Quinolones are a family of antimicrobial agents that have been used in antibacterial and anticancer chemotherapy. Fluoroquinolone targets DNA gyrase and topoisomerase IV enzymes affecting several cellular processes, like cell death and proliferation; the best way to act is in the form of carboxylic acid or, recently, as quinolone-metal complex. In this work, the use of boron is shown as an alternative of metal to form a complex by incorporating to fluoroquinolone as an electron withdrawing substituent to activate the C-7 position chemoselectively for the production of new fluoroquinolone hybrids and test their effects on cell proliferation. Fluoroquinolone-boron complexes were synthesized according to the Gould–Jacobs cyclization method, and five hybrid fluoroquinolone-boron compounds were obtained by SNAr reaction, yielding 31 to 46%, at 80°C, and in 10 to 25 hours of reaction. The effect of the five fluoroquinolone-boron hybrids was evaluated in cervical cancer cell lines by cell proliferation assay. 7-hydantoin-fluoroquinolone-boron and 7-dihydropyridine-fluoroquinolone-boron complexes showed the strongest effect according to dose-response assay, respectively. The fluoroquinolone-boron hybrid complex showed proliferation inhibition in SiHa and CasKi cells, opening the possibility to use them as potential agents for the treatment of cancer.
The antibacterial quinolones are synthetic compounds based on 4-oxo-1,4-dihydroquinoline-3-carboxylic acid skeleton and are used in the treatment of infectious diseases [
Metal quinolone chelates play an important role in drug bioavailability, and decreased absorption is produced when it is coadministered with magnesium-aluminum antacids [
In this paper, the use of boron is shown as an alternative to form a complex with metal that is incorporated to fluoroquinolone as electron withdrawing substituent to activate the C-7 position chemoselectively [
The melting points were obtained with an Electrothermal, IA 9000 melting point apparatus model. The IR spectra were recorded on a Nicolet iS10 FT-IT (Thermo-Scientific) spectrometer with Smart iTR-ATR diamond. The NMR spectra were obtained on a Varian Mercury 400 MHz spectrometer using TMS as an internal standard.
Fluoroquinolone-boron complex
The HPV-16 positive cervical tumor lines SiHa and CasKi were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) (Invitrogen Corporation, Carlsbad CA) enriched with 5% fetal bovine serum (FBS). The cell lines were kindly provided by Ph.D. Gariglio’s Lab from CINVESTAV-IPN.
The cells were harvested, and 5 × 104 cells were seeded and incubated for 24 hours before treated with the five new compounds at different concentrations and incubated for 72 hours. The cells were harvested and countered in a hemocytometer in triplicate. Floating and adherent cells were collected and included in the counting analysis. Data were subjected to a two-tailed Student’s
A general procedure for the synthesis of difluoroboryl 1-ethyl-6,7-difluoro-1,4-dihydroquinoline-3-carboxylate
Synthesis of hybrid fluoroquinolone-boron complex
With the use of fluoroquinolone-boron complex
Incorporation of 1,4-dihydropyridine heterocycle into fluoroquinolone-boron complex
The five compounds
The subsequent hydrolysis of
The
SiHa and CasKi cells were treated with the five hybrid fluoroquinolones
In the same sense,
With the use of fluoroquinolone-boron, complex
The data used to support the findings of this study are included within the article.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
We thank Ph.D. Gariglio from CINVESTAV-IPN for the dotation of cervical cancer cell lines. This work was supported by Programa para el Desarrollo Docente, para el Tipo Superior (PRODEP) [UAZ-PTC-198].