Synthesis and in-vitro anti-proliferative evaluation of some pyrazolo[1,5-a]pyrimidines as novel larotrectinib analogs

• Published in: Bioorganic chemistry Vol. 94; pp. 103458 - 103469
• Main Authors: Attia, Mohamed H., Elrazaz, Eman Z., El-Emam, Soad Z., Taher, Azza T., Abdel-Aziz, Hatem A., Abouzid, Khaled A.M.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.01.2020; Elsevier
• Subjects: Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; MDA-MB231 cell line; Molecular Structure; Physical Sciences; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazolo[15-a]pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; Synthesis; MDA-MB231 cell line; Synthesis; Pyrazolo[15-a]pyrimidine; Anticancer activity; DESIGN; PHENYL AMIDES; BIOLOGICAL EVALUATION; PYRIDINES; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103458

Pyrazolopyrimidines 11f, 16b and 11i showed potent antiproliferative activity towards Huh-7, HeLa and MCF-7 cell lines with IC50 = 6.3, 7.8 and 3.0 µM, whereas 11i and 16b exhibited IC50 = 4.32 µM and 5.74 µM, against MDA-MB231 cell lines. 11i induced a reduction in G1 phase with arrest in S phase and G2/M phase of MCF-7 cells. 16b induced a reduction in G1 phase and arrest in G2/M phase of Hela cells. 11i induced arrest in G1 phase and reduction in S phase of MDA-MB-231 cells. 11i induced an arrest in G1 phase with reduction in S phase of MDA-MB-231. [Display omitted] •A series of pyrazolo[1,5-a]pyrimidines 11a–j, 16a–c and 22 were synthesized.•11f, 16b and 11i emerged as the most active compounds against 4 tested cells.•11i and 16b showed potent activity against MDA-MB231 cell lines.•11i induced a reduction in G1 phase with arrest in S and G2/M phase of MCF-7 cells.•16b induced a reduction in G1 phase with arrest in G2/M phase of Hela cells. A series of 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3-carbonitriles 11a–j and 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles 16a–c was synthesized by the reaction of 5-amino-3-phenyl-1H-pyrazole-4-carbonitrile (5) with 3-(dimethylamino)-1-arylprop-2-en-1-ones 6a–j or 2-aryl-3-(dimethylamino)acrylonitriles 12a–c, respectively. In addition, 7-amino-5-oxo-2-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (22) was prepared from the reaction of compound 5 with ethyl cyanoacetate. The anticancer activity of the newly synthesized compounds against Huh-7, HeLa, MCF-7 and MDA-MB231 cell lines showed moderate activity of compound 11f as anti-proliferative agent against Huh-7 cell line with IC50 = 6.3 µM when compared with doxorubicin (IC50 = 3.2 µM). On the other hand, compound 16b revealed potent anti-proliferative activity against HeLa cell line with IC50 = 7.8 µM when compared with doxorubicin (IC50 = 8.1 µM). Also compound 11i exhibited a promising anti-proliferative activity against MCF-7 cell line (IC50 = 3.0 µM) whereas IC50 of doxorubicin = 5.9 µM, finally compounds 11i and 16b have potent activity as anti-proliferative agents against MDA-MB231 cell line with IC50 = 4.32 and 5.74 µM, respectively when compared with doxorubicin (IC50 = 6.0 µM).