RESUMEN
A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M - HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33-80 µM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 µM), demonstrated good activity (IC50 = 17 µM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 µM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.
Asunto(s)
Acetilglucosamina , Antineoplásicos , Antioxidantes , Simulación del Acoplamiento Molecular , Organofosfonatos , Humanos , Organofosfonatos/química , Organofosfonatos/farmacología , Organofosfonatos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Acetilglucosamina/química , Acetilglucosamina/farmacología , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Proliferación Celular/efectos de los fármacosRESUMEN
A series of conjugates of diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) and N-acetyl-D-glucosamine was synthesised and their cytotoxicity against several human cancer cell lines (M-Hela, MCF-7, Hep G2, Panc-1, PC-3), as well as normal human cell lines (WI-38, Chang liver) was assayed. Most of the conjugates were found to be cytotoxic against the mentioned cancer cell lines in the range of IC50 values 13-89 µM. Two lead compounds 14a and 14b showed selective cytotoxicity against M-Hela (IC50 13 and 14 µM) that was two times as high as the cytotoxicity of the anti-cancer drug Tamoxifen in control (IC50 28 µM). It was found that cytotoxic activity of the lead compounds against M-Hela cells is due to induction of apoptosis.
Asunto(s)
Acetilglucosamina/síntesis química , Acetilglucosamina/farmacología , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Acetilglucosamina/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Diterpenos/química , Diterpenos de Tipo Kaurano/química , Ensayos de Selección de Medicamentos Antitumorales , Hemólisis/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
Several glycoconjugates of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with a 1,2,3-triazolyl moiety were synthesized, and their cytotoxicity was evaluated against some human cancer and normal cell lines. Most of the synthesized compounds demonstrated weak inhibitory activities against the M-HeLa and MCF-7 human cancer cell lines. Three lead compounds, 54, 56 and 57, exhibited high selective cytotoxic activity against M-HeLa cells (IC50 = 1.7-1.9 µM) that corresponded to the activity of the anticancer drug doxorubicin (IC50 = 3.0 µM). Moreover, the lead compounds were not cytotoxic with respect to a Chang liver human normal cell line (IC50 > 100 µM), whereas doxorubicin was cytotoxic to this cell line (IC50 = 3.0 µM). It was found that cytotoxic activity of the lead compounds is due to induction of apoptosis proceeding along the mitochondrial pathway. The present findings suggest that 1,2,3-triazolyl-ring-containing glycoconjugates of isosteviol are a promising scaffold for the design of novel anticancer agents.
Asunto(s)
Diterpenos de Tipo Kaurano/síntesis química , Glicoconjugados/química , Glicósidos/química , Triazoles/química , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura MolecularRESUMEN
A series of glycosides and glycoconjugates of diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with various monosaccharide residues were synthesized and their cytotoxicity against some human cancer and normal cell lines was assayed. Most of the synthesized compounds demonstrated moderate to significant cytotoxicity against human cancer cell lines M-HeLa and MCF-7. Three lead compounds exhibited selective cytotoxic activities against M-HeLa (IC50 = 10.0-15.1 µM) that were three times better than the cytotoxicity of the anti-cancer drug Tamoxifen (IC50 = 28.0 µM). Moreover, the lead compounds were not cytotoxic with respect to the normal human cell line Chang liver (IC50 > 100 µM), whereas Tamoxifen inhibited the viability of normal human Chang liver cells with an IC50 value of 46.0 µM. It was determined that the cytotoxicity of the lead compounds was due to induction of apoptosis proceeding along the mitochondrial pathway. The cytotoxic activity of the synthesized compounds substantially depended on the nature of the monosaccharide residue and its position, that is, whether the monosaccharide residue was attached directly to the isosteviol skeleton or was moved away from it by means of a polymethylene linker.
RESUMEN
The first macrocyclic glycoterpenoids comprising glucosamine and diterpenoid isosteviol moieties were synthesized and evaluated for inhibition activity against Mycobacterium tuberculosis H37Rv.