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

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

Журнал

Medicinal Chemistry Research
ISSN: 1054-2523 , E-ISSN: 1554-8120

Вых. Данные

Год: 2019, Том: 28, Номер: 4, Страницы: 545-558 Страниц : 14 DOI: 10.1007/s00044-019-02314-8

Ключевые слова

Pyrimidines; Alkynes; Multicomponent reactions; Cytotoxicity; Molecular docking; CDK inhibitors

Авторы

Cheremnykh Kirill P. ¹ , Savelyev Victor A. ¹ , Pokrovskii Mikhail A. ² , Baev Dmitry S. ^1,2 , Tolstikova Tatyana G. ¹ , Pokrovskii Andrey G. ² , Shults Elvira E. ^1,2

Организации

1	(Данные Web of science) Novosibirsk Organ Chem Inst, Med Chem Lab, Siberian Branch, Novosibirsk 630090, Russia
2	(Данные Web of science) Novosibirsk State Univ, Novosibirsk, Russia

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.

Cheremnykh K.P. , Savelyev V.A. , Pokrovskii M.A. , Baev D.S. , Tolstikova T.G. , Pokrovskii A.G. , Shults E.E.
Design, synthesis, cytotoxicity, and molecular modeling study of 2,4,6-trisubstituted pyrimidines with anthranilate ester moiety
Medicinal Chemistry Research. 2019. V.28. N4. P.545-558. DOI: 10.1007/s00044-019-02314-8 WOS Scopus РИНЦ

Опубликована online:	23 февр. 2019 г.
Опубликована в печати:	1 апр. 2019 г.

Web of science	WOS:000462753900011
Scopus	2-s2.0-85062035804
РИНЦ	38682267
OpenAlex	W2916726471