“…As might be predicted from the crystal structure, para-or meta-chlorine substitution (3 and 19) afforded similarly potent compounds in both biochemical and cellular assays. ortho-Chloro substitution (20) led to a 10-fold drop in biochemical potency, perhaps because this substitution induced an unfavorable twist between the two unsaturated systems. However, the ortho-methyl and para-chloro substitutions (23) were tolerated, leading to a compound with potency similar to that of the parent, suggesting that the ortho-chloro substituent was not tolerated due to an unfavorable electrostatic interaction, rather than a steric one.…”