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Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)? in Solvent-Free Conditions.

ABSTRACT: Novel 1,4-naphthoquinones possessing indole scaffolds were prepared by the reaction of 2-hydroxy-1,4-naphthoquinone-substituted salicylic aldehydes and indoles using In(OTf)? as a catalyst. The method has the advantages of simple operation, mild reaction conditions, and friendly environment.

SUBMITTER: Yang X

PROVIDER: S-EPMC6222671 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)₃ in Solvent-Free Conditions.

Yang Xiaojuan X Wu Liqiang L

Molecules (Basel, Switzerland) 20180806 8

Novel 1,4-naphthoquinones possessing indole scaffolds were prepared by the reaction of 2-hydroxy-1,4-naphthoquinone-substituted salicylic aldehydes and indoles using In(OTf)₃ as a catalyst. The method has the advantages of simple operation, mild reaction conditions, and friendly environment. ...[more]

PMID: 30082583

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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.

Dataset Information

Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)? in Solvent-Free Conditions.

Publications

Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)₃ in Solvent-Free Conditions.

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