Synthesis and anti-leukaemic activity of pyrrolo[3,2,1-hi]indole-1,2-diones, pyrrolo[3,2,1-ij]quinoline-1,2-diones and other polycyclic isatin derivatives

Abstract

2012Synthesis and anti-leukaemic activity of pyrrolo [3,2,1-hi] Synthesis and anti-leukaemic activity of pyrrolo[3,2,1-hi]indole-1,2-diones, pyrrolo[3,2,1-ij]quinoline-1,2-diones and other polycyclic isatin derivatives AbstractTo further expand the structure-cytotoxic activity relationships of isatin derivatives and to reduce flexibility in substituent groups at nitrogen, 20 analogues incorporating a ring system between the N1 and C7 atoms of isatin were prepared using a variety of synthetic strategies. This yielded pyrroloindole-, pyrroloquinoline-, pyrroloacridine-, pyrrolophenanthridine-and benzopyrrolophenanthridine-based systems with embedded isatin moieties, the latter possessing a novel carbon skeleton. These compounds were subsequently assessed for their in vitro cytotoxicity against human U937 lymphoma cells, with the brominated pyrroloacridine dione 27 showing the most promising activity (IC50 3.01 μM) after 24 h.

Spiro[3H‐pyrazole‐3,3′‐oxindoles] Derived from 1,2,3,4‐Tetrahydroquinoline

“…5,6‐Dihydro‐4 H ‐pyrrolo[3,2,1‐ ij ]quinoline‐1,2‐dione ( 3 ) was prepared following a literature procedure in which 1,2,3,4‐tetrahydroquinoline was reacted with oxalyl chloride and the resulting amide‐acid chloride cyclized by treatment with aluminum chloride.…”

Hexahydrospiro‐pyrazolo[3,4‐b]pyridine‐4,1′‐pyrrolo[3,2,1‐ij]quinolines Derived from 5,6‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐dione

“…5,6‐Dihydro‐4 H ‐pyrrolo[3,2,1‐ ij ]quinoline‐1,2‐dione ( 1 ) was prepared following a literature procedure in which 1,2,3,4‐tetrahydroquinoline was reacted with oxalyl chloride and the resulting amide‐acid chloride cyclized in an intramolecular Friedel–Crafts process by treatment with aluminum chloride.…”

Spiro[4H‐2,3‐dihydropyran‐3,3′‐oxindoles] derived from 1,2,3,4‐tetrahydroquinoline

“…The starting tricyclic isatin, 5,6‐dihydro‐4 H ‐pyrrolo[3,2,1‐ ij ]quinoline‐1,2‐dione ( 3 ), was prepared following a literature procedure in which 1,2,3,4‐tetrahydroquinoline was reacted with oxalyl chloride and the resulting amide‐acid chloride cyclized by treatment with aluminum chloride. Reaction of amido‐ketone 3 was initially attempted following the earlier three‐component protocol by heating together 5,5‐dimethylcyclohexane‐1,3‐dione (dimedone) 11b , a cyanomethyl aryl ketone 9 , and 4‐( N,N ‐dimethylamino)pyridine (DMAP) in refluxing ethanol.…”

“…We have reported several investigations of the synthesis of spiro‐oxindoles starting from the tricyclic isatin 3 , 5,6‐dihydro‐4 H ‐pyrrolo[3,2,1‐ ij ]quinoline‐1,2‐dione . No previous work had employed 3 until our investigations that showed “normal” isatin behavior in conversions that produced spirocyclic products exemplified in Figure , 4 – 6 .…”