Discovery of indeno[1,2- $$c$$ c ]quinoline derivatives as dual topoisomerases I/II inhibitors: Part 3

Abstract

(E) -6-Hydroxy-9-methoxy-6-(piperazin-1-yl)-11H -indeno[1,2-c ]quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime (2c) was identified as a potential dual topo I/II inhibitor in our previous paper. In continuation for the search of more potent compounds, we describe herein the preparation of certain indeno[1,2-c ]quinoline derivatives and evaluation of their antiproliferation, DNA binding affinity, and topoisomerases (topo I and topo II) inhibitory activities. Among them, (E) -9-[3-(dimethylamino)propoxy]-11H -indeno[1,2-c ]quinolin-11-one O-3-(dimethylamino)propyl oxime (11b) and its analog 11c exhibited approximately equal activity to the lead compound 2c against the growth of HeLa and A549 cancer cells. Both compounds 11b and 11c were more active than 2c in the inhibition of topo I and topo II. However, none of them exhibited significant DNA binding affinity while 2c was a very strong DNA binding agent. Compound 11b exhibited a high oral bioavailability of 39.8 % while the oral bioavailability of 2c and 11c was only 10.9 and 8.6 %, respectively. The in vivo anti-tumor evaluation of 11b in nude mice bearing subcutaneous breast cancer tumors revealed that treatment with low (10 mg/kg) or high (30 mg/kg) doses of 11b dramatically diminished tumor growth. Therefore, compound 11b is identified as a potential non-DNA intercalating dual topo I/II inhibitor.

Iron-Mediated Carboarylation/Cyclization of Propargylanilines with Acetals: A Concise Route to Indeno[2,1-c]quinolines

“…Construction of functionalized carbo- and heteropolycyclic architectures with minimum operations from relatively simple building blocks has been a challenging task in organic synthesis . Tetracyclic indenoquinoline fused with quinoline and indene frameworks is a common structural unit in a number of biologically active natural products and pharmaceuticals such as DNA topoisomerase inhibitor TAS-103 and its analogues I and II , , etc., for anticancer treatment. Time-consuming multistep procedures have usually been applied to access an indeno[2,1- c ]quinoline core consisting of tetracycles A–D, involving Diels–Alder and Friedel–Crafts reactions, cyclization, and addition to carbonyl compounds .…”

Design, Synthesis, and Anticancer Activity of Novel Fused Purine Analogues

“…Our scope was extended to study the effect of various five‐membered rings fused to the purine nucleus and encouraged by the fact that various reports stated potent anticancer activities for imidazole rings . So compound 1 was reacted with different reagents: cyanamide and thioacetamide to produce imidazo[1,5,4‐ gh ]purin‐5‐amine 8 and 5‐methylimidazo[1,5,4‐ gh ]purine 9 , respectively.…”

A Short Review on Heterocyclic Compounds Showing Anti-Breast Cancer Activity

“…3-Amino-N-(3-chlorophenyl)-5-oxo-5,6,7,8-tetrahydrothien of [2,3b]quinoline-2carboxamide (compound 19) as a putative phosphoinositide specific-phospholipase C-ɣ enzyme inhibitor, affected the proliferation, morphology, and migration of a host of breast cancer cell lines, and arrests cell cycle in the G2/M phases [22].…”