Indazole-based microtubule-targeting agents as potential candidates for anticancer drugs discovery

• Published in: Bioorganic chemistry 2022-05, Vol.122, p.105735-105735, Article 105735
• Main Authors: Pal, Dilipkumar, Song, In-ho, Dashrath Warkad, Shrikant, Song, Keum-soo, Seong Yeom, Gyu, Saha, Supriyo, Shinde, Pramod B., Balasaheb Nimse, Satish
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - chemistry; Binding Sites; Cancer; Cell Line, Tumor; Cell Proliferation; Colchicine - metabolism; Colchicine - pharmacology; Drug development; Indazole; Indazoles - metabolism; Indazoles - pharmacology; Microtubule targeting agents; Microtubules - metabolism; Scaffold; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemistry
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105735

[Display omitted] Tremendous research is focused on developing novel drug candidates targeting microtubules to inhibit their function in several cellular processes, including cell division. In this regard, several indazole derivatives were sought to target the colchicine binding site on the β-tubulin, a crucial protein required to form microtubules, to develop microtubule targeting agents. Even though there are several reviews on the indazole-based compounds, none of them focused on using indazole scaffold to develop microtubule targeting agents. Therefore, this review aims to present the advances in research on compounds containing indazole scaffolds as microtubule targeting agents based on the articles published in the last two decades. Among the articles reviewed, we found that compounds 6 and 7 showed the lowest IC50 values of 0.6 ∼ 0.9 nM in the cell line studies, making them the strongest indazole derivatives that target microtubules. The compounds 30, 31, 37 (IC50 = ∼ 1 nM) and compounds 8, 38 (IC50 = ∼ 2 nM) have proved to be potent microtubule inhibitors. The compounds 18, 31, 44, 45 also showed strong anticancer activity (IC50 = ∼ 8 nM). It is important to notice that except for compounds 9, 12, 13, 15, and SRF, the top activity compounds including 6, 7, 8, 10, 11, 30, 31, 37, 44, and 45 contain 3,4,5‑trimethoxyphenyl substitution similar to that of colchicine. Therefore, it appears that the 3,4,5‑trimethoxyphenyl substituent on the indazole scaffold is crucial for targeting CBS.