Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Abstract

Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds’ activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogues were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons.

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…[282][283][284] Later studies performed out of concern about the toxicity of the nitro group revealed that chlorine and fluorine were acceptable bioisosteric replacements. 285,286 Fluorine was especially effective, and 3-fluoro indenoisoquinolines induced γ-H2AX formation at nanomolar concentrations within 30 minutes, indicating rapid cell uptake. 287 Generally, the 8,9-methylenedioxy moiety confers the highest activity on the indenone (D)-ring, and the SAR for the 9-position of the indenone overlaps with that of position 11 for 1 derivatives, suggesting a similar binding mode.…”

“…Generally, substituents such as nitro (on the isoquinolone portion, or A‐ring) were most effective, possibly because of H‐bonding or electrostatic interactions with the enzyme or base pairs . Later studies performed out of concern about the toxicity of the nitro group revealed that chlorine and fluorine were acceptable bioisosteric replacements …”

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

“…In this study, 18 nitrated 7‐, 8‐, 9‐, and 10‐hydroxyindenoisoquinolines bearing a 3‐nitro substituent were synthesized and investigated. Compared with 2,3‐dimethoxy and dioxolane ring derivatives, indenoisoquinolines derivatives with a 3‐nitro group in the A‐ring and a hydroxyl group in the D‐ring of indenoisoquinolines were previously shown to enhance both Top1 inhibitory and antiproliferative activities, respectively. The hydroxyl group is also advantageous because it can serve as a point of attachment for prodrug modules, targeting moieties, or antibodies.…”

“…While developing 3‐nitro 8‐hydroxyindenoisoquinolines, Top1 poisons with halogens at the 3‐position rather than nitro group were also developed, because the latter produce genotoxic metabolites . Although halogenated derivatives are generally less effective Top1 poisons than nitro derivatives, the authors successfully obtained halogenated derivatives with an activity comparable with that of nitro derivatives.…”

Design, synthesis, molecular docking and cytotoxicity evaluation of some novel 5-arylidene-3-(substituted phenyl)-2-(p-tolylamino)-4-imidazolones

“…In rapidly proliferated cells the replication fork of DNA is thought to collide with the trapped topo I-DNA complex leading to double strand breaks and apoptotic cell death (Topcu, 2001;Staker et al, 2005;Alonso et al, 2016;Beck et al, 2016;Jeon et al, 2016;Park et al, 2017).…”