Abstract
Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC50 values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound 10a showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan.
Highlights
Genomic instability is one of the major driving forces of carcinogenesis
tyrosyl-DNA phosphodiesterase 1 (TDP1) activity may be a possible cause of tumor resistance to topoisomerase 1 (TOP1) inhibitors
TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the clinically used anticancer drug topotecan (Tpc), which is a TOP1 inhibitor
Summary
Genomic instability is one of the major driving forces of carcinogenesis. Studies of DNA repair mechanisms and their regulation are directly related to the search for the optimal ways of treating oncological and other human diseases. Anticancer chemotherapeutic drugs, by their principle of action, damage DNA in a targeted manner. Researchers are actively searching for new compounds that suppress the DNA repair enzymes activity to increase the efficiency of anticancer therapy. Tyrosyl-DNA phosphodiesterase 1 (TDP1) and poly(ADP-ribose) polymerase 1 (PARP1) are considered as promising target DNA repair enzymes for creating drugs [1,2]. Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Simultaneous suppression of the activity of these two enzymes can be used to increase the effectiveness of a large set of clinically important anticancer drugs, TOP1 and TOP2 inhibitors. IInn oorrddeerr ttoo fiffiinndd oouutt tthheessttrruuccttuurree––aaccttiivviittyyrreellaattiioonnsshhiipp((SSAARR)),,wweessyynntthheessiizzeeddtthheesseett ooofff uuusssnnniiiccc aaaccciiiddd (((UUUAAA))) dddeeerrriiivvvaaatttiiivvveeesss ooofff 777,,, wwwiiittthhh fiffiivvveee--- aaannnddd hhheeexxxaaa---mmmeeemmmbbbeeerrreeeddd mmmooonnnooo--- aaannnddd bbbiiicccyyycccllliiiccc hdihdihdinnneeuueuttpptprrreeeeeerrrrrreTeTTeooddodssshhcchceeeeeeyyeeyessnnsnccccccddccdcllrrlreieieieeiieicccbbbsssoooaaeeiiaeiffrrfrlddldleeooeNNoNdddnneeneaaaaagaggnnnOOOrrrooowllwlwHHyyHyvvviiiee.et.[[t.[th44hll4ThlTT11a1aahhnnhn]]n]nne,,eo,eoodddbbbnntnttayyayka-k-k-hrhrhrnnnrrgrggeeeeeooeoeetetatawawewtetetcccrrtrtttntnonthohoihiiococoicUiUUioyonynoyneAceAAcecootlotltlihihfihftcfttcchehhebebbaariraiirrrrosnoosnsnoooedeewdwmdmwmttthhhaeaeaoeooecerecrcruuueryreryeyssssssccoconnonl7l77lbibiibiiaicaacccctctt–a––asasaasakikkuiuiunccncnbiwibwewibeddedsdssddeteett66i6rirriitititeneeunwwunwuessse4e4ii4iynyytnt9nt99hhnhtnn–t–t–ssts9ttt9t.9th.hh.hh4h44eee%ee%e%sssciciiczyzzoyoyoeeeirririededdrerrleleledduduussspsp(ssp((SiiioSoSonnncncncnghgghhdddetetteiihmihhnmnmneeeggegeepppt1tt1hr1hrrh)o)oo)i.ii..ococcoeleellss-s--.
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