新型吡唑并[3,4-d]嘧啶类化合物作为潜在的细胞毒剂：设计、合成、分子对接和 CDK2 抑制。
Novel Pyrazolo[3,4-d]pyrimidines as Potential Cytotoxic Agents: Design, Synthesis, Molecular Docking and CDK2 Inhibition.
机构信息
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
出版信息
Anticancer Agents Med Chem. 2019;19(11):1368-1381. doi: 10.2174/1871520619666190417153350.
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, H NMR, C 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 IC 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 IC 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 IC values 0.64, 0.78 and 1.9μM, respectively. Compound 4 showed promising potency against leukemia (HL-60) and CNS (SNB-75) cell lines (IC = 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 (IC = 0.69 and 0.67μM, respectively) that were comparable to roscovitine (IC=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.
背景
吡唑并[3,4-d]嘧啶支架被报道具有有效的细胞毒性和 CDK2 抑制活性，是罗西维林类似物。
目的
设计并合成新型 1-(4-氟苯基)吡唑并[3,4-d]嘧啶衍生物，作为罗西维林的生物等排体，具有潜在的细胞毒性和 CDK2 抑制活性。
方法
设计并合成了一系列新型 1-(4-氟苯基)吡唑并[3,4-d]嘧啶。通过 MS、H NMR、C NMR 和 IR 光谱技术对所有新合成的化合物进行了结构确证。通过美国国家癌症研究所（NCI）对 60 种不同的人癌细胞系进行筛选，评估了 8 种化合物的细胞毒性。化合物 2a、4、6、7b、8a 和 8b 进一步通过测定对最敏感细胞系的 IC 值来研究。测定了化合物 2a 和 4 对 CDK2 酶的抑制活性。
结果
化合物 4 对代表所有人类癌症类型的 42 种细胞系表现出最显著的广谱细胞毒性活性，其生长抑制率为 53.19%至 99.39%。化合物 2a 对几种细胞系表现出良好的选择性。此外，所有测试化合物均表现出纳米至微摩尔范围内的有效细胞毒性，IC 值范围为 0.58 至 8.32μM。化合物 2a 对 CNS（SNB-75）、肺（NCI-H460）和卵巢（OVCAR-4）癌细胞系具有显著的细胞毒性活性，IC 值分别为 0.64、0.78 和 1.9μM。化合物 4 对白血病（HL-60）和 CNS（SNB-75）细胞系表现出良好的潜力（IC = 0.58 和 0.94μM，分别）。此外，化合物 2a 和 4 的抗增殖活性似乎与其在亚微摩尔水平抑制 CDK2 的能力密切相关（IC = 0.69 和 0.67μM，分别），与罗西维林（IC=0.44μM）相当。分子对接结果表明，化合物 4 与罗西维林在 CDK2 酶的活性部位与相同的关键氨基酸相互作用，具有显著的对接评分（-14.1031 kcal/mol）。
结论
1-(4-氟苯基)吡唑并[3,4-d]嘧啶是设计和合成有效细胞毒性先导物的有前途的支架。
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