Next Article in Journal
Anticancer Phenolics from Dryopteris fragrans (L.) Schott
Next Article in Special Issue
A Novel Class of Cationic and Non-Peptidic Small Molecules as Hits for the Development of Antimicrobial Agents
Previous Article in Journal
Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC)
Previous Article in Special Issue
Regioselective Synthesis of Procyanidin B6, A 4-6-Condensed (+)-Catechin Dimer, by Intramolecular Condensation
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessFeature PaperArticle
Molecules 2018, 23(3), 679; https://doi.org/10.3390/molecules23030679

Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

1
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, acad. Lavrentjev ave. 9, Novosibirsk 630090, Russia
2
Novosibirsk Institute of Chemical Biology and Fundamental Medicine, SB RAS, acad. Lavrentjev ave. 8, Novosibirsk 630090, Russia
3
School of Chemical Sciences, University of Auckland, Auckland 1142, New Zealand
4
Novosibirsk State University, Pirogova str. 2, Novosibirsk 630090, Russia
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 2 March 2018 / Revised: 14 March 2018 / Accepted: 16 March 2018 / Published: 17 March 2018
(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)
Full-Text   |   PDF [1335 KB, uploaded 3 May 2018]   |  

Abstract

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme. View Full-Text
Keywords: deoxycholic acid; chenodeoxycholic acid; ursodeoxycholic acid; amide; Tdp1 inhibitor; cancer; tumor; virtual screening; molecular modelling deoxycholic acid; chenodeoxycholic acid; ursodeoxycholic acid; amide; Tdp1 inhibitor; cancer; tumor; virtual screening; molecular modelling
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Salomatina, O.V.; Popadyuk, I.I.; Zakharenko, A.L.; Zakharova, O.D.; Fadeev, D.S.; Komarova, N.I.; Reynisson, J.; Arabshahi, H.J.; Chand, R.; Volcho, K.P.; Salakhutdinov, N.F.; Lavrik, O.I. Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Molecules 2018, 23, 679.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top