Pyrrolo[3,4-c]Quinoline-1,3-Diones as Potent Caspase-3 Inhibitors: Synthesis and SAR of 8-Sulfamoyl-1,3-Dioxo-2,3-Dihydro-1H-Pyrrolo[3,4- c]Quinolines

Abstract

Synthesis, biological evaluation and structure-activity relationships for a series of 8-sulfamoyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several potent inhibitors have been identified. The most active compounds within this series inhibited caspase-3 with IC 50 in the range of 23-30 nM.

Synthesis of 3,3-dichloroindolin-2-ones from isatin-3-hydrazones and (dichloroiodo)benzene

“…9a), which can be accomplished by deoxygenation of isatin using WCl 6 , 21 ClSO 3 H, 22 SO 2 Cl 2 , 23 and PCl 5 24 (Fig. 20 Among the myriad of structural modifications made to the isatin core is generation of the C-3 dichloro group (e.g.…”

“…20 Among the myriad of structural modifications made to the isatin core is generation of the C-3 dichloro group (e.g. 9a), which can be accomplished by deoxygenation of isatin using WCl 6 , 21 ClSO 3 H, 22 SO 2 Cl 2 , 23 and PCl 5 24 (Fig. 1, path a).…”

Environmentally Friendly Protocol for 2,3-Difunctionlization of Indole Derivatives

“…Murphy described (dichloroiodo)­benzene (PhICl 2 )-mediated a,a -dichlorination of isatin-3- p -tosylhydrazones or isatin-3-hydrazones, leading to the formation of 3,3-dichloroindolin-2-ones . Phosphorus pentachloride (PCl 5 ), , sulfonylchloride (SO 2 Cl 2 ), chlorosulfonic acid (ClSO 3 H), and tungsten­(VI) chloride (WCl 6 ) were used as chlorine sources for chlorination of isatins. The halogenation–decarboxylation of indolecarboxylic acids with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) and phenyliodine diacetate (PIDA) was also achieved .…”

SO2ClF: A Reagent for Controllable Chlorination and Chlorooxidation of Simple Unprotected Indoles

“…However, only one example of N -H indole was disclosed with a low yield of 25%. For the synthesis of 3,3-dichloro-2-oxindoles, many strategies starting from isatins with various chlorination reagents have been established . Other examples to prepare 3,3-dichloro-2-oxindoles, however, necessitate a functionalized indole derivative or N -protected indole .…”