Maher, M., A. S. M. A. A. E. KASSAB, A. S. H. R. A. F. F. ZAHER, and Z. Mahmoud, "Novel pyrazolo[3,4-d]pyrimidines as potential cytotoxic agents: Design, synthesis, molecular docking and CDK2 inhibition.", Anti-cancer agents in medicinal chemistry, 2019. Abstract

BACKGROUND: Pyrazolo[3,4-d]pyrimidine scaffold was reported to possess potent cytotoxic and CDK2 inhibitory activity as analogue of roscovitine.

OBJECTIVE: Design and synthesis of 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 was 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 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 8.32 μM. 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 1.9 μM, respectively. Compound 4 showed promising potency against leukemia (HL-60) and CNS (SNB-75) cell lines (IC50 = 0.58 and 0.94 μM, sequentially). Moreover, the anti-proliferative activities of compounds 2a and 4 appeared to correlate well with their ability to inhibit CDK2 at sub-micromolar level (IC50 = 0.69 and 0.67 μM, respectively) that were comparable to roscovitine (IC50=0.44 μM). 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.

Maher, M., Synthesis of Some Fused Pyrazolopyrimidine Derivatives with Expected Anticancer Activity., , Cairo, Faculty of Pharmacy - Cairo University, Submitted.
Maher, M., A. S. M. A. A. E. KASSAB, A. S. H. R. A. F. F. ZAHER, and Z. Mahmoud, "Design, synthesis and anticancer activity of novel pyrazolo[3,4-d]pyrimidines as bioisosteres of roscovitine leading to identification of potent CDK2 inhibitor.", Ninth International Scientific Conference of Faculty of Pharmacy, Cairo University - “Globally Recognized Egyptian Pharmaceutical Ingredients - A National Priority”, Central Library of Cairo University, El-Kassemy Hall - Cairo University Campus - Cairo - Egypt, 25th-26th April, 2018.
Maher, M., A. S. M. A. A. E. KASSAB, A. S. H. R. A. F. F. ZAHER, and Z. Mahmoud, "Novel pyrazolo[3,4-d]pyrimidines: design, synthesis, anticancer activity, dual EGFR/ErbB2 receptor tyrosine kinases inhibitory activity, effects on cell cycle profile and caspase-3-mediated apoptosis.", Journal of enzyme inhibition and medicinal chemistry, vol. 34, issue 1, pp. 532-546, 2019. Abstract

A series of novel pyrazolo[3,4-d]pyrimidines was synthesised. Twelve synthesised compounds were evaluated for their anticancer activity against 60 human tumour cell lines by NCI (USA). Compound 7d proved prominent anticancer activity. It showed 1.6-fold more potent anti-proliferative activity against OVCAR-4 cell line with IC = 1.74 μM. It also exhibited promising potent anticancer activity against ACHN cell line with IC value 5.53 μM, representing 2.2-fold more potency than Erlotinib. Regarding NCI-H460 cell line, compound 7d (IC = 4.44 μM) was 1.9-fold more potent than Erlotinib. It inhibited EGFR and ErbB2 kinases at sub-micromolar level (IC = 0.18 and 0.25 µM, respectively). Dual inhibition of EGFR and ErbB2 caused induction of apoptosis which was confirmed by a significant increase in the level of active caspase-3 (11-fold). It showed accumulation of cells in pre-G1 phase and cell cycle arrest at G2/M phase.

Tourism