TY - JOUR

T1 - Sulfide, Sulfoxide, and Sulfone Derivatives of Usnic Acid as Inhibitors of Human TDP1 and TDP2 Enzymes

AU - Filimonov, Aleksandr S.

AU - Mikhailova, Marina A.

AU - Dyrkheeva, Nadezhda S.

AU - Chernyshova, Irina A.

AU - Kornienko, Tatyana E.

AU - Naumenko, Konstantin A.

AU - Anarbaev, Rashid O.

AU - Nefedov, Andrey A.

AU - Achara, Chigozie

AU - Curtis, Anthony D.M.

AU - Luzina, Olga A.

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

AU - Reynisson, Jóhannes

N1 - The work was supported by a grant 23-74-01078 of the Russian Science Foundation.

PY - 2024/12/17

Y1 - 2024/12/17

N2 - Tyrosyl-DNA phosphodiesterases 1 and 2 (TDP1 and TDP2) are important DNA repair enzymes that remove various adducts from the 3′- and 5′-ends of DNA, respectively. The suppression of the activity of these enzymes is considered as a promising adjuvant therapy for oncological diseases in combination with topoisomerase inhibitors. The simultaneous inhibition of TDP1 and TDP2 may result in greater antitumor effects, as these enzymes can mimic each other’s functions. We have previously shown that usnic acid-based sulfides can act as dual inhibitors, with TDP1 activity in the low micromolar range and their TDP2 at 1 mM. The oxidation of their sulfide moieties to sulfoxides led to an order of magnitude decrease in their cytotoxicity potential, while their TDP1 and TDP2 activity was preserved. In this work, we synthesized new series of usnic acid-based sulfides and their oxidized analogues, i.e., sulfoxides and sulfones, to systematically study these irregularities. The new compounds inhibit TDP1 with IC50 values (the concentration of inhibitor required to reduce enzyme activity by half) in the 0.33–25 μM range. Most sulfides and some sulfoxides and sulfones inhibit TDP2 with an IC50 = 138−421 μM. In addition, the most active compounds synergized (×4) with topotecan on the HeLa cell line as well as causing dose-dependent DNA damage, as confirmed by Comet assay. Sulfides with the 6-methylbenzoimidazol-2-yl substituent (8f, IC50 = 0.33/138 μM, TDP1/2) and sulfones containing a pyridine-2-yl fragment (12k, IC50 = 2/228 μM, TDP1/2) are the most potent derivatives and, therefore, are promising for further development.

AB - Tyrosyl-DNA phosphodiesterases 1 and 2 (TDP1 and TDP2) are important DNA repair enzymes that remove various adducts from the 3′- and 5′-ends of DNA, respectively. The suppression of the activity of these enzymes is considered as a promising adjuvant therapy for oncological diseases in combination with topoisomerase inhibitors. The simultaneous inhibition of TDP1 and TDP2 may result in greater antitumor effects, as these enzymes can mimic each other’s functions. We have previously shown that usnic acid-based sulfides can act as dual inhibitors, with TDP1 activity in the low micromolar range and their TDP2 at 1 mM. The oxidation of their sulfide moieties to sulfoxides led to an order of magnitude decrease in their cytotoxicity potential, while their TDP1 and TDP2 activity was preserved. In this work, we synthesized new series of usnic acid-based sulfides and their oxidized analogues, i.e., sulfoxides and sulfones, to systematically study these irregularities. The new compounds inhibit TDP1 with IC50 values (the concentration of inhibitor required to reduce enzyme activity by half) in the 0.33–25 μM range. Most sulfides and some sulfoxides and sulfones inhibit TDP2 with an IC50 = 138−421 μM. In addition, the most active compounds synergized (×4) with topotecan on the HeLa cell line as well as causing dose-dependent DNA damage, as confirmed by Comet assay. Sulfides with the 6-methylbenzoimidazol-2-yl substituent (8f, IC50 = 0.33/138 μM, TDP1/2) and sulfones containing a pyridine-2-yl fragment (12k, IC50 = 2/228 μM, TDP1/2) are the most potent derivatives and, therefore, are promising for further development.

KW - TDP1 inhibitor

KW - TDP2 inhibitor

KW - cancer

KW - sulfides

KW - sulfone

KW - sulfoxide

KW - topotecan

KW - tyrosyl-DNA phosphodiesterase

KW - usnic acid

KW - Scopus

UR - https://www.mendeley.com/catalogue/933c7813-9b71-3151-a9d5-6b9b7cb03f36/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85213333634&origin=inward&txGid=af47a2c1ce65680792dafca65788b291

U2 - 10.3390/chemistry6060101

DO - 10.3390/chemistry6060101

M3 - Article

VL - 6

SP - 1658

EP - 1679

JO - Chemistry (Switzerland)

JF - Chemistry (Switzerland)

SN - 2624-8549

IS - 6

ER -