Tyrosyl-DNA Phosphodiesterase 1 Targeting for Modulation of Camptothecin-Based Treatment

Abstract

The targeting of specific DNA repair mechanisms may be a promising strategy to improve the efficacy of antitumor therapy. The cytotoxic effects of the clinically relevant topoisomerase 1 (Top1) poison camptothecins are related to the generation of DNA lesions and tumor cells may be resistant to DNA damaging agents due to increased repair. Tyrosyl- DNA phosphodiesterase 1 (TDP1) is implicated in the repair of strand breaks by removing abortive Top1/DNA complexes. Thus, a role for TDP1 in counteracting DNA damage induced by camptothecins has been proposed. Here, we review the role of TDP1 in DNA repair with particular reference to TDP1 function, its cooperation with other pathways and the development of pharmacological inhibitors.

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

“…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)). 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)).…”

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

“…1 H NMR (CDCl 3 , d H ): 2.53-2.85 (m, 2H-C(10), 2H-C(13)), 3.25 (br s, 2H-C(9)), 3.62-3.97 (m, 2H-C(11) 2H-C(12)), 7.76 (br d, J(4,6) = 1.8, H-C(4)), 8.90 (br s, H-C(6)), 10.73 (br s, NH). 13 [1,2,3,4,5]pentathiepin-6-yl)propanamide (3g)…”

“…11,12 This hypothesis is supported by a number of studies, for example, tdp1À/À mice and human cell lines with SCAN1 (spinocerebellar ataxia with axonal neuropathy) mutation are hypersensitive to camptothecin. 13,14 Furthermore, camptothecin and etoposide cause less DNA damages in cells with heightened TDP1 expression. [15][16][17][18] In addition, TDP1 activity suppression makes tumor cells hypersensitive to the anticancer agent temozolomide (purine methylation), 19 methyl methanesulfonate (AP-sites generation), bleomycin (single/double strand breaks with 3 0 -phosphoglycolates), H 2 O 2 and ionizing radiation (breaks and other lesion types).…”

Other Anticancer Drugs Targeting DNA and DNA-Associated Enzymes

“…125 Consequently, inhibitors of the DNA repair enzymes have been foreseen as an adjunct therapy (see Chapter 13). 126 …”