Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment.

IF 4.3 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2024-10-17 eCollection Date: 2025-02-19 DOI:10.1021/acsbiomedchemau.4c00079

Patamawadee Silalai, Pimpisa Teeyakasem, Dumnoensun Pruksakorn, Rungnapha Saeeng

{"title":"Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment.","authors":"Patamawadee Silalai, Pimpisa Teeyakasem, Dumnoensun Pruksakorn, Rungnapha Saeeng","doi":"10.1021/acsbiomedchemau.4c00079","DOIUrl":null,"url":null,"abstract":"Mycophenolic acid (MPA), a natural compound, was modified to new MPA analogues via the classical method of silylation and esterification. Their cytotoxicity was evaluated in vitro on four osteosarcoma cancer cell lines (MNNG/HOS, U2OS, 143B, and SaOS-2) and human normal cells (hFOB 1.19). The most potent silicon-containing compound 2d (R1 = TPS, R2 = H) exhibited good cytotoxic activity against all osteosarcoma cancer cell lines with IC50 values ranging from 0.64 to 2.27 μM and showing low cytotoxicity against normal cells. Further investigations revealed that compound 2d (R1 = TPS, R2 = H) displayed significant inhibition of IMPDH2 with K i app 1.8 μM. Furthermore, molecular modeling studies were performed to investigate the binding affinity of 2d (R1 = TPS, R2 = H) which can effectively bind to critical amino acids of three proteins (vascular endothelial growth factor receptor 2; VEGFR-2, cyclin-dependent kinase 2; CDK2, inosine-5'-monophosphate dehydrogenase; IMPDH) involved in cancer therapy. This finding suggests that triphenylsilyl-MPA (TPS-MPA) analogue could serve as a promising starting point for developing new anticancer drugs for osteosarcoma.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"106-118"},"PeriodicalIF":4.3000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843339/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Bio & Med Chem Au","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1021/acsbiomedchemau.4c00079","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/19 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Mycophenolic acid (MPA), a natural compound, was modified to new MPA analogues via the classical method of silylation and esterification. Their cytotoxicity was evaluated in vitro on four osteosarcoma cancer cell lines (MNNG/HOS, U2OS, 143B, and SaOS-2) and human normal cells (hFOB 1.19). The most potent silicon-containing compound 2d (R¹ = TPS, R² = H) exhibited good cytotoxic activity against all osteosarcoma cancer cell lines with IC₅₀ values ranging from 0.64 to 2.27 μM and showing low cytotoxicity against normal cells. Further investigations revealed that compound 2d (R¹ = TPS, R² = H) displayed significant inhibition of IMPDH2 with K _i _app 1.8 μM. Furthermore, molecular modeling studies were performed to investigate the binding affinity of 2d (R¹ = TPS, R² = H) which can effectively bind to critical amino acids of three proteins (vascular endothelial growth factor receptor 2; VEGFR-2, cyclin-dependent kinase 2; CDK2, inosine-5'-monophosphate dehydrogenase; IMPDH) involved in cancer therapy. This finding suggests that triphenylsilyl-MPA (TPS-MPA) analogue could serve as a promising starting point for developing new anticancer drugs for osteosarcoma.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

治疗骨肉瘤的霉酚酸类似物的设计与合成。

摘要对天然化合物霉酚酸（MPA）进行了经典的硅基化和酯化改性，得到了新的类似物。体外对4种骨肉瘤细胞系（MNNG/HOS、U2OS、143B和SaOS-2）和人正常细胞（hFOB 1.19）进行细胞毒性评价。最有效的含硅化合物2d （R1 = TPS, R2 = H）对所有骨肉瘤细胞系具有良好的细胞毒活性，IC50值在0.64 ~ 2.27 μM之间，对正常细胞具有较低的细胞毒性。进一步研究发现，化合物2d （R1 = TPS, R2 = H）在1.8 μM的K浓度下对IMPDH2有明显的抑制作用。此外，通过分子模拟研究，研究了2d （R1 = TPS, R2 = H）的结合亲和力，它可以有效地结合三种蛋白质的关键氨基酸(血管内皮生长因子受体2；VEGFR-2，周期蛋白依赖性激酶2；CDK2，肌苷-5′-单磷酸脱氢酶；IMPDH)参与癌症治疗。这一发现提示，三苯基硅基- mpa （TPS-MPA）类似物可作为开发骨肉瘤新抗癌药物的一个有希望的起点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

ACS Bio & Med Chem Au 药物、生物、化学-

CiteScore

4.10

自引率

0.00%

发文量

期刊介绍： ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.