Synthesis and Biological Evaluation of Nitrated 7-, 8-, 9-, and 10-Hydroxyindenoisoquinolines as Potential Dual Topoisomerase I (Top1)–Tyrosyl-DNA Phosphodiesterase I (TDP1) Inhibitors

Abstract

The structure-activity relationships and hit-to-lead optimization of dual Top1-TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual Top1-TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the Top1-mediated DNA cleavage assay. One member of this series was a more potent Top1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug-DNA-Top1 cleavage complex than CPT.

Investigation of the Structure–Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons

“…Bis(indenoisoquinoline) 5 displays potent Top1 inhibitory activity and its IC 50 values versus purified and whole cell extract-containing TDP1 are each approximately 1 μM, 24, 25 and a number of monomeric indenoisoquinolines have also displayed TDP1 inhibitory activity, suggesting that the azaindenoisoquinolines should also be investigated for TDP1 and TDP2 inhibitory activity. 26–28 …”

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

“…tm, 2H, J(10,11)=6.2, 2H-C(10)); 2.72 (tm, 2H, J(13,12)=6.2, 2H-C(13)); 3.80 (s, 3H-C(21)); 5.07 (s, 2H, 2H-C(14)); 6.84 (d, 1H, J(9,7)=2.5, H-C(9)); 6.85 (ddd, 1H, J(18,19)=8.3, J(18,16)=2.6, J(18,20)=0.9, H-C(18)); 6.88 (dd, 1H, J(7,6)=8.8, J(7,9)=2.5, H-C(7)); 6.95 (dd, 1H, J(16,18)=2.6, J(16,20)=1.6, H-C(16)); 6.98 (ddd, 1H, J(20,19)=7.5, J(20,16)=1.6, J(20,18)=0.9, H-C(20)); 7.28 (dd, 1H, J(19,18)=8.3, J(19,20)=7.5, H-C(19)); 7.43 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.33 (s, C(1)); 161.97 (s, C(2)); 120.58 (s, C(3)); 147.07 (s, C(4)); 113.89 (s, C(5)); 124.01 (d, C(6)); 112.48 (d, C(7)); 160.31 (d, C(8)); 101.65 (d, C(9)); 23.73 (t, C(10)); 21.57 (t, C(11)); 21.28 (t, C(12)); 25.10 (t, C(13)); 70.13 (t, C(14)); 137.53 (s, C(15)); 112.83 (d, C(16)); 159.81 (s, C(17)); 113.59 (d, C(18)); 129.66 (d, C(19)); 119.49 (d, C(20)); 55.14 (q, C(21)).…”

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

“…A subsequent study continued research on indenoisoquinoline derivatives as dual Top1/Tdp1 inhibitors . In this study, 18 nitrated 7‐, 8‐, 9‐, and 10‐hydroxyindenoisoquinolines bearing a 3‐nitro substituent were synthesized and investigated.…”

“…A, O‐2 substituted indenoisoquinoline 22 . B, Hypothetical binding mode of compound 22 in the active site of Tdp1 (PDB ID: 1RFF) . All distances are measured from heavy atom to heavy atom.…”