69844-34-4Relevant academic research and scientific papers
Electrochemistry of potentially bioreductive alkylating quinones. Part 4. Qualitative and quantitative structure-activity relationships of aziridinylquinones
Driebergen, R. J.,Moret, E. E.,Janssen, L. H. M.,Beijnen, J. H.,Holthuis, J. J. M.,et al.
, p. 174 - 185 (1993)
The concept of bioreductive alkylation as a mechanism of action of aziridinylquinoid anticancer agents has been investigated.The influence of quinone substituents on quinone reduction, on protonation of the aziridines prior to and following quinone reduction and on partitioning properties of the compound was examined.Parameters obtained from a combined electrochemical, chemical-stability and lipophilicity study describing these processes were determined and correlated quantitatively in a Hansch-type QSAR study with biological data obtained from three experimental tumor models.Poor quantitative correlations between cytotoxicity in a L1210 clonogenic assay and the parameters were obtained.Good linear relationships, however, between antitumor activity in vivo (vs.L1210 leukemic mice and vs.B16 melanoma-bearing mice) and the lipophilic properties of the quinone were found.These relationships, showing a negative correlation between antitumor activity and lipophilicity, can be used to predict the activity of new, unknown compounds.No trend was evident between antitumor activity and other parameters, although some indications for potential importance of electronic and steric properties of the substituents and of their ability to form hydrogen bonds were found.
Synthesis, anticancer activity, and molecular modeling of 1,4-naphthoquinones that inhibit MKK7 and Cdc25
Schepetkin, Igor A.,Karpenko, Alexander S.,Khlebnikov, Andrei I.,Shibinska, Marina O.,Levandovskiy, Igor A.,Kirpotina, Liliya N.,Danilenko, Nadezhda V.,Quinn, Mark T.
, (2019/09/30)
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.
Dioxonaphthoimidazoliums are Potent and Selective Rogue Stem Cell Clearing Agents with SOX2-Suppressing Properties
Ho, Si-Han Sherman,Ali, Azhar,Ng, Yi-Cheng,Lam, Kuen-Kuen Millie,Wang, Shu,Chan, Woon-Khiong,Chin, Tan-Min,Go, Mei-Lin
supporting information, p. 1944 - 1955 (2016/10/06)
Pluripotent stem cells are uniquely positioned for regenerative medicine, but their clinical potential can only be realized if their tumorigenic tendencies are decoupled from their pluripotent properties. Deploying small molecules to remove remnant undifferentiated pluripotent cells, which would otherwise transform into teratomas and teratomacarcinomas, offers several advantages over non-pharmacological methods. Dioxonapthoimidazolium YM155, a survivin suppressant, induced selective and potent cell death of undifferentiated stem cells. Herein, the structural requirements for stemotoxicity were investigated and found to be closely aligned with those essential for cytotoxicity in malignant cells. There was a critical reliance on the quinone and imidazolium moieties but a lesser dependence on ring substituents, which served mainly to fine-tune activity. Several potent analogues were identified which, like YM155, suppressed survivin and decreased SOX2 in stem cells. The decrease in SOX2 would cause an imbalance in pluripotent factors that could potentially prompt cells to differentiate and hence decrease the risk of aberrant teratoma formation. As phosphorylation of the NF-κB p50 subunit was also suppressed, the crosstalk between phospho-p50, SOX2, and survivin could implicate a causal role for NF-κB signaling in mediating the stem cell clearing properties of dioxonaphthoimidazoliums.
Synthesis, antitumor activity and docking of 2,3-(substituted)-1,4-naphthoquinone derivatives containing nitrogen, oxygen and sulfur
Delarmelina, Maicon,Daltoé, Renata D.,Cerri, Murilo F.,Madeira, Klesia P.,Rangel, Leticia B. A.,Júnior, Valdemar Lacerda,Rom?o, Wanderson,Taranto, Alex G.,Greco, Sandro J.
, p. 1804 - 1816 (2015/09/22)
Eleven 2,3-(substituted)-1,4-naphthoquinone derivatives were synthesized in yields ranging from 52-89percent. These derivatives were evaluated for their cytotoxic effects on human lungs (H460), triple-negative breast (MDA-MB-231) and ovarian (A2780) cancer cell lines. Compounds 5f and 8 showed IC50 values of 3.048 × 10-5 mol L-1 and 4.24 × 10-6 mol L-1 for H460; 5c and 8 showed IC50 values of 2.16 × 10-5 mol L-1 and 1.60 × 10-5 mol L-1 for MDA-MB-231, and 5g and 8 showed IC50 values of 2.68 × 10-6 mol L-1 and 3.89 × 10-6 mol L-1 for A2780. Additionally, we conducted a docking study with the four most active compounds and the therapeutic targets PI3K and topoisomerase II showing the pharmacophoric conformation of these compounds.
NAPHTHAQUINONE METHYLTRANSFERASE INHIBITORS AND USES THEREOF
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Page/Page column 87; 88; 96, (2015/11/27)
Provided herein are compounds of (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof. Also provided are pharmaceutical compositions and methods involving the inventive compounds for the treatment of proliferative diseases (e.g., cancer (e.g., leukemia, breast cancer, melanoma, metastatic cancer) and diseases associated with inappropriate SET8 activity. Also provided are methods for inhibiting SET8 and methods for labelling SET8.
Design, synthesis, and biological evaluation of novel naphthoquinone derivatives with CDC25 phosphatase inhibitory activity
Brun, Marie-Priscille,Braud, Emmanuelle,Angotti, Delphine,Mondesert, Odile,Quaranta, Muriel,Montes, Matthieu,Miteva, Maria,Gresh, Nohad,Ducommun, Bernard,Garbay, Christiane
, p. 4871 - 4879 (2007/10/03)
CDC25 dual-specificity phosphatases are essential key regulators of eukaryotic cell cycle progression and the CDC25A and B isoforms are over-expressed in different tumors and related cancer cell lines. CDC25s are now considered to be interesting targets in the search for novel anticancer agents. We describe new compounds derived from vitamin K3 that inhibit CDC25B activity with IC50 values in the low micromolar range. These naphthoquinone derivatives also display antiproliferative activity on HeLa cells as expected for CDC25 inhibitors and inhibit cell growth in a clonogenic assay at submicromolar concentrations. They increase inhibitory tyrosine 15 phosphorylation of CDK and induce the cleavage of PARP, a hallmark of apoptosis.
