3-Aroylindazoles: Their synthesis and potential use for cancer treatment

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A series of 3-aroyl indazoles was synthesized. The core indazole compound had an IC₅₀ of 64 nM in an H460 human lung cancer cell line cytotoxicity assay. Modification of the C-7 position resulted in a significant SAR with acetylene modifications conferring unusual potency. The activity of the simple acetylene derivative was increased by 20 times (IC₅₀ = 3 nM vs 64 nM for the core), while the propyne derivative proved to be the most potent compound being 60 times more potent (IC₅₀ = 1 nM) than the non substituted core. Alcohols were well tolerated with the linear substituted alcohols demonstrating significant potency. The tertiary alcohol was found to be much less active. Amino substitution was less tolerated, with the propargyl amine derivative being about 15 times less active than the corresponding alcohol analogue. The cis allyl alcohol derivative had comparable activity to the propargyl alcohol, while the completely hydrogenated propanol was much less active (IC₅₀ = 8 nM for propargyl alcohol derivatives vs IC₅₀ = 13 nM for allyl alcohol derivative vs IC₅₀ = 283 nM for propanol derivative). The most potent compounds are more active than combretastatin A4 (CA-4) showing single digit nM IC₅₀ values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds.