Eman M H Abbas, Rehab Sabour, Norah A Alsaiari, Hanadi Y Medrasi, Asmaa F Kassem, Thoraya A Farghaly
{"title":"作为具有潜在抗乳腺癌活性的强效 Hsp90 抑制剂的新型托烷杂交化合物的设计、合成和对接。","authors":"Eman M H Abbas, Rehab Sabour, Norah A Alsaiari, Hanadi Y Medrasi, Asmaa F Kassem, Thoraya A Farghaly","doi":"10.2174/0109298673313163240829094557","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Breast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231).</p><p><strong>Methods: </strong>Novel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened in vitro to determine their ability to inhibit the activity of Hsp90.</p><p><strong>Results: </strong>All tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC50 values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC50 = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC50 value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme.</p><p><strong>Conclusion: </strong>We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity.\",\"authors\":\"Eman M H Abbas, Rehab Sabour, Norah A Alsaiari, Hanadi Y Medrasi, Asmaa F Kassem, Thoraya A Farghaly\",\"doi\":\"10.2174/0109298673313163240829094557\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Breast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231).</p><p><strong>Methods: </strong>Novel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened in vitro to determine their ability to inhibit the activity of Hsp90.</p><p><strong>Results: </strong>All tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC50 values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC50 = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC50 value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme.</p><p><strong>Conclusion: </strong>We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.</p>\",\"PeriodicalId\":10984,\"journal\":{\"name\":\"Current medicinal chemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0109298673313163240829094557\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0109298673313163240829094557","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity.
Background and objective: Breast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231).
Methods: Novel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened in vitro to determine their ability to inhibit the activity of Hsp90.
Results: All tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC50 values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC50 = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC50 value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme.
Conclusion: We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.
期刊介绍:
Aims & Scope
Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.