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Anticancer activity and SAR studies of substituted 1,4-naphthoquinones.

ABSTRACT: In this paper, we report the structure-activity relationship studies of substituted 1,4-naphthoquinones for its anticancer properties. 1,4-Naphthoquinone, Juglone, Menadione, Plumbagin and LLL12.1 were used as lead molecules to design PD compounds. Most of the PD compounds showed improved antiproliferative activity in comparison to the lead molecule in prostate (DU-145), breast (MDA-MB-231) and colon (HT-29) cancer cell lines. PD9, PD10, PD11, PD13, PD14 and PD15 were found to be the most potent compound with an IC? value of 1-3 ?M in all cancer cell lines. Fluorescent polarization assay was employed to study the inhibition of STAT3 dimerization by PD compounds. PD9 and PD18 were found to be potent STAT3 dimerization inhibitors.

SUBMITTER: Bhasin D

PROVIDER: S-EPMC4304211 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Anticancer activity and SAR studies of substituted 1,4-naphthoquinones.

Bhasin Deepak D Chettiar Somsundaram N SN Etter Jonathan P JP Mok May M Li Pui-Kai PK

Bioorganic & medicinal chemistry 20130518 15

In this paper, we report the structure-activity relationship studies of substituted 1,4-naphthoquinones for its anticancer properties. 1,4-Naphthoquinone, Juglone, Menadione, Plumbagin and LLL12.1 were used as lead molecules to design PD compounds. Most of the PD compounds showed improved antiproliferative activity in comparison to the lead molecule in prostate (DU-145), breast (MDA-MB-231) and colon (HT-29) cancer cell lines. PD9, PD10, PD11, PD13, PD14 and PD15 were found to be the most potent ...[more]

PMID: 23791367

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Project description:Cell division cycle 25 (Cdc25) and mitogen-activated protein kinase kinase 7 (MKK7) are enzymes involved in intracellular signaling but can also contribute to tumorigenesis. We synthesized and characterized the biological activity of 1,4-naphthoquinones structurally similar to reported Cdc25 and(or) MKK7 inhibitors with anticancer activity. Compound 7 (3-[(1,4-dioxonaphthalen-2-yl)sulfanyl]propanoic acid) exhibited high binding affinity for MKK7 (Kd = 230 nM), which was greater than the affinity of NSC 95397 (Kd = 1.1 μM). Although plumbagin had a lower binding affinity for MKK7, this compound and sulfur-containing derivatives 4 and 6-8 were potent inhibitors of Cdc25A and Cdc25B. Derivative 22e containing a phenylamino side chain was selective for MKK7 versus MKK4 and Cdc25 A/B, and its isomer 22f was a selective inhibitor of Cdc25 A/B. Docking studies performed on several naphthoquinones highlighted interesting aspects concerning the molecule orientation and hydrogen bonding interactions, which could help to explain the activity of the compounds toward MKK7 and Cdc25B. The most potent naphthoquinone-based inhibitors of MKK7 and/or Cdc25 A/B were also screened for their cytotoxicity against nine cancer cell lines and primary human mononuclear cells, and a correlation was found between Cdc25 A/B inhibitory activity and cytotoxicity of the compounds. Quantum chemical calculations using BP86 and ωB97X-D3 functionals were performed on 20 naphthoquinone derivatives to obtain a set of molecular electronic properties and to correlate these properties with cytotoxic activities. Systematic theoretical DFT calculations with subsequent correlation analysis indicated that energy of the lowest unoccupied molecular orbital E(LUMO), vertical electron affinity (VEA), and reactivity index ω of these molecules were important characteristics related to their cytotoxicity. The reactivity index ω was also a key characteristic related to Cdc25 A/B phosphatase inhibitory activity. Thus, 1,4-naphthoquinones displaying sulfur-containing and phenylamino side chains with additional polar groups could be successfully utilized for further development of efficacious Cdc25 A/B and MKK7 inhibitors with anticancer activity.

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Anticancer activity and SAR studies of substituted 1,4-naphthoquinones.

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Anticancer activity and SAR studies of substituted 1,4-naphthoquinones.

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