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. 2017 Aug 31;22(9):1440.
doi: 10.3390/molecules22091440.

Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation

Patrick M Kelly  1 , Niall O Keely  2 , Sandra A Bright  3 , Bassem Yassin  4 , Gloria Ana  5 , Darren Fayne  6 , Daniela M Zisterer  7 , Mary J Meegan  8   9
Affiliations

Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation

Patrick M Kelly et al. Molecules. .

Abstract

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e. g. , the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERα (IC50 = 19 nM) and ERβ (IC50 = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC50 = 5. 7 nM) and binding affinity to ERα (IC50 = 15 nM) and ERβ (IC50 = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers. VSports手机版.

Keywords: apoptosis; combretastatin A-4(CA-4); cyclofenil; endoxifen; estrogen receptor ligands; hormone-dependent breast cancer; selective estrogen receptor modulators; tumour targeting conjugates V体育安卓版. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Estradiol, selected ER antagonists and combretastatin A-4.
Scheme 1
Scheme 1
Synthesis of acrylic acids 1a–1r: Reagents and conditions: (i) (CH3CO)2O, Et3N, microwaves, 100 °C, 0.5 h, followed by conc HCl.
Scheme 2
Scheme 2
Synthesis of combretastatin-endoxifen conjugates 3a–3m. Reagents and Conditions: a (i) DCC, HOBt, CH2Cl2, 24 h, 20 °C; (ii)TBAF, THF, 0.5 h, 20 °C; b (i) EDC, HOBt, CH2Cl2, 24 h, 20 °C; (ii) TBAF, THF, 0.5 h, 20 °C.
Scheme 3
Scheme 3
Synthesis of combretastatin-amides 3n–3q: Reagents and conditions: 3o, 3q (i) Mukaiyama’s reagent, Et3N, DCM, 3 h, 20 °C; 3n (ii) (COCl)2, DMF, DCM, 1 2h,20 °C, followed by NH4OH; 3p (iii) SOCl2, DCM, Et3N, 2 h followed by NH4OH, 12 h, 20 °C.
Scheme 4
Scheme 4
Synthesis of cinnamic and propanoic acid-combretastatin hybrid conjugates 5a–5d. Reagents and conditions: (i) DCC or EDC, HOBt, CH2Cl2, 24 h, 20 °C; (ii) TBAF, THF, 0.5–24 h, 20 °C.
Scheme 5
Scheme 5
Synthesis of cyclofenil-combretastatin hybrid conjugates 13a–13e. Reagents and conditions: (i) TBDMSCl, imidazole, DMF; (ii) Zn, TiCl4; (iii) Br2(CH2)2, NaOH(aq), nBu)4NHSO3, CH2Cl2; (iv) CH3NH2, sealed tube, 60 °C; (v) TBAF, THF; (vi) EDC, HOBt, CH2Cl2, 24 h, 0 °C; (vii) TBAF, THF, 0.5 h, 0 °C.
Scheme 6
Scheme 6
Synthesis of endoxifen-combretastatin conjugates 16a–16c. Reagents and Conditions: (i) DCC, DMAP, DCM; (ii) (a) DCC, DMAP, DCM (b) TBAF, THF.
Figure 2
Figure 2
Compounds 3i, 11c, 11e, 13d and 13e potently induce apoptosis in MCF-7 cells, but not healthy PBMCs. Cells were treated for 72 h with a vehicle or the indicated compounds. After the required incubation period, cells were fixed in 1 mL ethanol and 100 μL PBS and stained with propidium iodide. Cells were subsequently analysed by flow cytometry to determine the percentage of apoptotic (A) MCF-7 cells and (B) PBMCs and G2/M-arrested (C) MCF-7 cells and (D) PBMCs. Values represent the mean ± SEM of three independent experiments.
Figure 3
Figure 3
Ranked poses of 11e in ERα and ERβ overlaid on 4-OHT X-ray structure. Carbon atoms of 11e are illustrated in dark green in ERα, dark blue in ERβ and grey in 4-OHT (oxygen atoms are red; nitrogen in dark blue; sulphur in yellow). ERα and associated water molecules are in light green, ERβ and associated water molecules are in light blue. Amino acid numbering is for ERα except when different in ERβ where both labels are used. PDB structures 3ERT [69] and 1NDE [70] were used for molecular docking.
Figure 4
Figure 4
Ranked poses of 13e in ERα and ERβ overlaid on 4-OHT X-ray structure. The potential clashing interaction between Leu525/476 (rendered in tube style) of ERβ with the methylamide of 13e is present. Carbon atoms of 13e are illustrated in dark green in ERα, dark blue in ERβ and grey in 4-OHT (oxygen atoms are red; nitrogen in dark blue; sulphur in yellow). ERα and associated water molecules are in light green, ERβ and associated water molecules are in light blue. Amino acid numbering is for ERα except when different in ERβ where both labels are used. PDB structures 3ERT [69] and 1NDE [70] were used for molecular docking.
Figure 5
Figure 5
Ranked poses of 16b in ERα and ERβ overlaid on 4-OHT X-ray structure. The potential clashing interaction between Leu525/476 (rendered in tube style) of ERβ with the methylamide of 16b is circled in red. Carbon atoms of 16b are illustrated in dark green in ERα, dark blue in ERβ and grey in 4-OHT (oxygen atoms are red; nitrogen in dark blue; sulphur in yellow). ERα and associated water molecules are in light green, ERβ and associated water molecules are in light blue. Amino acid numbering is for ERα except when different in ERβ where both labels are used. PDB structures 3ERT [69] and 1NDE [70] were used for molecular docking.
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