Inhibition of cancer cell growth and migration by dihydroxynaphthyl aryl ketones

Benites, Julio; Valderrama, Jaime A.; Ríos, David; Lagos, Rosalba; Monasterio, Octavio; Calderón, Pedro Buc

doi:10.1007/s13273-016-0028-8

Cited by 5 publications

(5 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with other research groups, we support the hypothesis that a pro-oxidant treatment contributes, in a substantive way, to the elimination of cancer cells, via the induction of an oxidative stress leading to different manners of cell demise [ 18 22]. In this context, we have synthesized several quinone compounds and their biological activities have been assessed on a variety of human cancer cells [23][24][25][26][27][28][29].…”

Section: Introductionsupporting

confidence: 90%

Discovery of New 2-Phenylamino-3-Acyl-1,4-Naphthoquinones as Inhibitors of Cancer Cells Proliferation. Searching for Intra-cellular Targets Playing a Role in Cancer Cells Survival

Benites¹,

Valderrama²,

Contreras³

et al. 2023

Preprint

View full text Add to dashboard Cite

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors like half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 display the highest antiproliferative activity against the three cancer cells, therefore, they were subject to further studies. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Furthermore, the expression of some key genes was studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking show that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.

show abstract

Section: Introductionsupporting

confidence: 90%

Discovery of New 2-Phenylamino-3-Acyl-1,4-Naphthoquinones as Inhibitors of Cancer Cells Proliferation. Searching for Intra-cellular Targets Playing a Role in Cancer Cells Survival

Benites¹,

Valderrama²,

Contreras³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In line with previous work, we support the hypothesis that a pro-oxidant treatment significantly contributes to the elimination of cancer cells via the induction of an oxidative stress leading to different manners of cell demise [18][19][20][21][22]. Within this framework, we have synthesized several quinone compounds and their biological activities have been assessed on a variety of human cancer cells [23][24][25][26][27][28][29]. In short, we have shown that quinones are important tools in the search for intracellular targets that play a role in cancer cell survival.…”

Section: Introductionsupporting

confidence: 88%

Discovery of New 2-Phenylamino-3-acyl-1,4-naphthoquinones as Inhibitors of Cancer Cells Proliferation: Searching for Intra-Cellular Targets Playing a Role in Cancer Cells Survival

et al. 2023

Self Cite

View full text Add to dashboard Cite

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors such as half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 displayed the highest antiproliferative activity against the three cancer cells and were therefore further investigated. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Moreover, the expressions of key genes were studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking shows that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.

show abstract

“…Finally, it is interesting to remark that dNAK 4 is a very good inhibitor of FtsZ polymerization because it binds to the GDP conformation of FtsZ. The affinity of this binding is better than some antibiotics that are currently in use, and the fact that it does not affect eukaryotic cells in the range of its inhibitory concentrations (Benites et al, 2016) makes this compound a very good antibiotic candidate.…”

Section: Resultsmentioning

confidence: 99%

“…In a similar way, we synthesized dihydroxynaphthyl ketones with different heterocycles called diaryl naphtyl ketone (dNAKs), analogs of colchicine and naphtyl phenstatins, as potential inhibitors of tubulin polymerization (Benites et al, 2011). Among them, five dNAKs were good inhibitors of tubulin polymerization (Gutiérrez et al, 2015), and its potential use as antitumor agents was evaluated using cancer cells from prostate, bladder, and breast (Benites et al, 2016). The best inhibitor for in vitro tubulin polymerization was [(1,4-dihydroxy-naphthalen-2-yl)-(1 H -pyrrol-2-yl)-methanone] (dNAK 4 in this work) with a Kd of 1.02 ± 0.23 μM, although it showed no effect on normal and cancer cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…In this work, we evaluated the inhibition of Escherichia coli FtsZ polymerization by the dNAK derivatives, being dNAK 4 the best inhibitor. This result and the lack of a cytotoxic effect of dNAK 4 on animal cells (Benites et al, 2016) makes this compound a good candidate for studying its use as a potential antibiotic. We characterized the effect of dNAK 4 on the in vitro assembly of FtsZ filaments using purified FtsZ from E. coli and Bacillus subtilis , as well as the effect of this compound on the growth of both bacterial strains.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Escherichia coli and Bacillus subtilis FtsZ Polymerization and Bacillus subtilis Growth by Dihydroxynaphtyl Aryl Ketones

et al. 2019

Self Cite

View full text Add to dashboard Cite

The increasing detection of virulent and/or multidrug resistant bacterial strains makes necessary the development of new antimicrobial agents acting through novel mechanisms and cellular targets. A good choice are molecules aimed to interfere with the cell division machinery or divisome , which is indispensable for bacterial survival and propagation. A key component of this machinery, and thus a good target, is FtsZ, a highly conserved GTPase protein that polymerizes in the middle of the cell on the inner face of the cytoplasmic membrane forming the Z ring, which acts as a scaffold for the recruitment of the divisome proteins at the division site. In this work, we tested the inhibitory effect of five diaryl naphtyl ketone (dNAK) molecules on the in vitro polymerization of both Escherichia coli and Bacillus subtilis FtsZ (EcFtsZ and BsFtsZ, respectively). Among these compounds, dNAK 4 showed the strongest inhibition of FtsZ polymerization in vitro , with an IC 50 of 2.3 ± 0.06 μM for EcFtsZ and 9.13 ± 0.66 μM for BsFtsZ. We found that dNAK 4 binds to GDP-FtsZ polymers but not to the monomer in GTP or GDP state. This led to the polymerization of short and curved filaments, rings, open rings forming clusters, and in the case of BsFtsZ, a novel cylindrical structure of stacked open rings. In vivo , dNAK 4 had almost no effect on the growth of E. coli in liquid culture, in contrast to the strong inhibitory effect observed over B. subtilis growth. The insensitivity of E. coli to this compound is probably related to the impermeability of dNAK 4 to the outer membrane. The low amount of this compound required to inhibit several of the bacterial strains tested and the lack of a cytotoxic effect at the concentrations used, makes dNAK 4 a very good candidate as a starting molecule for the development of a new antibiotic.

show abstract

Inhibition of cancer cell growth and migration by dihydroxynaphthyl aryl ketones

Cited by 5 publications

References 20 publications

Discovery of New 2-Phenylamino-3-Acyl-1,4-Naphthoquinones as Inhibitors of Cancer Cells Proliferation. Searching for Intra-cellular Targets Playing a Role in Cancer Cells Survival

Discovery of New 2-Phenylamino-3-Acyl-1,4-Naphthoquinones as Inhibitors of Cancer Cells Proliferation. Searching for Intra-cellular Targets Playing a Role in Cancer Cells Survival

Discovery of New 2-Phenylamino-3-acyl-1,4-naphthoquinones as Inhibitors of Cancer Cells Proliferation: Searching for Intra-Cellular Targets Playing a Role in Cancer Cells Survival

Inhibition of Escherichia coli and Bacillus subtilis FtsZ Polymerization and Bacillus subtilis Growth by Dihydroxynaphtyl Aryl Ketones

Contact Info

Product

Resources

About