Inhibition of topoisomerase I by naphthoquinone derivatives

Plyta, Zoi F.; Li, Tianhu; Papageorgiou, Vassilios P.; Mellidis, Antonios S.; Assimopoulou, Andreana N.; Pitsinos, Emmanuel N.; Couladouros, Elias A.

doi:10.1016/s0960-894x(98)00600-3

Cited by 83 publications

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“…4 Shikonin is one of the active ingredients isolated from the roots of the traditional oriental medicinal herb Lithospermium erythrorhizon. 5 Many studies showed that shikonin exerted antitumor effects by inhibiting cancer cell growth, 6 inducing apoptosis 7 and inhibiting DNA topoisomerase I/II activity, [8][9][10] antitelomerase activity 11 and antiangiogenesis. 12 Because of its poor solubility and toxicity, shikonin have little potential to be an anticancer drug.…”

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confidence: 99%

“…8 Couladouros also found that acetylshikonin and isovalylshikonin possessed more potent topoisomerase I inhibitory activity than shikonin. 9 Encouraged by these findings, we synthesized a series of racemic versions of shikonin and its analogues, 11 and shikonin derivatives with side chains of different heteroaromatic acyl moieties. Some of them showed good antitumor activities, and 1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7) (Fig.…”

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SH‐7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor

Yang

Chen

Duan

et al. 2006

Intl Journal of Cancer

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1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7), a new naphthoquinone compound, derived from shikonin, exhibited obvious inhibitory actions on topoisomerase II (Topo II) and topoisomerase I (Topo I), which were stronger than its mother compound shikonin. Notably, the SH-7's inhibitory potency on Topo II was much stronger than that on Topo I. In addition, SH-7 significantly stabilized Topo II-DNA cleavable complex and elevated the expression of phosphorylated-H2AX. The in vitro cell-based investigation demonstrated that SH-7 displayed wide cytotoxicity in diversified cancer cell lines with the mean IC 50 value of 7.75 lM. One important finding is SH-7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC 50 value nearly equivalent to that of the corresponding parental cell lines. The average resistance factor (RF) of SH-7 was 1.74, which was much lower than those of reference drugs VP-16 (RF 145.92), ADR (RF 105.97) and VCR (RF 197.39). Further studies illustrated that SH-7 had the marked apoptosis-inducing function on leukemia HL-60 cells, which was validated to be of mitochondria-dependence. The in vivo experiments showed that SH-7 had inhibitory effects on S-180 sarcoma implanted to mice, SMMC-7721, BEL-7402 human hepatocellular carcinoma and PC-3 human prostate cancer implanted to nude mice. Taken together, these results suggest that SH-7 induces DSBs as a Topo II inhibitor, which was crucial to activate the apoptotic process, and subsequently accounts for its both in vitro and in vivo antitumor activities. The well-defined Topo II inhibitory activity, antitumor effects particularly with its obvious anti-MDR action, better solubility and less toxicity make SH-7 as a potential antitumor drug candidate for further research and development.

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confidence: 99%

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SH‐7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor

Yang

Chen

Duan

et al. 2006

Intl Journal of Cancer

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“…[5][6][7] In this context, amino-naphthoquinones, which has embedded in their structure the N-C=C-C=O enaminone moiety, have been synthesized and tested for pharmacological activities. [8][9][10][11][12][13] Among these chemical compounds, a particular bioactive derivative is the 2-benzylamino-1,4-naphthoquinone 1, since this compound is a useful intermediate in the synthesis of densely substituted nitrogen heterocycles. 2,14,15 Despite 1 has been described many years ago, new developments in its preparations have been reported, 16,17 and considering its synthetic and biological applications, no structural study of such compound seems to be described in the literature.…”

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confidence: 99%

Structural and reactivity analyses of 2-benzylamino-1,4-naphthoquinone by X-ray characterization, electrochemical measurements, and dft single-molecule calculations

Cunha¹,

Santos²,

Rocha³

et al. 2010

Quím. Nova

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Recebido em 30/6/10; aceito em 14/9/10; publicado na web em 27/10/10This study represents an integrated approach towards understanding the electronic and structural aspects of 2-benzylamino-1,4-naphthalenedione, a representative 2-amino-napfthoquinone. To this end, theoretical calculations performed at the B3PW91/6-31+G(d) level of density functional theory, electrochemical and X-ray structural investigation were employed. Two intramolecular H-bonds and other two intermolecular H-bonds were observed, including non-classical interactions. Cyclic voltammogram (CV) and differential pulse voltammetry (DPV) show two pairs of peaks, being each one a monoelectronic process.

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“…Owing to their wide ranging activities such as anti-tumor, 1) radical-scavenging, 2) enzyme-inhibitory, 3) immunoenhancement, 4) platelet activation-inhibition, 5) and RNase H activity inhibition associated with human immunodeficiency virus-1 reverse transcriptase 6) activity, 1,4-naphoquinones have attracted much attention, and numerous 1,4-napthoquinone derivatives have been found in nature or synthesized artificially. Some of them are currently used as medicines or chemical reagents.…”

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“…Further, hybridoma cells can be contaminated with microorganisms. On the other hand, recent advances in recombinant DNA technology have enabled the production of single-chain variable (scFv) antibodies, which have variable regions of heavy (VH) and light (VL) chains with the short, flexible peptide (Gly 4 Ser) 3 in bacteria. Once the gene for construction of recombinant antibodies is established, it can be kept as gene and used to construct various kinds of recombinant antibodies.…”

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Construction and Expression of Specificity-Improved Single-Chain Variable Fragments against the Bioactive Naphthoquinone, Plumbagin

Sakamoto

Taura

Putalun

et al. 2009

Biological & Pharmaceutical Bulletin

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We constructed a single-chain variable fragment (scFv) antibody against plumbagin (PL) with improved specific binding to PL. Variable heavy-and light-chain genes were cloned directly from the cDNA of hybridoma cell line 3A3 and assembled using the splice-overlap extension polymerase chain reaction (SOE-PCR) with specific primers including flexible peptide (Gly 4 Ser) 3 linker primers. The constructed scFv gene was ligated into the pET28a expression vector and transformed into Escherichia coli BL21 (DE3). The denatured protein expressed as inclusion bodies in E. coli was solubilized, purified, and refolded by a stepwise dialysis. Intriguingly, the refolded scFv against PL displayed higher PL-binding specificity than that of its parental monoclonal antibody, MAb 3A3, which suggests the possibility of improving the function by constructing the scFv antibody. These notable properties of the recombinant antibody against PL made it possible to develop an enzyme-linked immunosorbent assay (ELISA) for reliable determination of PL.

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Inhibition of topoisomerase I by naphthoquinone derivatives

Cited by 83 publications

References 12 publications

SH‐7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor

SH‐7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor

Structural and reactivity analyses of 2-benzylamino-1,4-naphthoquinone by X-ray characterization, electrochemical measurements, and dft single-molecule calculations

Construction and Expression of Specificity-Improved Single-Chain Variable Fragments against the Bioactive Naphthoquinone, Plumbagin

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