TY - JOUR

T1 - Design, synthesis, cytotoxicity, and molecular modeling study of 2,4,6-trisubstituted pyrimidines with anthranilate ester moiety

AU - Cheremnykh, Kirill P.

AU - Savelyev, Victor A.

AU - Pokrovskii, Mikhail A.

AU - Baev, Dmitry S.

AU - Tolstikova, Tatyana G.

AU - Pokrovskii, Andrey G.

AU - Shults, Elvira E.

N1 - Publisher Copyright: © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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.

AB - 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.

KW - Alkynes

KW - CDK inhibitors

KW - Cytotoxicity

KW - Molecular docking

KW - Multicomponent reactions

KW - Pyrimidines

UR - http://www.scopus.com/inward/record.url?scp=85062035804&partnerID=8YFLogxK

U2 - 10.1007/s00044-019-02314-8

DO - 10.1007/s00044-019-02314-8

M3 - Article

AN - SCOPUS:85062035804

VL - 28

SP - 545

EP - 558

JO - Medicinal Chemistry Research

JF - Medicinal Chemistry Research

SN - 1054-2523

IS - 4

ER -