ABSTRACT
The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Oxadiazoles/chemical synthesis , Ribose/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Ribose/chemical synthesis , Ribose/pharmacology , Structure-Activity RelationshipABSTRACT
New d-ribofuranoside derivatives containing two five membered heterocycles, isoxazole and triazole or two triazole rings, were synthesized. The final products as well as the synthetic precursors were physically and spectroscopically characterized. These new diheterocyclic derivatives together with other d-riboside compounds were assessed for their impact on PC3 cell line viability. We found that exposure of prostate cancer cells to some of these compounds caused a significant inhibition of cell growth and a G0/G1 cell cycle arrest, which was concomitant with alterations in the expression of proteins involved in cell cycle progression. Furthermore, the inhibitory activity was improved in di-heterocycles when the carbohydrate moiety was protected with a cyclopentylidene group compared to the isopropylidene analogues.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Survival/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Prostatic Neoplasms/drug therapy , Resting Phase, Cell Cycle/drug effects , Alkenes/pharmacology , Carbohydrates , Cell Line, Tumor , Humans , Isoxazoles/pharmacology , Male , Triazoles/pharmacologyABSTRACT
Herein we report the design, synthesis and characterization of novel 1,2,4-triazole d-ribose derivatives, as well as their synthetic precursors. The antitumoral activity against T cell lymphoma cell line of these products was studied. Structures containing a 1,2,4-triazolic ring linked by sulfur to the carbohydrate moiety showed a moderate antiproliferative activity. The presence of the second heterocyclic ring did not show significant changes in their biological activity. Meanwhile, structures with 3-thiobenzyl-5-substituted-1,2,4-triazole ring linked by nitrogen leads to compounds with a biphasic behavior, stimulating cell proliferation at low concentrations and inhibiting it at higher ones. An increment in the polarity was associated with a decrease in the activity of the evaluated compounds. A preliminary antitumoral screening pointed the 1,2,4-triazolic structures linked to protected sugars as promising leaders for further studies.
