Synthesis and biological activity of naphthalene analogues of phenstatins: Naphthylphenstatins

Novel phenstatin analogues with a 2-naphthyl moiety combined with either a 2,3,4- or a 3,4,5-trimethoxyphenyl ring have been synthesized, and their tubulin polymerization inhibiting and cytotoxic activities have been evaluated. The 2-naphthyl ring is a better replacement for the 3-hydroxy-4-methoxyphenyl ring in the phenstatin series than in the combretastatin series. For the naphthylphenstatins, the carbonyl is required, and the preferred orientation of the trimethoxyphenyl ring is the one found in combretastatins.

Graphical abstractThe synthesis and biological activity of a new family of phenstatin analogues, carrying a 2-naphthyl moiety, is reported. Compound 7 (IC50[TPI] = 1.1 μM) is more potent than combretastatin A4 (IC50[TPI] = 3 μM) in tubulin polymerization inhibition assays (TPI). The replacement of the 3-hydroxy-4-methoxyphenyl ring by a 2-naphthyl system is more favourable in the phenstatin than in the combretastatin series.Figure optionsDownload full-size imageDownload as PowerPoint slide