11.beta.-Substituted Estradiol Derivatives, Potential High-Affinity Carbon-11-Labeled Probes for the Estrogen Receptor: A Structure-Affinity Relationship Study

Napolitano, Elio; Fiaschi, Rita; Carlson, Kathryn E.; Katzenellenbogen, John A.

doi:10.1021/jm00003a005

Cited by 30 publications

(23 citation statements)

References 8 publications

(16 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This route is a more efficient and versatile method than the alternative approach which involves Grignard addition to an 11-oxo derivative followed by eventual deoxygenation. 33,34,67 …”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 11β-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists

Hanson¹,

Hua²,

Hendricks³

et al. 2012

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Introduction As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11β-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11β-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11β-aryl estradiol analogs or their potential as scaffolds for drug conjugation. Methods We prepared and characterized a series of 11β-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ERβ-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists. Results The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ERα-LBD, ranging from 13–83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11β-substituent than upon the nature of the terminal group Conclusions We have developed a synthetic strategy that provides facile access to potent 11β-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ERα-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11β-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11β-aryl estradiol analogs as potential drug delivery systems and imaging agents.

show abstract

“…This route is a more efficient and versatile method than the alternative approach which involves Grignard addition to an 11-oxo derivative followed by eventual deoxygenation. 33,34,67 …”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 11β-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists

Hanson¹,

Hua²,

Hendricks³

et al. 2012

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…The compounds of these four sets are included in Tables I–IV, along with their observed biological activities in terms of RBA values. The first set of derivatives contains 21 compounds 21, the second set contains 17 compounds 22, 23, the third set contains 29 compounds 24, and the fourth set contains 38 compounds 25. The eigenvalue of frontier orbitals (HOMO and LUMO) and the values of absolute hardness (η), global softness ( S ), electronegativity (χ), and chemical potential (μ) for the estrogen derivatives were calculated and are presented in Tables V–VIII.…”

Section: Resultsmentioning

confidence: 99%

“…The 105 estrogen derivatives used as study material are listed in Tables I–IV along with their observed biological activity in terms of RBA. The relative binding affinity of estrogens was collected from the literature 21–25. These binding affinity determinations, which have often been done by different competitive binding affinity assay methods using different receptor preparation, were all placed on a common “relative binding affinity” RBA scale.…”

Section: Methodsmentioning

confidence: 99%

QSAR study of estrogens with the help of PM3‐based descriptors

Pasha

Srivastava²,

Singh³

2005

Int J of Quantum Chemistry

View full text Add to dashboard Cite

Quantum chemical descriptors (⑀ HOMO , ⑀ LUMO , absolute hardness, global softness, chemical potential, and electronegativity) and energy descriptors (Q min , ⌬H f 0 , E T , and E E ) based QSAR study of estrogen derivatives was made with the help of PM3 calculations on WinMOPAC 7.21 software. The observed RBA values of estrogens were taken from the literature. QSAR models were made using different quantum chemical and energy descriptors with the help of multiple linear regression analysis. Regression models indicate that absolute hardness in combination with different energy descriptors provide better correlation between observed relative binding affinity (RBA) and predicted relative binding affinity (PA). Regression models for other quantum chemical descriptors with energy descriptors are not as clear as in the case of absolute hardness. Hardness provides a better picture due to the maximum hardness principle and can be used as a QSAR model for predicting the biological activity of any compound.

show abstract

“…In vivo the complexes may achieve high antitumor effects identical to high dosed steroidal or non-steroidal estrogens. However, a participation of the cytotoxic PtL 2 moi----2) Introduction of various substituents at position 7α of estradiol results in pure antiestrogens [23] while substituents such as a 11β-ethyl group enhance the receptor affinity of E2 to RBA = 3000 [24] . Figure 9.…”

Section: Meso-1-ptsomentioning

confidence: 99%

Structure Activity Studies on Leaving Group Derivatives of [meso-1,2-Bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-platinum(II)

Gust¹,

Keilitz

Krauser

et al. 1999

Arch. Pharm. Pharm. Med. Chem.

View full text Add to dashboard Cite

The spatial structures of leaving group derivatives of [meso‐1,2‐bis(2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamine]platinum(II) (meso‐1‐PtL2; L2 = SO4, Cl2, I2, CBDC (cyclobutane‐1,1‐dicarboxylate)) were investigated by NMR methods and correlated with their reactivity against nucleophiles, their estrogenic potency, and their activity on the hormone dependent MCF‐7 mammary carcinoma cell line. It was demonstrated that beside the non‐leaving group meso‐1 the PtL2 moiety of meso‐PtL2 complexes is important for the estrogen receptor binding. Among the tested complexes meso‐1‐PtI2 possesses the highest affinity for the estrogen receptor (RBA = 2.6) and represents a strong estrogen on the MCF‐7‐2a cell line. The use of CBDC as leaving group decreases the effects. Meso‐1‐PtCBDC shows an RBA of 0.06 and has only half of the estrogenic activity. Both complexes are sufficiently stable under physiological conditions, so a transformation into the dichloroplatinum( II) complex prior to the binding to the estrogen receptor can be excluded. Due to their high stability meso‐1‐PtI2 and meso‐1‐ PtCBDC were only marginally active on the human estrogen receptor positive MCF‐7 cell line, while meso‐1‐PtSO4 and meso‐1‐PtCl2 reduced the cell growth to T/Cmax = 45% and 25%, respectively.

show abstract

11.beta.-Substituted Estradiol Derivatives, Potential High-Affinity Carbon-11-Labeled Probes for the Estrogen Receptor: A Structure-Affinity Relationship Study

Cited by 30 publications

References 8 publications

Synthesis and evaluation of 11β-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists

Synthesis and evaluation of 11β-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists

QSAR study of estrogens with the help of PM3‐based descriptors

Structure Activity Studies on Leaving Group Derivatives of [meso-1,2-Bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-platinum(II)

Contact Info

Product

Resources

About