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Combined Acylselenourea-Diselenide Structures: New Potent and Selective Antitumoral Agents as Autophagy Activators.

ABSTRACT: A series of 16 new diselenide-acylselenourea conjugates have been designed following the fragment-based drug strategy. Compound in vitro cytotoxic potential was evaluated against six human cancer cell lines and two nonmalignant derived cell lines with the aim of determining their potency and selectivity. Nine derivatives exhibited GI50 values under 10 ?M in at least four cancer cell lines. A clear gap situated phenyl substitution over heterocyclic moieties in terms of selectivity. Among carbocyclic compounds, derivatives 2 and 7 significantly inhibited cell growth of breast adenocarcinoma cells with GI50 values of 1.30 and 0.15 nM, respectively, with selectivity indexes 12 and 121 times higher than those obtained for doxorubicin. Preliminary mechanistic studies indicated that compounds 2 and 7 induce cell cycle arrest and autophagy-dependent cell death evidenced by the blockage of cell death with pretreatment with wortmannin or chloroquine and confirmed by the upregulation of the markers Beclin1 and LC3B in MCF-7 cells.

SUBMITTER: Garnica P

PROVIDER: S-EPMC5900345 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Combined Acylselenourea-Diselenide Structures: New Potent and Selective Antitumoral Agents as Autophagy Activators.

Garnica Pablo P Encío Ignacio I Plano Daniel D Palop Juan A JA Sanmartín Carmen C

ACS medicinal chemistry letters 20180313 4

A series of 16 new diselenide-acylselenourea conjugates have been designed following the fragment-based drug strategy. Compound <i>in vitro</i> cytotoxic potential was evaluated against six human cancer cell lines and two nonmalignant derived cell lines with the aim of determining their potency and selectivity. Nine derivatives exhibited GI<sub>50</sub> values under 10 μM in at least four cancer cell lines. A clear gap situated phenyl substitution over heterocyclic moieties in terms of selectivi ...[more]

PMID: 29670691

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Project description: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.

Dataset Information

Combined Acylselenourea-Diselenide Structures: New Potent and Selective Antitumoral Agents as Autophagy Activators.

Publications

Combined Acylselenourea-Diselenide Structures: New Potent and Selective Antitumoral Agents as Autophagy Activators.

Similar Datasets

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