Bandaru Praveen Kumar, Nidasanametla Satya Kameswara Rao, Shyamala Pulipaka
Department of Chemistry, Andhra University, Vishakhapatnam, Andhra Pradesh, India.
Aragen Life Sciences Pvt. Ltd., Hyderabad, Telangana, India.
Anticancer Agents Med Chem. 2025;25(6):420-432. doi: 10.2174/0118715206333935241004070350.
The development of new therapies targeting crucial kinases involved in cancer progression is a promising area of research. Pyrazolo pyrimidine derivatives have emerged as potential candidates for this purpose.
This study aims to synthesize pyrazolo pyrimidine derivatives (5a-5r), evaluate their molecular docking against key kinases, and assess their anticancer activity.
The synthesis involved a multi-step procedure starting with the cyclization of 6-amino-2- methylpyrimidin-4(3H)-one (1) to form 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-ol (2). This was followed by chlorination to yield 4-chloro-2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine (3) and nucleophilic substitution to produce 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-amine (4). The final derivatives (5a-5r) were synthesized through amide bond formation with various carboxylic acids using DCC and DMAP. Structural elucidation was confirmed via NMR, mass spectrometry, and HRMS. Molecular docking studies were conducted against Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and cyclin-dependent kinase 4 (CDK4). Anticancer activity was evaluated against MCF-7, SET-2, and HCT-116 cell lines.
Structural elucidation confirmed the successful synthesis of the derivatives. Molecular docking studies revealed promising binding affinities for selected derivatives, particularly those with heterocyclic substitutions. Anticancer activity evaluation showed diverse potency profiles, with several derivatives demonstrating IC50 values comparable to the reference drug, doxorubicin. Derivatives featuring nitro and heterocyclic moieties exhibited significant anticancer activity.
The synthesized pyrazolo pyrimidine derivatives showed potential as lead compounds for further development due to their promising binding affinities and significant anticancer activity, particularly those with nitro and heterocyclic moieties.
开发针对参与癌症进展的关键激酶的新疗法是一个很有前景的研究领域。吡唑并嘧啶衍生物已成为实现这一目标的潜在候选物。
本研究旨在合成吡唑并嘧啶衍生物（5a - 5r），评估它们与关键激酶的分子对接情况，并评估它们的抗癌活性。
合成过程涉及多步反应，首先是6 - 氨基 - 2 - 甲基嘧啶 - 4(3H) - 酮（1）环化形成2 - 甲基 - 4,7 - 二氢 - 3H - 吡咯并[2,3 - d]嘧啶 - 4 - 醇（2）。接着进行氯化反应生成4 - 氯 - 2 - 甲基 - 4,7 - 二氢 - 3H - 吡咯并[2,3 - d]嘧啶（3），然后通过亲核取代反应制备2 - 甲基 - 4,7 - 二氢 - 3H - 吡咯并[2,3 - d]嘧啶 - 4 - 胺（4）。最终的衍生物（5a - 5r）通过使用二环己基碳二亚胺（DCC）和4 - 二甲氨基吡啶（DMAP）与各种羧酸形成酰胺键来合成。通过核磁共振（NMR）、质谱和高分辨质谱（HRMS）对结构进行了确证。针对 Janus 激酶 1（JAK1）、Janus 激酶 2（JAK2）和细胞周期蛋白依赖性激酶 4（CDK4）进行了分子对接研究。针对 MCF - 7、SET - 2 和 HCT - 116 细胞系评估了抗癌活性。
结构确证证实了衍生物的成功合成。分子对接研究显示所选衍生物具有良好的结合亲和力，特别是那些具有杂环取代的衍生物。抗癌活性评估显示出不同的效力概况，几种衍生物的半数抑制浓度（IC50）值与参考药物阿霉素相当。具有硝基和杂环部分的衍生物表现出显著的抗癌活性。
合成的吡唑并嘧啶衍生物因其良好的结合亲和力和显著的抗癌活性，特别是那些具有硝基和杂环部分的衍生物，显示出作为进一步开发的先导化合物的潜力。
