New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2

Abstract

A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.

The Molecular Mechanisms of Oleanane Aldehyde-β-enone Cytotoxicity against Doxorubicin-Resistant Cancer Cells

“…The drug resistance of cancer cells is often attributed to the activity of P-gp, the protein participating in the efflux of drugs from the cells. High P-gp expression was demonstrated in resistant subclones of HBL-100/Dox, K562/i-S9 and K562/i-S9_Dox [ 19 , 23 ]. Briefly, P-gp expression in parental HBL-100 and K562 cell lines was negligible, and P-gp-positive cells were practically absent in parental cell lines.…”

“…Pentacyclic triterpenoids with cell-proliferation-inhibitory properties most often act as inducers of intrinsic and extrinsic apoptotic signaling pathways [ 16 ]. Among the multiple molecular targets and cell proliferation regulatory pathways of triterpenic derivatives, the ability of triterpenoids to reverse various potential mechanisms contributing to the MDR of cancer cells has been increasingly reported in recent years [ 17 , 18 , 19 ]. Previously, we demonstrated the ability of the semi-synthetic derivatives of the triterpenoid betulin to effectively suppress the expression of ABC genes and the transport functions of the P-gp protein [ 20 ].…”

Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1

“…To investigate the effect of bulky substituents attached to hydroxyl groups in bile acids’ framework on the inhibitory activity of relevant compounds, substances have been synthesized containing a benzyl, ether, or aromatic moiety (p-bromobenzene, indole, or 2,6-bis-tert-butylphenol) attached to the steroid through various linkers [ 94 ]. All the compounds inhibited TDP1 in a submicromolar concentration range (IC 50 = 0.23–1.2 μM) and had low intrinsic toxicity to HEK293A (human embryonic kidney) cells and HeLa (cervical carcinoma) cells.…”

Transcriptomic Analysis of CRISPR/Cas9-Mediated PARP1-Knockout Cells under the Influence of Topotecan and TDP1 Inhibitor

“…TDP1 deficiency increases the likelihood of TOP1-SSB and DSB formation [ 34 , 35 ]. The inhibition of TDP1 sensitizes tumor cells to TOP1 poisons [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Thus, TDP1 plays an important role in maintaining genome stability and is considered as a potential therapeutic target in cancer treatment [ 11 ].…”