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. 2006 Apr 20;49(8):2496-511.
doi: 10.1021/jm0512037.

Fluorine-substituted cyclofenil derivatives as estrogen receptor ligands: synthesis and structure-affinity relationship study of potential positron emission tomography agents for imaging estrogen receptors in breast cancer

Jai Woong Seo  1 , John S Comninos, Dae Yoon Chi, Dong Wook Kim, Kathryn E Carlson, John A Katzenellenbogen
Affiliations

Fluorine-substituted cyclofenil derivatives as estrogen receptor ligands: synthesis and structure-affinity relationship study of potential positron emission tomography agents for imaging estrogen receptors in breast cancer

Jai Woong Seo et al. J Med Chem. .

Abstract

In a search for estrogen receptor (ER) ligands to be radiolabeled with fluorine-18 for imaging of ER-positive breast tumors with positron emission tomography (PET), we investigated cyclofenil analogues substituted at the C3 or C4 position of the cyclohexyl group. McMurry coupling of 4,4'-dihydroxybenzophenone with various ketones produced key cyclofenil intermediates, from which C3 and C4 substituents containing alkyl and various oxygen or fluorine-substituted alkyl groups were elaborated. Binding assays to both ERalpha and ERbeta revealed that the C3 site is more tolerant of steric bulk and polar groups than the C4 site, consistent with a computational model of the ERalpha ligand binding pocket. Fluorine substitution is tolerated very well at some sites, giving some compounds having affinities comparable to or higher than that of estradiol. These fluoro and fluoroalkyl cyclofenils merit further consideration as fluorine-18 labeled ER ligands for PET imaging of ERs in breast tumors.

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Figures

Figure 1
Figure 1
ER ligands and a pharmacophore model
Figure 2
Figure 2
Two types of cyclofenil analogues
Figure 3
Figure 3
Schematic and computational model of substituted cyclofenil interaction with the ligand binding pocket of the estrogen receptor, ERα. Panel A. Schematic picture of the interactions of the phenolic hydroxyls and the C3 and C4 cyclofenil substituents with residues in the ligand binding pocket. ERα residue numbers precede ERβ residue numbers. Panel B. Representative computational model of 4-fluorocyclofenil (20) in the ligand binding pocket of ERα. The hydrophobic residues near the C4 position are indicated. The surface shown is the ERα binding pocket displayed as dots mapped with the lipophilic potential. Residues identities are for ERα. Panel C. Representative computational model of 3-(2-fluoropropyl)cyclofenil (37c) in the ligand binding pocket of ERα. The surface is the same as Panel B. Residues identities are for ERα.
Scheme 1
Scheme 1
Reagents: (a) TiCl4, Zn, THF, reflux, 4 h.
Scheme 2
Scheme 2. Syntheses of cyclohexanones
Reagents: (a) Jones reagent, acetone, 0 °C-rt, 45 min; (b) Ac2O, pyridine, rt, 24 h; (c) methyl (triphenylphosphoranylidene)acetate, toluene, 110 °C, 8 h; (d) Pd/C, H2, EtOH, rt, 6 h; (e) SOCl2, MeOH, rt, 3 h; (f) dimethyl malonate, NaOEt (cat.), rt, 2 h; (g) i. MeMgCl, THF, −78 °C-rt, 20 min; ii. Mg, 1,2-dibromoethane, THF, rt-90 °C, 2 h; iii. 13, CuBr, THF, −78 °C-0 °C, 1 h; (h) Ac2O, pyridine, CH2Cl2, rt, 18 h.
Scheme 3
Scheme 3
Reagents: (a) 8, TiCl4, Zn, THF, reflux, 4 h; (b) methoxymethyl chloride, NaH, DMF, 0 °C-rt, 1 h; (c) K2CO3, MeOH:H2O (5:1), rt, 12 h; (d) DAST, CH2Cl2, −78 °C-rt, 1 h; (e) HCl, MeOH, rt, 12 h.
Scheme 4
Scheme 4
Reagents: (a) TiCl4, Zn, THF, reflux, 4 h; (b) methoxymethyl chloride, NaH, DMF, 0 °C-rt, 1 h; (c) LAH (1 M solution in THF), THF, 0 °C-rt, 1 h; (d) methanesulfonyl anhydride, TEA, CH2Cl2, 0 °C-rt, 1 h; (e) CsF, H2O, 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]), acetonitrile, 100 °C, 2 h; (f) HCl, MeOH, rt, 12 h; (g) bromoethane, NaH, DMF, 100 °C, 24 h; (h) 1-bromo-4-fluorobutane, NaH, DMF, 0–100 °C, 24 h.
Scheme 5
Scheme 5
Reagents: (a) TiCl4, Zn, THF, reflux, 4 h; (b) 2 M NaOH, MeOH, reflux, 2 h; (c) diglyme, 160 °C, 1 h; (d) SOCl2, MeOH, rt, 90 min; (e) methoxymethyl chloride, NaH, DMF, 0 °C-rt, 1 h; (f) i. in case of 33a,b, LAH (1 M solution in THF), THF, 0 °C-rt, 1 h, ii. in case of 30c and 33c, K2CO3, MeOH:H2O (5:1), rt, 12 h; (g) methanesulfonyl anhydride, TEA, CH2Cl2, 0 °C-rt, 1 h; (h) CsF, H2O,1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]), acetonitrile, 100 °C, 2 h; (i) HCl, MeOH, rt, 12 h; (j) DAST, CH2Cl2, −78 °C-rt, 1 h.
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