Aryl Cyclopentadienyl Tricarbonyl Rhenium Complexes: Novel Ligands for the Estrogen Receptor with Potential Use as Estrogen Radiopharmaceuticals

Mull, Eric; Sattigeri, Viswajanani J.; Rodriguez, Alice L.; Katzenellenbogen, John A.

doi:10.1016/s0968-0896(01)00406-0

Cited by 64 publications

(51 citation statements)

References 46 publications

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“…21 The aryl cyclopentadienyl tricarbonyl rhenium complexes and their organic analogues, aryl cyclopentadienes, form the basis of our study. In order to compare our Re results to previously studied organic ligands, we included several steroidal analogues of estradiol.…”

Section: Resultsmentioning

confidence: 99%

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

Wolohan

Reichert

2007

Steroids

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OPLS all atom force field parameters were developed in order to model a diverse set of novel rhenium based estrogen receptor ligands whose relative binding affinities (RBA) to the estrogen receptor alpha isoform (ERα) with respect to 17β-Estradiol were available. The binding properties of these novel rhenium based organometallic complexes were studied with a combination of Comparative Molecular Similarity Indices Analysis (CoMSIA) and docking. A total of 29 estrogen receptor ligands consisting of 11 rhenium complexes and 18 organic ligands were docked inside the ligand-binding domain (LBD) of ERα utilizing the program Gold. The top ranked pose was used to construct CoMSIA models from a training set of 22 of the estrogen receptor ligands which were selected at random. In addition scoring functions from the docking runs and the polar volume (PV) were also studied to investigate their ability to predict RBA ERα. A partial least-squares analysis consisting of the CoMSIA steric, electrostatic and hydrophobic indices together with the polar volume proved sufficiently predictive having a correlation coefficient, r 2 , of 0.94 and a cross-validated correlation coefficient, q 2 , utilizing the leave one out method of 0.68. Analysis of the scoring functions from Gold showed particularly poor correlation to RBA ERα which did not improve when the rhenium complexes were extracted to leave the organic ligands. The combined CoMSIA and polar volume model ranked correctly the ligands in order of increasing RBA ERα, illustrating the utility of this method as a prescreening tool in the development of novel rhenium based estrogen receptor ligands.

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Section: Resultsmentioning

confidence: 99%

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

Wolohan

Reichert

2007

Steroids

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“…Mull and Katzenellenbogen synthesized a rhenium tricarbonyl species to target oestrogen-receptor positive tumours. [19] The steroid mimic contained a substituted cyclopentadienyl with phenol groups radiating from the central core. This concept produced a high affinity ligand for the oestrogen receptor, and was the first example of an organometallic rhenium core being situated directly in a receptor-binding pocket.…”

Section: Probe Design: Pendant Versus Integratedmentioning

confidence: 99%

An Integrated Imaging Probe Design: The Synthesis of ^99mTc/Re‐Containing Macrocyclic Peptide Scaffolds

Hickey

Simpson

Hou³

et al. 2014

Chemistry A European J

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β-Sheets account for over 30 % of all secondary structural conformations found in proteins. The intramolecular hydrogen bonding that exists between the two peptide strands is imperative in maintaining this secondary structure. With the proper design, cyclic peptides may act as scaffolds emulating active β-sheet regions, enabling investigation of their importance in molecular recognition and protein aggregation. Starting from Fmoc-Lys(Fmoc)-OH, macrocyclic peptides were synthesized on a solid support, with peptide-chain elongation extending from both the alpha and epsilon amines of the lysine. The branching peptides were cyclized with a pyridyl tridentate chelation core followed by coordination using [(99m) Tc/Re(CO)3 (H2 O)3 ](+) . Variable temperature (1) H NMR spectroscopy studies were performed, demonstrating that intramolecular hydrogen bonding exists between the two sides of the uncoordinated macrocyclic peptide scaffolds. Additionally, computational modelling and circular dichroism spectroscopic analysis revealed that the peptide backbone exists in a similar conformation both before and after metal coordination. The ability to seamlessly incorporate a tridentate chelation core into the backbone of a macrocyclic peptide, without disrupting the secondary structure, can greatly assist in the design of metal-centric peptidomimetic imaging agents. This novel integrated imaging probe approach may facilitate the investigation into protein-protein interactions using macrocyclic β-sheet scaffolds.

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“…15 -17 In addition, recent papers have used molecular modelling as an aid to understanding the structure-affinity relationships of several 1,1-diaryl-ethylene motifs with the ERs binding site. 18,19 We have also previously used this approach in the OHferrocifen series. 20 Based on Katzenellenbogen's work 21 for 1,1-paradiphenol motifs, we suggest that the binding of one of the phenols in 1a is similar to the association of the A ring of estradiol with Glu 353, H 2 O, Arg 394 while the other phenol group is directed towards the 11-β pocket (Scheme 6).…”

Section: Biochemical Studiesmentioning

confidence: 99%

“…More recently, Mull et al reported the synthesis of substituted cyclopentadienyltricarbonylrhenium species from the corresponding cyclopentadienyllithium compounds at room temperature using [BrRe(CO) 3 THF] 2 with yields ranging from 37 to 83%. 13 THF is the solvent of choice for this reaction because it can also act as a labile ligand after replacement of two carbonyls on the rhenium complex before transmetallation. Nevertheless, the lowest reflux temperature of that solvent in comparison with toluene's one is not in favour of such a substitution within 3 h (the formation of [BrRe(CO) 3 THF] 2 from BrRe(CO) 5 needs 22 h to be complete) and could explain the difference in yields in these two solvents (Table 1, entries 1 and 8).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of cyclopentadienyltricarbonylrhenium substituted benzhydryl species and oestrogen receptor binding properties

Plażuk

Bideau

Pérez‐Luna

et al. 2006

Applied Organom Chemis

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6-(4-Methoxyphenyl)fulvene has been efficiently engaged in a process implying nucleophilic attack of methyllithium followed by a transmetallation reaction in the presence of different organorhenium sources {XRe(CO) 5 : X = Cl, Br, OTf; BrRe(CH 3 CN) 2 (CO) 3 , [BrRe(CO) 3 THF] 2 } to afford the corresponding cyclopentadienyltricarbonylrhenium-substituted compound. This study allowed us to determine the best complex for that transformation, and similar reaction conditions were used with success to provide new potential radiopharmaceuticals in the cold series. One of these compounds [the (4,4 -dihydroxybenzhydryl)cyclopentadienyltricarbonylrhenium] displays a good recognition for the α form of the oestrogen receptor.

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Aryl Cyclopentadienyl Tricarbonyl Rhenium Complexes: Novel Ligands for the Estrogen Receptor with Potential Use as Estrogen Radiopharmaceuticals

Cited by 64 publications

References 46 publications

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

An Integrated Imaging Probe Design: The Synthesis of ^99mTc/Re‐Containing Macrocyclic Peptide Scaffolds

Synthesis of cyclopentadienyltricarbonylrhenium substituted benzhydryl species and oestrogen receptor binding properties

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Aryl Cyclopentadienyl Tricarbonyl Rhenium Complexes: Novel Ligands for the Estrogen Receptor with Potential Use as Estrogen Radiopharmaceuticals

Cited by 64 publications

References 46 publications

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

An Integrated Imaging Probe Design: The Synthesis of 99mTc/Re‐Containing Macrocyclic Peptide Scaffolds

Synthesis of cyclopentadienyltricarbonylrhenium substituted benzhydryl species and oestrogen receptor binding properties

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An Integrated Imaging Probe Design: The Synthesis of ^99mTc/Re‐Containing Macrocyclic Peptide Scaffolds