TY - JOUR

T1 - 1-Hydroxyanthraquinones Containing Aryl Substituents as Potent and Selective Anticancer Agents

AU - Sirazhetdinova, Nafisa S.

AU - Savelyev, Victor A.

AU - Frolova, Tatyana S.

AU - Baev, Dmitry S.

AU - Klimenko, Lyubov S.

AU - Chernikov, Ivan V.

AU - Oleshko, Olga S.

AU - Sarojan, Teresa A.

AU - Pokrovskii, Andrey G.

AU - Shults, Elvira E.

N1 - Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/6

Y1 - 2020/6

N2 - A series of 1,2-, 1,4-disubstituted or 1,2,4-trisubstituted anthraquinone-based compounds was designed, synthesized, characterized and biologically evaluated for anticancer efficacy. 2- or 4-arylated 1-hydroxy-9,10-antraquinones (anthracene-9,10-diones) were prepared by Suzuki-Miyaura cross-coupling reaction of 1-hydroxy-2-bromoanthraquinone, 1-hydroxy-4-iodoanthraquinone or 1-hydroxy-2,4-dibromoanthraquinone with arylboronic acids. The cross-coupling reaction of 2,4-dibromo-9,10-anthraquinone with arylboronic acids provide a convenient approach to 2,4-bis arylated 1-hydroxyanthraquinones with a variety of aryl substituent in the 2 and 4 position. The cytotoxicity of new anthraquinone derivatives was evaluated using the conventional MTT assays. The data revealed that six of the aryl substituted compounds among the entire series 3, 15, 16, 25, 27, 28 were comparable potent with the commercially available reference drug doxorubicin on the human glioblastoma cells SNB-19, prostate cancer DU-145 or breast cancer cells MDA-MB-231 and were relatively safe towards human telomerase (h-TERT)immortalized lung fibroblasts cells. The results suggested that the in vitro antitumor activity of synthesized 2-aryl, 4-aryl- and 2,4-diaryl substituted 1-hydroxyanthraquinones depends on the nature of the substituent within the cyclic backbone. Docking interaction of 2-, 4-substituted and 2,4-disubstituted 1-hydroxyanthraquinones indicates intercalative mode of binding of compounds with DNA topoisomerase. The interaction with the DNA of 4-aryl-13, 15, 16 and 4-(furan-3-yl)-23 1-hydroxyanthraquinones was experimentally confirmed through a change in electroforetic mobility. Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 μM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines.

AB - A series of 1,2-, 1,4-disubstituted or 1,2,4-trisubstituted anthraquinone-based compounds was designed, synthesized, characterized and biologically evaluated for anticancer efficacy. 2- or 4-arylated 1-hydroxy-9,10-antraquinones (anthracene-9,10-diones) were prepared by Suzuki-Miyaura cross-coupling reaction of 1-hydroxy-2-bromoanthraquinone, 1-hydroxy-4-iodoanthraquinone or 1-hydroxy-2,4-dibromoanthraquinone with arylboronic acids. The cross-coupling reaction of 2,4-dibromo-9,10-anthraquinone with arylboronic acids provide a convenient approach to 2,4-bis arylated 1-hydroxyanthraquinones with a variety of aryl substituent in the 2 and 4 position. The cytotoxicity of new anthraquinone derivatives was evaluated using the conventional MTT assays. The data revealed that six of the aryl substituted compounds among the entire series 3, 15, 16, 25, 27, 28 were comparable potent with the commercially available reference drug doxorubicin on the human glioblastoma cells SNB-19, prostate cancer DU-145 or breast cancer cells MDA-MB-231 and were relatively safe towards human telomerase (h-TERT)immortalized lung fibroblasts cells. The results suggested that the in vitro antitumor activity of synthesized 2-aryl, 4-aryl- and 2,4-diaryl substituted 1-hydroxyanthraquinones depends on the nature of the substituent within the cyclic backbone. Docking interaction of 2-, 4-substituted and 2,4-disubstituted 1-hydroxyanthraquinones indicates intercalative mode of binding of compounds with DNA topoisomerase. The interaction with the DNA of 4-aryl-13, 15, 16 and 4-(furan-3-yl)-23 1-hydroxyanthraquinones was experimentally confirmed through a change in electroforetic mobility. Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 μM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines.

KW - anthraquinones

KW - cytotoxicity

KW - DNA binding

KW - Suzuki cross-coupling reaction

KW - DESIGN

KW - MITOXANTRONE

KW - ANTHRAQUINONE DERIVATIVES

KW - PROLIFERATION

KW - KNIPHOLONE

KW - INHIBITORS

KW - CANCER

KW - MOLECULES

KW - Cytotoxicity

KW - Anthraquinones

KW - Humans

KW - Telomerase/metabolism

KW - Structure-Activity Relationship

KW - Antineoplastic Agents/pharmacology

KW - Drug Design

KW - Molecular Structure

KW - Cell Proliferation/drug effects

KW - Magnetic Resonance Spectroscopy

KW - Anthraquinones/chemical synthesis

KW - DNA/chemistry

KW - Cell Line, Tumor

KW - Molecular Docking Simulation

KW - Apoptosis

KW - Drug Screening Assays, Antitumor

UR - http://www.scopus.com/inward/record.url?scp=85085909526&partnerID=8YFLogxK

U2 - 10.3390/molecules25112547

DO - 10.3390/molecules25112547

M3 - Article

C2 - 32486108

AN - SCOPUS:85085909526

VL - 25

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 11

M1 - 2547

ER -