Design, synthesis, cytotoxicity, and molecular modeling study of 2,4,6-trisubstituted pyrimidines with anthranilate ester moiety

• Published in: Medicinal chemistry research Vol. 28; no. 4; pp. 545 - 558
• Main Authors: Cheremnykh, Kirill P., Savelyev, Victor A., Pokrovskii, Mikhail A., Baev, Dmitry S., Tolstikova, Tatyana G., Pokrovskii, Andrey G., Shults, Elvira E.
• Format: Journal Article
• Language: English
• Published: New York Springer US 15-04-2019; Springer Nature B.V
• Subjects: Anticancer properties; Antitumor agents; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Breast cancer; Cancer; Cell Biology; Chemical synthesis; Cyclin-dependent kinase; Cyclin-dependent kinase 9; Cyclin-dependent kinases; Cytotoxicity; Doxorubicin; Kinases; Modelling; Molecular modelling; Monocytes; Original Research; Pharmacology/Toxicology; Prostate; Pyridines; Pyrimidines; Selectivity; Substitutes; Toxicity; Tumor cell lines; Cytotoxicity; Pyrimidines; Multicomponent reactions; CDK inhibitors; Molecular docking; Alkynes
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-019-02314-8

A series of 2,4,6-trisubstituted pyrimidines with antharanilic acid ester moiety have been designed and synthesized by employing a one-pot multicomponent approach from methyl 5-(ethynyl)anthranilate, aroyl or cinnamoyl chlorides and various amidines. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, U-937, MDA-MB-231, BT-474, DU-145) using conventional MTT assays. Structure-activity relationship analysis revealed that 4,6-diarylpyrimidines
13
–
17
, substituted with a pyridine or a pyrimidine ring in the 2 position displayed an increasing of activity compared to 2-methyl or 2-phenyl substituted pyrimidines. The 2-amino substututed compound
9
showed selectivity on the human monocyte-like cells U-937. Trisubstituted pyrimidines
18
–
21
, containing a (E)-styryl substituent in the 6 position of the pyrimidine core, demonstrated an increasing of activity against the breast cancer cell lines MDA-MB-231, BT-474, and also against the human prostate cell lines DU-145. Compounds
18
and
20
shown the best potency towards the cancer cell lines MDA-MB-231; theirs activity was comparable with the activity of Doxorubicin on this cell lines. These compounds were confirmed to be cyclin-dependent kinase 9 (CDK9) inhibitors through in silico molecular modeling studies for the mode of action. The newly synthesized compounds may serve as lead molecules for the future research regarding the identification of new anticancer agents in the pyrimidine series.