Review
Pharmacology & Pharmacy
Ashima Dhiman, Rupam Sharma, Rajesh K. Singh
Summary: Cancer, the second leading cause of death after heart disease, is characterized by the uncontrolled growth of cells. Targeting specific genes and proteins involved in the growth and survival of cancer cells has become a top priority in global research. Indole moiety, a combination of aromatic-heterocyclic compounds, has emerged as a promising scaffold for the development of anticancer drugs due to its bioavailability, unique chemical properties, and significant pharmacological behaviors. Recent advances in the medicinal chemistry of indole derivatives, including the synthesis of potential anticancer compounds and their mechanism of action, are discussed in this review.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Biochemistry & Molecular Biology
Yu Hong, Yuan-Yuan Zhu, Qiuqin He, Shuang-Xi Gu
Summary: This review summarizes the recent progress in the development of indole derivatives as tubulin polymerization inhibitors from 2010 to present. It provides useful clues and inspirations for the further design of outstanding inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Gang Li, Jia-Qiang Wu, Xiaojia Cai, Wen Guan, Zhijun Zeng, Yanghui Ou, Xiaoyun Wu, Jiayu Li, Xiangxiang Fang, Jinling Liu, Yali Zhang, Huamin Wang, Canqiang Yin, Hongliang Yao
Summary: A series of diaryl heterocyclic analogues were synthesized as tubulin polymerization inhibitors. Compound 6y exhibited the highest antiproliferative activity against HCT-116 colon cancer cells and effectively inhibited tubulin polymerization in vitro. It also showed high metabolic stability on human liver microsomes and suppressed tumor growth in a HCT-116 mouse colon model without toxicity. These results suggest that 6y represents a new class of tubulin inhibitors worthy of further investigation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Bharat Goel, Shivani Jaiswal, Shreyans K. K. Jain
Summary: Microtubules are important intracellular targets for anticancer activity. Various drugs, such as paclitaxel and vinblastine, act by altering the dynamics of microtubules. In this study, the potential of indole derivatives as colchicine-binding site inhibitors is reviewed. These derivatives have shown the ability to inhibit cancer cell proliferation, induce apoptosis, and disrupt microtubule formation. Understanding the structure-activity relationship of these compounds could lead to the development of novel and effective cancer therapies.
ARCHIV DER PHARMAZIE
(2023)
Article
Biochemistry & Molecular Biology
Magdalena Peruzynska, Aleksandra Borzyszkowska-Ledwig, Jacek G. Sosnicki, Lukasz Struk, Tomasz J. Idzik, Gabriela Maciejewska, Lukasz Skalski, Katarzyna Piotrowska, Pawel Lukasik, Marek Drozdzik, Mateusz Kurzawski
Summary: This study successfully obtained a mitotic-specific inhibitor with high antiproliferative activity and selectivity through structural modifications. By inhibiting tubulin polymerization in a dose-dependent manner, aberrant mitotic spindle formation was induced, leading to cell cycle arrest and apoptosis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Yingying Kang, Yuanyuan Pei, Jinling Qin, Yixin Zhang, Yongtao Duan, Hua Yang, Yongfang Yao, Moran Sun
Summary: A library of new pyrimidine analogs was synthesized and compound K10 showed the most potent activity against four cancer cell lines, inhibiting microtubule polymerization and inducing apoptosis in HepG2 cells. It also inhibited the migration and invasion of HepG2 cells. Overall, this study suggests that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5-trimethoxyphenyl ring may be a promising candidate for cancer therapy.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Pharmacology & Pharmacy
Laura Gallego-Yerga, Valentin Cena, Rafael Pelaez
Summary: The use of benzothiazole scaffold in designing colchicine site ligands has resulted in a new family of ligands with high water solubility. These ligands exhibit antiproliferative activity against various cancer cell lines, with high selectivity towards cancer cells. The most potent derivatives show nanomolar range IC50 values, even in difficult-to-treat glioblastoma cells. Flow cytometry experiments and confocal microscopy observations confirm the cell cycle arrest and apoptotic cell death induced by these ligands, which are attributed to their ability to disrupt microtubule network. Docking studies further support the interaction of the ligands at the colchicine binding site. These results validate the effective strategy of developing potent anticancer colchicine ligands with improved water solubility.
