Tethered indoles as functionalizable ligands for the estrogen receptor

Abstract

To create ligands for the estrogen receptor that contain pendant groups for tethering to a poly(amido)amine (PAMAM) dendrimer, we have explored a class of N-substituted 2-phenyl indoles. Attachment of tethers of different length and chemical nature to this non-steroidal indole scaffold gave high affinity ligand-tether conjugates that can be easily functionalized. To further explore the utility of this system, an indole-conjugated dendrimer was prepared and evaluated as an estrogen receptor ligand.

Figure 1

Estradiol (E2) and 2-phenylindole estrogens

Scheme 1

(a) HCl, EtOH, 80 °C, 6 h, 84%; (b) BBr₃, CH₂Cl₂, −78 °C to r.t., 18 h, 82%; (c) 2-bromopropane, TBAH, acetone, 60 °C, 24 h, 46%.

Scheme 2

(a) NaH, 4-(3-iodopropoxy)benzaldehyde, DMF, 79%; (b) EtSH, AlCl₃, r.t. 89%-quant; (c) – i.) NH₂(CH₂)₂NHAc, MeOH, 65 °C; ii.) NaBH₄, MeOH; (d) NaH, 4-iodobutylphthalimide, r.t., 62-83%; (e) H₂NNH₂, CH₂Cl₂CHCl₂, MeOH, r.t., quant; (f) – i.) 16, CH₂Cl₂, quant; ii.) Pd/C, MeOH, quant.

Scheme 3

(a) NaH, 4-iodobutylphthalimide, DMF, 0 °C to r.t., 83%; (b) EtSH, AlCl₃, r.t., 85%; (c) TBDMSCl, imidazole, DMF, 91%; (d) H₂NNH₂, CH₂Cl₂, MeOH, r.t., 80%; (e) 21, CH₂Cl₂, THF, r.t., 80%; (f) H⁺, acetone, r.t., 72%; (g) - i.) NH₂CH₂CH₂NHAc, CH₂Cl₂, ii.) NaBH₄; (h) 1N HCl/MeOH, r.t., quant; (i) - i.) G-6 PAMAM, MeOH, Δ; ii.) NaBH₄, quant.