acid (2-mercaptoethyl)-amide (20). These inhibitors can inhibit the caspase-3 activity with different inhibition mechanisms: N-nitrosoanilines are general inhibitors of cysteine-dependent enzymes; dithiocarbamates are able to block the activation of the caspase-3 proenzyme (21); anilinoquinazolines and isatin sulfonamide analogues are competitive inhibitors of caspase-3 (16); 1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c]quinolines are reversible and noncompetitive inhibitors of caspase-3 (19); and 2-(2,4-dichlorophenoxy)-N-(2-mercaptoethyl)-acetamide and 5-fluoro-1H-indole-2-carboxylic acid (2-mercaptoethyl)-amide are able to bind at an allosteric site and can inhibit both caspase-3 and caspase-7.…”

“…These inhibitors can inhibit the caspase-3 activity with different inhibition mechanisms: N-nitrosoanilines are general inhibitors of cysteine-dependent enzymes; dithiocarbamates are able to block the activation of the caspase-3 proenzyme (21); anilinoquinazolines and isatin sulfonamide analogues are competitive inhibitors of caspase-3 (16); 1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c]quinolines are reversible and noncompetitive inhibitors of caspase-3 (19); and 2-(2,4-dichlorophenoxy)-N-(2-mercaptoethyl)-acetamide and 5-fluoro-1H-indole-2-carboxylic acid (2-mercaptoethyl)-amide are able to bind at an allosteric site and can inhibit both caspase-3 and caspase-7. Several of these compounds could prevent apoptosis in cell-based models such as Jurkat cells, chondrocytes, and mouse bone marrow neutrophils (15)(16)(17)19). …”

Screening for Caspase-3 Inhibitors: A New Class of Potent Small-Molecule Inhibitors of Caspase-3

“…Two chemotype libraries, which produced potent inhibitors, are described elsewhere. 16,17 Here we describe in more detail 2 new chemotypes found among the hits belonging to 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), which are based on the general template I ( Table 1). …”

Design, synthesis, and testing of an isoquinoline-3-carboxylic-based novel anti-tumor lead

“…[1][2][3] Certain isoquinoline alkaloids can inhibit a number of cancer-related enzymes, including inosine 5 0 -monophosphate dehydrogenase, 4 Pfmrk, 5 P-glycoprotein, 6 kinase B/Akt, 7 cyclin dependent kinase 4, 8 topoisomerase I, 9 TRPV1, 10 IkB kinase-b, 11 caspase-3, 12 and mammalian sterile 20 kinase. 13 Isoquinolines alkaloids have attracted considerable attention for use as antitumor agents, since the isolation of naphthyridinomycin in 1974.…”