Article
Biochemistry & Molecular Biology
Laura Gallego-Yerga, Andrea Jazmin Chiliquinga, Rafael Pelaez
Summary: Increasing awareness of the structure of microtubules has driven research on targeting tubulin for novel chemotherapies, particularly for glioblastoma multiforme (GBM) cells. Optimization of potently anti-tubulin drugs with improved pharmacokinetic properties is challenging, but the use of ensemble pharmacophore screening has led to the development of a new tetrazole-based tubulin inhibitor. This inhibitor demonstrated remarkable antimitotic effects against various cancer cells, especially GBM cells, with high selectivity and overcome the limitations typically associated with tubulin binding agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Guangcheng Wang, Min He, Wenjing Liu, Meiyan Fan, Yongjun Li, Zhiyun Peng
Summary: A series of new 2-phenyl-4,5,6,7-tetrahydro-1H-indole derivatives were synthesized and evaluated for their anti-proliferative activities, with one compound showing the most potent anticancer activity against breast cancer and lung cancer cells while sparing normal liver cells. Mechanism studies revealed that the compound arrested cell cycle and induced apoptosis, and effectively inhibited tubulin polymerization with an inhibitory mechanism similar to colchicine. Molecular docking studies indicated high binding affinities for the colchicine binding pocket of tubulin, suggesting potential as new tubulin polymerization inhibitors.
ARABIAN JOURNAL OF CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Dalal Sulaiman Alshaya, Rana M. O. Tawakul, Islam Zaki, Ali H. Abu Almaaty, Eman Fayad, Yasmin M. Abd El-Aziz
Summary: A new series of acrylic acid and acrylate ester derivatives were synthesized and evaluated for their antiproliferative activity against MCF-7 breast carcinoma cells. Methyl acrylate ester 6e showed the highest cytotoxicity with an IC50 value of 2.57 +/- 0.16 mu M and exhibited inhibition of beta-tubulin polymerization. Compound 6e arrested MCF-7 cells at the G2/M phase and enhanced apoptotic power, while also affecting the gene expression levels of p53, Bax, and Bcl-2.
Article
Biochemistry & Molecular Biology
Ahmed M. Almehdi, Sameh S. M. Soliman, Abdel-Nasser A. El-Shorbagi, Andrew D. Westwell, Rania Hamdy
Summary: This study designed and synthesized a series of indole-based compounds, and found that U2 and U3 exhibited the highest anticancer activity against MCF-7 cells and potential BCL-2 inhibition activity. Molecular docking analysis suggested stable interactions between U2 and Bcl-2 through multiple mechanisms. In addition, U2 induced apoptosis and cell cycle arrest. U2 also showed a favorable safety profile.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Medicinal
Fatima Naaz, Kumari Neha, Md Rafi Haider, Syed Shafi
Summary: Indole-based tubulin inhibitors are compounds that disrupt the dynamic equilibrium of microtubule polymerization and depolymerization. Indole moiety is significant for developing new drug candidates for cancer therapy. Synthetic indole derivatives with antitubulin activity have been identified and reported in the past decade, showcasing diverse structure-activity relationships and biological activities.
FUTURE MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Bharat Goel, Biswajit Dey, Essha Chatterjee, Nancy Tripathi, Nivedita Bhardwaj, Sanjay Kumar, Santosh Kumar Guru, Shreyans K. Jain
Summary: In this study, gloriosine and other compounds were isolated from Gloriosa superba roots and evaluated for their antiproliferative activities against various cancer cell lines. Gloriosine showed significant selective anticancer activity, inducing apoptosis and inhibiting cell migration.
Article
Chemistry, Physical
Mohammed Hawash, Deniz Cansen Kahraman, Abdurrahman Olgac, Sezen Guntekin Ergun, Ernest Hamel, Rengul Cetin-Atalay, Sultan Nacak Baytas
Summary: In this study, novel compounds with polar and nonpolar substitutions on the prop-2-en-1-on linker of the trans-indol-3-ylacrylamide scaffold were designed and synthesized. The antiproliferative activities of these compounds against hepatocellular carcinoma were evaluated, and five of the compounds showed moderate antitumor activities. Compound 13 was identified as a tubulin polymerization inhibitor and induced G2/M-phase arrest in Huh7 cells. The results suggest that polar substitutions enhance the potency against tubulin polymerization.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Chemistry, Multidisciplinary
Muhammad Khattab, Ahmed A. Al-Karmalawy
Summary: This study confirmed through quantum mechanics calculations and binding affinities that Flubendazole may be a promising candidate for anticancer therapy.
FRONTIERS IN CHEMISTRY
(2021)
