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糖和核苷类似物的合成及其抗癌和镇痛潜力的评估。

Synthesis of Sugar and Nucleoside Analogs and Evaluation of Their Anticancer and Analgesic Potentials.

机构信息

Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh.

Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Osaka 565-0871, Japan.

出版信息

Molecules. 2022 May 29;27(11):3499. doi: 10.3390/molecules27113499.

DOI:10.3390/molecules27113499
PMID:35684435
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9182362/
Abstract

Chemical modification of sugars and nucleosides has a long history of producing compounds with improved selectivity and efficacy. In this study, several modified sugars (-) and ribonucleoside analogs (-) have been synthesized from α-d-glucose in a total of 21 steps. The compounds were tested for peripheral anti-nociceptive characteristics in the acetic acid-induced writhing assay in mice, where compounds , , and showed a significant reduction in the number of writhes by 56%, 62%, and 63%, respectively. The compounds were also tested for their cytotoxic potential against human HeLa cell line via trypan blue dye exclusion test followed by cell counting kit-8 (CCK-8) assay. Compound demonstrated significant cytotoxic activity with an IC value of 54 µg/mL. Molecular docking simulations revealed that compounds , , and had a comparable binding affinity to cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Additionally, the bridged nucleoside analogs and potently inhibited adenosine kinase enzyme as well, which indicates an alternate mechanistic pathway behind their anti-nociceptive action. Cytotoxic compound demonstrated strong docking with cancer drug targets human cytidine deaminase, proto-oncogene tyrosine-protein kinase Src, human thymidine kinase 1, human thymidylate synthase, and human adenosine deaminase 2. This is the first ever reporting of the synthesis and analgesic property of compound and the cytotoxic potential of compound .

摘要

糖和核苷的化学修饰在产生具有改善的选择性和功效的化合物方面有着悠久的历史。在这项研究中，总共从α-d-葡萄糖合成了几种修饰的糖（-）和核糖核苷类似物（-）。这些化合物在小鼠醋酸诱导的扭体试验中测试了外周抗伤害感受特性，其中化合物、和分别使扭体次数减少了 56%、62%和 63%。这些化合物还通过台盼蓝染料排除试验和细胞计数试剂盒-8（CCK-8）试验测试了它们对人宫颈癌细胞系的细胞毒性潜力。化合物表现出显著的细胞毒性活性，IC 值为 54 µg/mL。分子对接模拟表明，化合物、和与环氧化酶-1（COX-1）和环氧化酶-2（COX-2）酶具有相当的结合亲和力。此外，桥接核苷类似物和也能强烈抑制腺苷激酶酶，这表明它们的镇痛作用背后存在另一种机制途径。细胞毒性化合物与癌症药物靶点人胞苷脱氨酶、原癌基因酪氨酸蛋白激酶Src、人胸苷激酶 1、人胸苷酸合成酶和人腺苷脱氨酶 2 具有很强的对接。这是首次报道化合物和化合物的合成和镇痛特性以及化合物的细胞毒性潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/101d5003b3b6/molecules-27-03499-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/59f6653bb8e6/molecules-27-03499-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/a8d83bbc8b3f/molecules-27-03499-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/8245a2d2f56b/molecules-27-03499-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/feb8cf957bc1/molecules-27-03499-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/43ef7fcb5690/molecules-27-03499-g004a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/7ded2beb135e/molecules-27-03499-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/409513fd49c0/molecules-27-03499-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/d6c46feca020/molecules-27-03499-g007a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/c61e22d76c70/molecules-27-03499-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/739fa56304fa/molecules-27-03499-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4b/9182362/101d5003b3b6/molecules-27-03499-g010.jpg

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