Qayyum Afreen Begum Abdul, Ali Syed Ayaz, Mokale Santosh Namdeo
Department of Pharmaceutical Chemistry, Y.B Chavan College of Pharmacy, Aurangabad, India.
Department of Pharmacology, Y.B Chavan College of Pharmacy, Aurangabad, India.
Med Chem. 2025;21(4):319-330. doi: 10.2174/0115734064316508240911032442.
Ethacrynic acid is a dynamic agent holding alpha-beta unsaturated carbonyl unit in its structure which imparts superiority and extraordinary advantage of displaying multiple biological activities such as anticancer, antiviral, anti-malarial effect, diuretic effect and inhibits the Glutathione-s-transferase p1-1 enzyme which produces hindrance in the pathway of apoptosis. Ethacrynic acid is an inhibitor of Glutathione-s-transferases. EtA by itself act as an anticancer agent at higher concentration and also increases effectiveness of other compounds used in cancer treatment by preventing their detoxification, all these facts attracted our attention to develop and evaluate novel structural analogues of ethacrynic acid for their inhibitory effect on GSTs and anti-cancer activity in breast cancer.
By attending rational drug design perspectives the research is aimed to develop and evaluate novel structural analogues of ethacrynic acid as Inhibitors of GSTs enzyme and with antibreast cancer activity.
Designed compounds were synthesized as per convenient route shown in the scheme of synthesis. Molecular docking studies were done against GSTP1-1 (PDB:3HJO). Structures of novel synthesized molecules were confirmed by spectral characterization such as FTIR, HNMR, CNMR and Mass spectrometry. ADME studies were done to ensure safety and drug like properties of the compounds. Ten structural analogues of ethacrynic acid were synthesized and evaluated for their inhibitory effect on activity of Glutathione-s-transferases which was measured by performing assay method. anti-breast cancer activity was done on MCF-7 and MDAMB-231 cell line by MTT assay.
Compound A3, A5 and A6 were found with greater inhibition of the activity of GSTs and maximum anti-proliferative activity in breast cancer.
We have effectively developed novel compounds possessing structural resemblance with ethacrynic acid Compounds of the series has shown moderate to higher inhibitory effect on GSTs and anti-proliferative activity in breast cancer. The compound A3 was found to be promising agent with high level of potency in each biological response. The research studies presented here may be an enlightening path in development of novel therapeutic agents with high level of inhibition in the activity of GSTs and anti-breast cancer effect.
依他尼酸是一种结构中含有α-β不饱和羰基单元的活性药物，具有多种生物学活性，如抗癌、抗病毒、抗疟疾作用、利尿作用，并能抑制谷胱甘肽-S-转移酶p1-1酶，该酶在细胞凋亡途径中产生阻碍。依他尼酸是谷胱甘肽-S-转移酶的抑制剂。依他尼酸本身在较高浓度时可作为抗癌剂，还可通过防止其他用于癌症治疗的化合物解毒来提高其有效性，所有这些事实引起了我们的关注，促使我们开发和评估依他尼酸的新型结构类似物，以研究其对谷胱甘肽-S-转移酶的抑制作用和对乳腺癌的抗癌活性。
从合理药物设计的角度出发，本研究旨在开发和评估依他尼酸的新型结构类似物，作为谷胱甘肽-S-转移酶的抑制剂并具有抗乳腺癌活性。
按照合成方案所示的简便路线合成设计的化合物。针对GSTP1-1（PDB：3HJO）进行分子对接研究。通过傅里叶变换红外光谱（FTIR）、核磁共振氢谱（HNMR）、核磁共振碳谱（CNMR）和质谱等光谱表征确定新合成分子的结构。进行药物代谢动力学（ADME）研究以确保化合物的安全性和类药物性质。合成了依他尼酸的10种结构类似物，并通过测定法评估它们对谷胱甘肽-S-转移酶活性的抑制作用。通过MTT法对MCF-7和MDAMB-231细胞系进行抗乳腺癌活性研究。
发现化合物A3、A5和A6对谷胱甘肽-S-转移酶活性的抑制作用更强，对乳腺癌的抗增殖活性最高。
我们有效地开发了与依他尼酸结构相似的新型化合物。该系列化合物对谷胱甘肽-S-转移酶显示出中度至高度的抑制作用以及对乳腺癌的抗增殖活性。发现化合物A3在每种生物学反应中都具有很高的效力，是一种很有前景的药物。本文提出的研究可能为开发对谷胱甘肽-S-转移酶活性具有高度抑制作用和抗乳腺癌作用的新型治疗药物提供一条有启发性的途径。
