Background: Indazole is a promising structure present in various biological activity compounds; in particular, many 6-aminoindazole-containing compounds demonstrated anticancer activity. In our previous research, we discovered some of the 6-aminoindazole derivatives with excellent cytotoxicity in the human colorectal cancer cell line (HCT116).
Objective: In this study, a series of 6-substituted amino-1H-indazole derivatives were designed and synthesized through simple and well-known chemical reactions, which were evaluated for anti-proliferative activity in four human cancer cell lines.
Methods: The title compounds were designed based on the structures of potential anticancer candidates in our previous report. The synthesis of 6-aminoindazole derivatives through acetylation and reductive amination with 6-amininoindazole as the starting material. Sulforhodamin B (SRB) assay was used for in vitro biological evaluation of synthesized compounds. Various physicochemical properties of them were predicted by online site Molinspiration.
Results: Seven out of eight synthesized compounds showed growth inhibitory activity with IC50 values from 2.9 to 59.0 μM range in all four tested cancer cell lines. Of them, the compound N-(4-fluorobenzyl)- 1H-indazol-6-amine (9f) exhibited a potent anti-proliferative activity, with an IC50 value of 14.3±4.4 μM in the human colorectal cancer cell (HCT116) and non-cytotoxicity in the normal cell (lung fibroblast cells, MRC5, IC50 >100 μM).
Conclusion: The bioactivity result and conformance of the physicochemical properties of the synthesized compounds to the "rule of three" for hit-like compounds suggested that 9f was effective and could be used as a hit for the development of novel anticancer agents.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00266] [PMID: 26487916]
[http://dx.doi.org/10.1021/jm0302039] [PMID: 14667220]
[http://dx.doi.org/10.1016/j.bmcl.2013.03.075] [PMID: 23566519]
[http://dx.doi.org/10.1021/jm801322h] [PMID: 19175319]
[http://dx.doi.org/10.1016/j.bmc.2017.12.041] [PMID: 29317150]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01626] [PMID: 28225269]
[http://dx.doi.org/10.1016/j.ejmech.2016.08.026] [PMID: 27573544]
[http://dx.doi.org/10.1002/ardp.201300390] [PMID: 24554280]
[http://dx.doi.org/10.1016/j.bmcl.2016.01.037] [PMID: 26810260]
[http://dx.doi.org/10.1093/jnci/82.13.1107] [PMID: 2359136]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00064] [PMID: 27003761]
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]