Design, Synthesis and Biological Evaluation of New Pyrimidine Derivatives as Anticancer Agents

Abstract

Background: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound—namely RDS 344—as a potential innovative anticancer agent. Methods: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells. Results: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 μM, 4–13 times more active of hit. Conclusions: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype.

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

“…The compounds 9 , 13 , 19 , 20 , 22 , 23 , 25 , 26 , and 28 were evaluated for cell viability effects using the MTT assay. Briefly, the U-87 MG cell line from the human brain (glioblastoma astrocytoma) (ATCC, Manassas, VA, USA) was seeded into 96-well microtiter plates (Nunclon, Nunc, Germany) at a density of 1.5 × 10 4 cells/well. , After 24 h, cells were exposed to increased concentrations of tested compounds (1, 5, 10, and 50 μM) in the cell culture medium. After an incubation time of 24 h, the medium was replaced by a new fresh medium containing 0.5 mg/mL MTT (Sigma, Deisenhofen, Germany).…”

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective

“…Each of synthesized compounds showed excellent anticancer activity. Among them, compound 11 showed excellent activity at 24 and 48 h time intervals with EC 50 values of 10.2, 22.0, 18.0, 9.7, and 26.2 and 5.4, 7.5, 7.9, 4.3, and 8.5 µM, respectively with control RDS 3442 (EC 50 values of 51.8, 75.2, 34.8, 54.2, and 69.3 at 48 h respectively) [ 125 ].…”

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking

“… Structure-activity of some selected CDK-2 inhibitors [ 5 , 6 , 7 , 8 , 36 , 37 ] and structure design of our newly synthesized compounds 3 – 9 . …”