Click chemistry to probe Hsp90: Synthesis and evaluation of a series of triazole-containing novobiocin analogues

Abstract

A series of triazole-containing novobiocin analogues has been designed, synthesized and their inhibitory activity determined. These compounds contain a triazole ring in lieu of the amide moiety present in the natural product. The anti-proliferative effects of these compounds were evaluated against two breast cancer cell lines (SKBr-3 and MCF-7), and manifested activities similar to their amide-containing counterparts. In addition, Hsp90-dependent client protein degradation was observed via Western blot analyses, supporting a common mode of Hsp90 inhibition for both structural classes.

Figure 1

Hsp90 C-terminal inhibitors

Figure 2

Western blot analysis for compound 14b

Scheme 1

Reagents:(a) (i) POCl₃, DMF, MeCN; (ii) H₂O (55%); (b) N-acetyl glycine, NaOAc, Ac₂O; (c) HCl, EtOH (d) NaNO₂, HCl, EtOH, H₂O, then NaN₃ (52% 3 steps); (e) Ac₂O, pyridine, CH₂Cl₂ (> 95%)

Scheme 2

"Click" procedure with various alkynes used. ^aThe TMS protected alkynes were used in these reactions with the addition of 1 eq. TBAF

Scheme 3

Noviosylation of triazole appended coumarins.