Chiral Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole Template: Synthesis, Absolute Configuration, and In Vitro Activity.

[摘要]：Compounds (More Than One Hetero Atom)) Section To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), the steroid sulfatase (STS) inhibitory pharmacophore was introduced to letrozole. Letrozole derivs., including sym. I (R1 = R3 = Br, OH, OMe, H2NSO2O; R2 = R4 = H, OH, H2NSO2O) and unsym. I (R1 = H, Cl, Br; R2 = OH, H2NSO2O; R3 = H; R4 = CN) derivs., bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents were synthesized. The most potent of the achiral and racemic aromatase inhibitor was I (R1 = Br; R2 = H2NSO2O; R3 = H; R4 = CN) (IC50 = 3.0 nM). Its phenolic precursor I (R1 = Br; R2 = OH; R3 = H; R4 = CN) was sepd. by chiral HPLC, and the abs. configuration of each enantiomer was detd. using vibrational and electronic CD in tandem with calcns. of the predicted spectra. Of the two enantiomers, (R)-phenol I (R1 = Br; R2 = OH; R3 = H; R4 = CN) was the most potent aromatase inhibitor (IC50 = 0.6 nM, comparable to letrozole), whereas the (S)-sulfamate I (R1 = Br; R2 = H2NSO2O; R3 = H; R4 = CN) inhibited STS most potently (IC50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compd.

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