Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines.

IF 2.2 4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Bioimpacts Pub Date : 2024-01-01 Epub Date: 2023-12-18 DOI:10.34172/bi.2023.29951
Chaithra R Shetty, C S Shastry, Parasuraman P, Srinivas Hebbar
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Abstract

Introduction: Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6.

Methods: We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site.

Results: The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c-6OQO complex.

Conclusion: By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements.

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噻唑并吡啶嘧啶:作为 CDK4/6 抑制、合成和乳腺癌细胞株细胞毒性筛选的先导药物的硅学评估。
简介吡啶嘧啶属于一类化合物,其特点是含有氮作为杂原子。这类化合物具有多种生物效应,尤其有望用作抗癌剂,包括抑制 CDK4/6 的作用:我们设计并合成了一系列取代的噻唑并吡啶嘧啶(4a-p)。利用 CDK4/6 的晶体结构进行了 ADME/T 计算分析和分子对接。随后,我们合成了得分最高的化合物,利用红外光谱、核磁共振和质谱对它们进行了表征,并利用 SRB 试验评估了它们对 MCF-7 和 MDAMB-231 细胞系的影响。为了进一步评估稳定性,对结合位点内两种最有希望的化合物进行了分子动力学模拟:对接得分表明,化合物 4a、4c、4d 和 4g 的相互作用更强。因此,这些特定的化合物(4a、4c、4d 和 4g)被选中进行合成和随后的筛选,以评估它们的细胞毒性作用。值得注意的是,化合物 4c 和 4a 在两种测试细胞系中的 IC50 值都表现出了最有希望的活性。此外,分子动力学模拟研究发现,4c-6OQO 复合物的稳定性更高:结论:综合计算、体外和分子动力学模拟研究结果,化合物 4c 成为未来研究的主要候选化合物。在吡啶嘧啶环上 8-苯基取代基的 C2 位置存在极性羟基似乎有助于提高该化合物的活性。通过对结构进行改进,可以进一步提高其细胞毒性潜力。
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来源期刊
Bioimpacts
Bioimpacts Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
4.80
自引率
7.70%
发文量
36
审稿时长
5 weeks
期刊介绍: BioImpacts (BI) is a peer-reviewed multidisciplinary international journal, covering original research articles, reviews, commentaries, hypotheses, methodologies, and visions/reflections dealing with all aspects of biological and biomedical researches at molecular, cellular, functional and translational dimensions.
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