Synthesis of Sulfones and Sulfoxides Based on (+)-usnic Acid

Sokolov, D. N.; Luzina, O. A.; Salakhutdinov, N. F.

doi:10.1007/s10600-018-2256-8

Cited by 1 publication

(1 citation statement)

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“…The hydrolysis was performed with (33%) sulfuric acid in glacial acetic acid to obtain the desired compound 9, with a 38% yield. The target sulfoxide derivatives of 10 were obtained using the procedure described in [42], which is by a peroxidation reaction of the corresponding thioethers 7g,h with mCPBA in CH2Cl2 at 0 °C (Scheme 3). The desired compounds 10a,b were obtained, with 70-75% yields.…”

Section: Chemistrymentioning

confidence: 99%

New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

Dyrkheeva

Filimonov

Luzina

et al. 2021

IJMS

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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.

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Section: Chemistrymentioning

confidence: 99%