Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety

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

“…36 4, H-C(9)); 6.81 (dd, 1H, J(7,6)=8.7, J (7,9)=2.4, H-C(7)); 7.40 (d, 1H, J(6,7)=8.7, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.30 (s, C(1)); 162.12 (s, C(2)); 120.29 (s, C(3)); 147.17 (s, C(4)); 113.54 (s, C(5)); 123.79 (d, C(6)); 112.62 (d, C(7)); 160.69 (s, C(8)); 101.49 (d, C(9)); 23.72 (t, C(10)); 21.60 (t, C(11)); 21.29 (t, C(12)); 25.10 (t, C(13)); 70.93 (t, C(14)); 143.12 (s, C(15)); 121.12 (d, C (16) 16), H-C(20)); 6.85 (d, 1H, J(9,7)=2.5, H-C(9)); 6.89 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.44 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.32 (s, C(1)); 162.00 (s, C(2)); 120.64 (s, C(3)); 147.12 (s, C(4));113.95 (s, C(5)); 124.05 (d, C(6)); 112.50 (d, C(7)); 160.27 (s, C(8)); 101.54 (d, C(9)); 23.72 (t, C(10)); 21.55 (t, C(11)); 21.26 (t, C(12)); 25.11 (t, C(13)); 70.53 (t, C (14) 17)); 6.75 (d, 1H, J(9,7)=2.5, H-C(9)); 6.79 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.41 (d, 1H, J(6,7)=8.8, H-C(6)).…”

“…13 C-NMR (CDCl 3 , δ C ): 153.30 (s, C(1)); 162.12 (s, C(2)); 120.29 (s, C(3)); 147.17 (s, C(4)); 113.54 (s, C(5)); 123.79 (d, C(6)); 112.62 (d, C(7)); 160.69 (s, C(8)); 101.49 (d, C(9)); 23.72 (t, C(10)); 21.60 (t, C(11)); 21.29 (t, C(12)); 25.10 (t, C(13)); 70.93 (t, C(14)); 143.12 (s, C(15)); 121.12 (d, C (16) 16), H-C(20)); 6.85 (d, 1H, J(9,7)=2.5, H-C(9)); 6.89 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.44 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.32 (s, C(1)); 162.00 (s, C(2)); 120.64 (s, C(3)); 147.12 (s, C(4));113.95 (s, C(5)); 124.05 (d, C(6)); 112.50 (d, C(7)); 160.27 (s, C(8)); 101.54 (d, C(9)); 23.72 (t, C(10)); 21.55 (t, C(11)); 21.26 (t, C(12)); 25.11 (t, C(13)); 70.53 (t, C (14) 17)); 6.75 (d, 1H, J(9,7)=2.5, H-C(9)); 6.79 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.41 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.36 (s, C(1)); 162.12 (s, C(2)); 120.24 (s, C(3)); 147.24 (s, C(4)); 113.49 (c, C(5)); 123.93 (d, C(6)); 112.32 (d, C(7)); 160.64 (s, C(8)); 100.94 (d, C(9)); 23.69 (t, C(10)); 21.27 (t, C(11)); 21.58 (t, C(12)); 25.10 (t, C(13); 66.68 (t, C(14)); 36.11 (t, C(15)); 143.95 (s, C(16)); 118.89 (d, C (17) (7,9)=2.5, H-C(7)); 6.90 (d, 1H, J(9,7)=2.5, H-C(9)); 6.95 (dd, 1H, J (15,17)=2.6, J (15,19)=1.6, H-C(15)); 6.98 (ddd, 1H, J (19,18)=7.6, J (19,15)=1.6, J (19,17)=1.0, H-C(19)); 7.29 (dd, 1H, J (18,17)=8.3, J (18,19)=7.…”

“…11), 2H-C(12)); 2.53 (tm, 2H, J(10,11)=6.2, 2H-C(10)); 2.71 (tm, 2H, J (13,12)=6.2, 2H-C(13)); 5.09 (s, 2H, 2H-C(14)); 6.84 (d, 1H, J(9,7) = 2.5, H-C(9)); 6.88 (dd, 1H, J(7,6)= 8.8, J (7,9) =2.5, H-C(7)); 7.32 (tt, 1H, J (18,17(19))=7.1, J (18,16(20))=1.5, H-C (18) (20)). 13 C-NMR (CDCl 3 , δ C ): 153.31 (s, C(1)); 161.95 (s, C(2)); 120.54 (s, C(3)); 147.05 (s, C(4)); 113.85 (s, C(5)); 124.00 (d, C(6)); 112.46 (d, C(7)); 160.33 (s, C(8)); 101.60 (d, C(9)); 23.71 (t, C(10)); 21.56 (t, C(11)); 21.26 (t, C(12)); 25.08 (t, C(13)); 70.24 (t, C(14)); 135.93 (s, C(15)); 127. 36 4, H-C(9)); 6.81 (dd, 1H, J(7,6)=8.7, J (7,9)=2.4, H-C(7)); 7.40 (d, 1H, J(6,7)=8.7, H-C(6)).…”

“…Sixteen compounds were selected for experimental testing and compound 6, which is 3-methoxybenzyl derivative of 7-hydroxycoumarin annelated with the cyclohexane ring (Scheme 1), was identified as a promising inhibitor with an IC 50 value of 5 μM using our oligonucleotide-based fluorescence assay. 13 Based on this result, we decided to synthesize structural analogs of compound 6 modified at the coumarin skeleton as well as containing other substituents at a hydroxyl group as shown in Scheme 1. Preliminary molecular modeling against the Tdp1 binding pocket indicated that the replacement of the aromatic substituent by bulky aliphatic substituents, for example with bicyclo[3.1.1]heptane framework, could improve the efficacy of the inhibitors.…”

“…32 Hexadecameric oligonucleotide were chosen as Tdp1 substrate, which had 5(6)-carboxyfluorescein (FAM) at the 5' end and fluorophore quencher BHQ1 (Black Hole Quencher-1) at the 3'-end. 13 This approach was used to measure Tdp1 activity and to determine inhibitory properties of the synthesized compounds.…”