Ertugrul Berrak, Aytatli Abdulmelik, Karatas Omer Faruk, Saracoglu Nurullah
Department of Chemistry, Faculty of Sciences, Ataturk University 25240 Erzurum Türkiye
Department of Molecular Biology and Genetics, Erzurum Technical University 25050 Erzurum Türkiye.
RSC Med Chem. 2023 May 29;14(7):1362-1376. doi: 10.1039/d3md00157a. eCollection 2023 Jul 20.
Modulation of existing drugs is an attractive strategy to achieve improved activity in cancer therapy by lowering their effective dose. Preparation of relatives has been suggested and explored to improve the therapeutic effect of anticancer agents. In the current study, we attempted to modulate tamoxifen (TMX) by replacing the -phenyl ring in its backbone with an indole or oxindole. In addition, it was possible to convert indole-modified tamoxifens to the corresponding 3,3'-bis(indolyl)methanes (BIMs) an electrophilic substitution reaction with various benzaldehydes. We analyzed the anticancer potential of these indole-modified tamoxifens against various breast cancer cell lines and identified certain tamoxifen relatives with the potential to treat estrogen receptor (ER)-positive breast cancers, based on preliminary results of cell viability and caspase activity assays. The indole-modified tamoxifen , , and selectively reduced the viability of receptor-sensitive breast cancer cells more effectively than tamoxifen and suppressed the expression of ER-regulated genes. Moreover, Caspase-8 activity showed a specific increase in MCF-7 cells treated with these compounds. Our results indicate that these compounds may be an alternative to tamoxifen for the treatment of breast cancer.
对现有药物进行结构修饰是一种颇具吸引力的策略，可通过降低有效剂量来提高癌症治疗活性。人们已提出并探索制备相关物以提高抗癌药物的治疗效果。在本研究中，我们尝试通过用吲哚或异吲哚取代他莫昔芬（TMX）主链中的苯环来对其进行结构修饰。此外，通过与各种苯甲醛进行亲电取代反应，有可能将吲哚修饰的他莫昔芬转化为相应的3,3'-双（吲哚基）甲烷（BIMs）。基于细胞活力和半胱天冬酶活性测定的初步结果，我们分析了这些吲哚修饰的他莫昔芬对各种乳腺癌细胞系的抗癌潜力，并鉴定出了某些具有治疗雌激素受体（ER）阳性乳腺癌潜力的他莫昔芬相关物。吲哚修饰的他莫昔芬 、 和 比他莫昔芬更有效地选择性降低了受体敏感型乳腺癌细胞的活力，并抑制了ER调控基因的表达。此外，在用这些化合物处理的MCF-7细胞中，半胱天冬酶-8活性呈现出特异性增加。我们的结果表明，这些化合物可能是治疗乳腺癌的他莫昔芬替代物。
