Design, Synthesis and Biochemical Evaluation of Estrogen Receptor Ligand Conjugates as Tumour Targeting Agents

Keely, Niall O.; Zisterer, Daniela M.; Meegan, Mary J.

doi:10.2174/157018012799129864

Cited by 4 publications

(6 citation statements)

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“…A bromoethylation reaction was carried out using an excess of dibromoethane in the presence of a phase-transfer catalyst(( n Bu) 4 NHSO 4 ) in basic conditions in order to introduce a bromoethylether functionality at the hydroxyl group position on the triarylethylene backbone in moderate yields (52%–54%). Methylamine undergoes reaction with the relevant bromide analogues 7 and 8 in a sealed tube to form the silyl-protected endoxifen 9 [ 16 ] and the disilylated endoxifen analogue 10 in moderate to high yields (55%–93%). The silyl ether protecting groups were removed using TBAF to afford the endoxifen 11 and hydroxyendoxifen 12 in high yields (80%–93%).…”

Section: Resultsmentioning

confidence: 99%

“…The reaction is worked up via the addition of a sodium carbonate/sodium hydrogencarbonate pH 10 buffer solution (50 mL) and the organics were extracted with dichloromethane (3 × 50 mL). The organic phases were combined, dried over sodium sulfate and the solvent evaporated in vacuo to afford a crude product, which is then purified via flash chromatography (dichloromethane:methanol) to afford the product 9 as a brown oil (0.38 g, 78%, E/Z = 1.3:1) [ 16 ]. 1 H-NMR (400 MHz, CDCl 3 ): δ 0.13 (s, 0.57 × 6H, Si(CH 3 ) 2 ), 0.26 (s, 0.43 × 6H, Si(CH 3 ) 2 ), 0.95–1.03 (m, 12H, (CH 3 ) 3 ), 2.45–2.53 (m, 5H, NCH 3 , CH 2 ), 2.89 (s, 0.43 × 2H, CH 2 ), 2.99 (s, 0.57 × 2H, CH 2 ), 3.36 (s, 1H, NH), 3.95 (t, 0.43 × 2H, J = 5.0 Hz, CH 2 ), 4.11 (t, 0.43 × 2H, J = 5.0 Hz, CH 2 ), 6.50–7.20 (m, 13H, ArH).…”

Section: Methodsmentioning

confidence: 99%

“…Conjugates have been designed containing multiple pharmacophore elements or ligands, individually separated by a linker group, which aim to exert a synergistic and improved selective action on the target disease [ 13 ]. To date, a number of ER-targeting conjugates have been reported which attempt to exploit the high affinity and receptor selectivity of estrogen receptor ligands to deliver cytotoxic drugs to tumour cells [ 14 , 15 , 16 , 17 , 18 ]. In our investigation, antagonistic ER-ligands are key structural components utilised as the conjugate’s targeting mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

et al. 2016

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Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC50 value: 0.9 nM) and ERβ (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

et al. 2016

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“…In the hybrid ligand 10 , ( Z / E )-4-OH-tamoxifen is attached to an aromatic ring of cyano-combretastatin using a succinamide linkage [ 43 ]. Compound 10 showed only moderate binding to ERα (IC 50 = 254 nM) and moderate antiproliferative activity (IC 50 = 1.64 µM) in MCF-7 cells.…”

Section: Hybrid Ligands Incorporating 4-hydroxytamoxifenmentioning

confidence: 99%

Anticancer Drug Conjugates Incorporating Estrogen Receptor Ligands

2022

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Hormone-dependent cancers, such as certain types of breast cancer are characterized by over-expression of estrogen receptors (ERs). Anticancer drug conjugates combining ER ligands with other classes of anticancer agents may not only benefit from dual action at both anti-cancer targets but also from selective delivery of cytotoxic agents to ER-positive tumor cells resulting in less toxicity and adverse effects. Moreover, they could also take advantage of overcoming resistance typical for anti-hormonal monotherapy such as tamoxifen. In this review, we discuss the design, structures and pharmacological effects of numerous series of drug conjugates containing ER ligands such as selective ER modulators (tamoxifen, 4-hydroxytamoxifen, endoxifen), selective ER degraders (ICI-164384) and ER agonists (estradiol) linked to diverse anti-cancer agents including histone-deacetylase inhibitors, DNA-alkylating agents, antimitotic agents and epidermal growth factor receptor inhibitors.

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“…ER ligand conjugates of cytotoxic agents, photodynamic therapeutic agents and radioligands which deliver cytotoxic agents have been reported [ 31 , 37 ]. We have previously reported stable conjugates of endoxifen (a tamoxifen metabolite and ER antagonist) with DNA alkylating agents, aromatase inhibitors, COX2 inhibitors and antitubulin compounds which demonstrate antiproliferative and ER binding effects [ 38 ]. We have also reported related conjugates based on the 2-arylindole scaffold structure which selectively target the ER in hormone dependent breast cancers [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Design, Synthesis and Biochemical Evaluation of Estrogen Receptor Ligand Conjugates as Tumour Targeting Agents

Cited by 4 publications

References 0 publications

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

Anticancer Drug Conjugates Incorporating Estrogen Receptor Ligands

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

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