Structure‐Activity Relationships and Potent Cytotoxic Activities of Terphenyllin Derivatives from a Small Compound Library

A small library of 120 compounds was established with seventy new alkylated derivatives of the natural product terphenyllin, together with 45 previous reported derivatives and four natural p‐terphenyl analogs. The 70 new derivatives were semi‐synthesized and evaluated for cytotoxic activities against four cancer cell lines. Interestingly, 2′,4′′‐diethoxyterphenyllin, 2′,4,4′′‐triisopropoxyterphenyllin, and 2′,4′′‐bis(cyclopentyloxy)terphenyllin showed potent activities with IC₅₀ values in a range from 0.13 to 5.51 μM, which were similar to those of the positive control, adriamycin. The preliminary structure–activity relationships indicated that the introduction of alkyl substituents including ethyl, allyl, propargyl, isopropyl, bromopropyl, isopentenyl, cyclopropylmethyl, and cyclopentylmethyl are important for improving the cytotoxicity.