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Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

The synthesis and in vitro biological evaluation (JEG‐3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave‐enhanced Suzuki cross‐coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem‐ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC50 value of 0.12 nM, although seven of its congeners are also highly potent (IC50≤0.5 nM). They all bear the (5‐triazolylmethyl‐2‐cyano)biphenyl structural motif. Docking of representative compounds into a homology model of human aromatase assists in the rationalisation of the SAR derived from the in vitro biological results and supports a crucial role for a cyano group on the “A” phenyl ring, which is accessible to hydrogen bond interactions with Ser 478. Further development of these compounds as potential therapeutic agents for the treatment of hormone‐dependent breast cancer is warranted given the high level of potency observed for this class of aromatase inhibitor in vitro.