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Novel Pyrazolo[3,4-d]pyrimidines as Potential Cytotoxic Agents: Design, Synthesis, Molecular Docking and CDK2 Inhibition.

Abstract：

BACKGROUND:Pyrazolo[3,4-d]pyrimidine scaffold was reported to possess potent cytotoxic and CDK2 inhibitory activity as analogue of roscovitine. OBJECTIVE:To design and synthesize novel 1-(4-flourophenyl)pyrazolo[3,4-d]pyrimidine derivatives as bioisosters of roscovitine with potential cytotoxic and CDK2 inhibitory activity. METHODS:A series of novel 1-(4-flourophenyl)pyrazolo[3,4-d]pyrimidines were designed and synthesized. Structural elucidation for all the newly synthesized compounds was achieved through performing MS, 1H NMR, 13C NMR and IR spectral techniques. Eight compounds were screened for their cytotoxic activity by National Cancer Institute (USA) against 60 different human cancer cell lines. Compounds 2a, 4, 6, 7b, 8a and 8b were further studied through the determination of their IC50 values against the most sensitive cell lines. The inhibitory activities of compounds 2a and 4 were evaluated against CDK2 enzyme. RESULTS:Compound 4 exhibited the most prominent broad-spectrum cytotoxic activity against 42 cell lines representing all human cancer types showing growth inhibition percentages from 53.19 to 99.39. Compound 2a showed promising selectivity against several cell lines. Moreover, all the test compounds exhibited potent cytotoxic activity in nanomolar to micromolar range with IC50 values ranging from 0.58 to 8.32μM. Compound 2a showed significant cytotoxic activity against CNS (SNB-75), lung (NCI-H460) and ovarian (OVCAR-4) cancer cell lines with IC50 values 0.64, 0.78 and 1.9μM, respectively. Compound 4 showed promising potency against leukemia (HL-60) and CNS (SNB-75) cell lines (IC50 = 0.58 and 0.94μM, sequentially). Moreover, the antiproliferative activities of compounds 2a and 4 appeared to correlate well with their ability to inhibit CDK2 at sub-micromolar level (IC50 = 0.69 and 0.67μM, respectively) that were comparable to roscovitine (IC50=0.44μM). The Molecular docking results revealed that compound 4 interacted with the same key amino acids as roscovitine in the active site of CDK2 enzyme with a marked docking score (-14.1031 kcal/mol). CONCLUSION:1-(4-Flourophenyl)pyrazolo[3,4-d]pyrimidine is a promising scaffold for the design and synthesis of potent cytotoxic leads.

journal_name

Anticancer Agents Med Chem

journal_title

Anti-cancer agents in medicinal chemistry

authors

Maher M,Kassab AE,Zaher AF,Mahmoud Z

doi

10.2174/1871520619666190417153350

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

1368-1381

issue

eissn

1871-5206

issn

1875-5992

pii

ACAMC-EPUB-98148

journal_volume

pub_type

杂志文章

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Novel Pyrazolo[3,4-d]pyrimidines as Potential Cytotoxic Agents: Design, Synthesis, Molecular Docking and CDK2 Inhibition.