A synthesis, in silico, in vitro and in vivo study of thieno[2,3-b]pyridine anticancer analogues

Abstract

The thieno[2,3-b]pyridines bind to TDP1 with the best analogue 9d with IC50 at 0.5 μM.

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

“…90 °C. 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.…”

“…Previous molecular modelling studies strongly indicate that hydrogen bonding to Histidine 263 is required for effective inhibition. 5,12 Also, the hydrophobic pocket in the binding site is occupied by the terpene moiety. It can therefore be stated that a plausible binding mode is predicted.…”

“…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

“…In addition, Tdp1 is gathering interest in cancer treatment because of its role in repairing various other DNA adducts induced by chemotherapeutics . Recently, new classes of Tdp1 inhibitors have been developed that are active in the micromolar to nanomolar range and have low intrinsic toxicity …”

“…Many other compounds have been identified as Tdp1 inhibitors from various chemical classes including orthovanadates and tungstates, progesterone derivatives, piperidinyl sulfamides, benzopentathiepine, sulfonic acid, diamidine, bile acids, thieno[2,3‐b]pyridine derivatives, aminoglycoside antibiotics, ribosome inhibitors, halenaquinones, and 5 arylidenethioxothiazolidinones . These compounds were generated for the inhibition of Tdp1 only, and some of them were analyzed as sensitizers of tumor cells to the action of Top1 poisons.…”