Department of Organic Chemistry and Drug Technology, Faculty of Pharmacy, Wroclaw Medical University, 211A Borowska Street, 50-556 Wrocław, Poland.
Department of Inorganic Chemistry, Faculty of Pharmacy, Wroclaw Medical University, 211A Borowska Street, 50-556 Wrocław, Poland.
Int J Mol Sci. 2022 Oct 2;23(19):11694. doi: 10.3390/ijms231911694.
Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME-administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound (with a 3-(,-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC) of 58.4 µM, exceeding the activity of fluorouracil (CC = 381.2 μM) and equaling the activity of cisplatin (CC = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound is a potentially promising candidate for the treatment of primary colorectal cancer.
癌症是一大类疾病，其中异常细胞的快速增殖通常会导致通过淋巴和血管转移到周围组织或更远的组织，使其成为全球第二大致死原因。设计现代抗癌疗法的主要挑战是开发利用特定分子靶标的选择性化合物。在这项工作中，设计、合成了新型的恶唑并[5,4-d]嘧啶衍生物，并对其进行了体外细胞毒性活性评价，针对一组四种人类癌细胞系（肺癌：A549、乳腺癌：MCF7、转移性结肠腺癌：LoVo、原发性结肠腺癌：HT29），以及它们对 P-糖蛋白的抑制能力和促凋亡活性。这些恶唑并[5,4-d]嘧啶衍生物通常与核酸嘌呤碱基结构相似，其特征在于在缩合杂环系统的 2 位具有药理学上有利的异恶唑取代基和脂肪族氨基链。获得的化合物的计算机分析确定了它们对人血管内皮生长因子受体-2（VEGFR-2）的强烈抑制活性。进行了分子对接以评估新衍生物与 VEGFR-2 活性位点的结合模式。然后，还预测了它们的物理化学、药代动力学和药理学特性（即 ADME-给药、分布、代谢和排泄），以评估其类药性。特别是，化合物（具有 3-（，-二甲基氨基）丙基取代基）对 HT29 细胞系的活性最强，其 50%细胞毒性浓度（CC）为 58.4 µM，超过了氟尿嘧啶（CC = 381.2 μM）和顺铂（CC = 47.2 µM）的活性，同时比这些参考药物对健康的人类细胞（如正常人皮肤成纤维细胞（NHDFs））的毒性更小。结果表明，化合物 是治疗原发性结直肠癌的有前途的候选药物。
