Glioblastoma multiforme (GBM) is a highly-aggressive, dreadful disease with poor prognosis and disappointing clinical success. There is an unmet medical need of molecularly-targeted therapeutics for GBM treatment. In the present work, a series of novel 2-phenyl-substituted 4-amino–6,7-dihydro-5H-cyclopenta[d]pyrimidines was designed, synthesized, purified, characterized, and evaluated for cytotoxicity against glioblastoma cell line U87-MG. The design process (virtual library enumeration around the core, physicochemical and molecular property prediction/calculation of the designs, filtering the undesirable ones, and the diversity analyses of the lead-like designs), was carefully curated so as to obtain a set of structurally-diverse, novel molecules (total 20), with a particular focus on the relatively unexplored core structure, 6,7-dihydro-5H-cyclopenta[d]pyrimidine. The preliminary screening was done using MTT assay at 10 and 100 μM concentrations of the title compounds F₁−F₂₀ and positive control cisplatin, which yielded six hits (% inhibition at 10 μM: ~50%)—F₂, F₃, F₅, F₇, F₁₅, and F₂₀, which were taken up for IC₅₀ determination. The top hits F₂ and F₇ (IC₅₀ < 10 μM) were further used for computational studies such as target prediction, followed by their molecular docking in the binding sites of the top-3 predicted targets (epidermal growth factor receptor kinase domain, cyclin-dependent kinase 2 [CDK2]) /cyclin E, and anaplastic lymphoma kinase [ALK]). The docking pose analyses revealed interesting trends. The relatively planar core structure, presence of favorable hinge-binding substructures, basic groups, all added up, and culminated in appreciable cytotoxicity against GBM cell line.

中文翻译：

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成功发现新型 2-苯基取代的 4-氨基–6,7-二氢-5H-环戊[d]嘧啶作为潜在的抗胶质母细胞瘤疗法：设计、合成、生物学评估和计算筛选

多形性胶质母细胞瘤 (GBM) 是一种高度侵袭性、可怕的疾病，预后不良且临床成功率令人失望。用于 GBM 治疗的分子靶向疗法存在未满足的医疗需求。在目前的工作中，一系列新型 2-苯基取代的 4-氨基-6,7-二氢-5 H-cyclopenta[d]pyrimidines 被设计、合成、纯化、表征，并评估了对胶质母细胞瘤细胞系 U87-MG 的细胞毒性。设计过程（围绕核心的虚拟库枚举、设计的物理化学和分子特性预测/计算、过滤不需要的设计以及类先导设计的多样性分析）经过精心策划，以获得一组结构-多样化的新型分子（总共 20 个），特别关注相对未开发的核心结构，6,7-dihydro-5 H -cyclopenta[d]pyrimidine。使用 MTT 法在 10 和 100 μM 浓度的标题化合物F ₁ - F _{20下进行初步筛选}和阳性对照顺铂，产生六次命中（10 μM 时的抑制百分比：~50%）— F ₂、F ₃、F ₅、F ₇、F ₁₅和F ₂₀，用于 IC ₅₀测定。顶部命中F ₂和F ₇ (IC ₅₀ < 10 μM) 进一步用于目标预测等计算研究，然后在前 3 个预测目标（表皮生长因子受体激酶结构域、细胞周期蛋白依赖性激酶 2 [CDK2]）/细胞周期蛋白的结合位点进行分子对接E，和间变性淋巴瘤激酶 [ALK]）。对接姿势分析揭示了有趣的趋势。相对平面的核心结构、有利的铰链结合亚结构、碱性基团的存在，所有这些加起来，最终导致对 GBM 细胞系的明显细胞毒性。