Novel estrogen receptor ligands based on an anthranylaldoxime structure: Role of the phenol-type pseudocycle in the binding process

Filippo Minutolo, Michela Antonello, Simone Bertini, Gabriella Ortore, Giorgio Placanica, Simona Rapposelli, Shubin Sheng, Kathryn E. Carlson, Benita S Katzenellenbogen, John A. Katzenellenbogen, Marco Macchia

Research output: Contribution to journalArticle

Abstract

The 3,4-diphenylsalicylaldoxime system 1 is an estrogen receptor (ER) ligand of unusual structure, having a hydrogen-bonded pseudocyclic A′-ring in place of the paradigmatic phenolic A-ring that is characteristic of most estrogens. We have investigated the role played by the pseudocycle A′ in binding to the ER by preparing 3,4-diphenylbenzaldoxime (4), a compound that completely lacks this ring but still preserves all of the other features of the original molecule 1, as well as a series of 3,4-diphenylanthranylaldoximes (5a-c) in which the nature of the heteroatom participating in the formation of pseudoring A′ has been changed from an oxygen (1) to a nitrogen that is either unsubstituted (5a) or substituted with small alkyl groups (a methyl in 5b, or an ethyl in 5c). The importance of hydrogen-bonded pseudocycle A′ in the binding process was confirmed by the fact that benzaldoxime 4 showed a greatly reduced binding affinity compared to salicylaldoxime 1. Moreover, the binding affinity improved considerably when the A′-ring contained either an unsubstituted nitrogen (5a) or an N-Me group (5b). On the other hand, the N-Et-substituted anthranyl derivative 5c showed a marked drop in binding affinity. Molecular modeling docking studies on ERα confirmed that compounds 5a and 5b fit nicely in the ligand binding pocket, with an especially comfortable fit for the N-Me group of 5b in a small hydrophobic pocket surrounded by nonpolar residues. The limited size of this pocket does not allow accommodation of N-substituents larger than a methyl group, which is consistent with the low binding affinity of the N-Et compound 5c.

Original languageEnglish (US)
Pages (from-to)4032-4042
Number of pages11
JournalJournal of Medicinal Chemistry
Volume46
Issue number19
DOIs
StatePublished - Sep 11 2003

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Phenol
Estrogen Receptors
Ligands
Hydrogen
Nitrogen
Estrogens
Oxygen

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Minutolo, F., Antonello, M., Bertini, S., Ortore, G., Placanica, G., Rapposelli, S., ... Macchia, M. (2003). Novel estrogen receptor ligands based on an anthranylaldoxime structure: Role of the phenol-type pseudocycle in the binding process. Journal of Medicinal Chemistry, 46(19), 4032-4042. https://doi.org/10.1021/jm0308390

Novel estrogen receptor ligands based on an anthranylaldoxime structure : Role of the phenol-type pseudocycle in the binding process. / Minutolo, Filippo; Antonello, Michela; Bertini, Simone; Ortore, Gabriella; Placanica, Giorgio; Rapposelli, Simona; Sheng, Shubin; Carlson, Kathryn E.; Katzenellenbogen, Benita S; Katzenellenbogen, John A.; Macchia, Marco.

In: Journal of Medicinal Chemistry, Vol. 46, No. 19, 11.09.2003, p. 4032-4042.

Research output: Contribution to journalArticle

Minutolo, F, Antonello, M, Bertini, S, Ortore, G, Placanica, G, Rapposelli, S, Sheng, S, Carlson, KE, Katzenellenbogen, BS, Katzenellenbogen, JA & Macchia, M 2003, 'Novel estrogen receptor ligands based on an anthranylaldoxime structure: Role of the phenol-type pseudocycle in the binding process', Journal of Medicinal Chemistry, vol. 46, no. 19, pp. 4032-4042. https://doi.org/10.1021/jm0308390
Minutolo, Filippo ; Antonello, Michela ; Bertini, Simone ; Ortore, Gabriella ; Placanica, Giorgio ; Rapposelli, Simona ; Sheng, Shubin ; Carlson, Kathryn E. ; Katzenellenbogen, Benita S ; Katzenellenbogen, John A. ; Macchia, Marco. / Novel estrogen receptor ligands based on an anthranylaldoxime structure : Role of the phenol-type pseudocycle in the binding process. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 19. pp. 4032-4042.
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abstract = "The 3,4-diphenylsalicylaldoxime system 1 is an estrogen receptor (ER) ligand of unusual structure, having a hydrogen-bonded pseudocyclic A′-ring in place of the paradigmatic phenolic A-ring that is characteristic of most estrogens. We have investigated the role played by the pseudocycle A′ in binding to the ER by preparing 3,4-diphenylbenzaldoxime (4), a compound that completely lacks this ring but still preserves all of the other features of the original molecule 1, as well as a series of 3,4-diphenylanthranylaldoximes (5a-c) in which the nature of the heteroatom participating in the formation of pseudoring A′ has been changed from an oxygen (1) to a nitrogen that is either unsubstituted (5a) or substituted with small alkyl groups (a methyl in 5b, or an ethyl in 5c). The importance of hydrogen-bonded pseudocycle A′ in the binding process was confirmed by the fact that benzaldoxime 4 showed a greatly reduced binding affinity compared to salicylaldoxime 1. Moreover, the binding affinity improved considerably when the A′-ring contained either an unsubstituted nitrogen (5a) or an N-Me group (5b). On the other hand, the N-Et-substituted anthranyl derivative 5c showed a marked drop in binding affinity. Molecular modeling docking studies on ERα confirmed that compounds 5a and 5b fit nicely in the ligand binding pocket, with an especially comfortable fit for the N-Me group of 5b in a small hydrophobic pocket surrounded by nonpolar residues. The limited size of this pocket does not allow accommodation of N-substituents larger than a methyl group, which is consistent with the low binding affinity of the N-Et compound 5c.",
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AU - Antonello, Michela

AU - Bertini, Simone

AU - Ortore, Gabriella

AU - Placanica, Giorgio

AU - Rapposelli, Simona

AU - Sheng, Shubin

AU - Carlson, Kathryn E.

AU - Katzenellenbogen, Benita S

AU - Katzenellenbogen, John A.

AU - Macchia, Marco

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N2 - The 3,4-diphenylsalicylaldoxime system 1 is an estrogen receptor (ER) ligand of unusual structure, having a hydrogen-bonded pseudocyclic A′-ring in place of the paradigmatic phenolic A-ring that is characteristic of most estrogens. We have investigated the role played by the pseudocycle A′ in binding to the ER by preparing 3,4-diphenylbenzaldoxime (4), a compound that completely lacks this ring but still preserves all of the other features of the original molecule 1, as well as a series of 3,4-diphenylanthranylaldoximes (5a-c) in which the nature of the heteroatom participating in the formation of pseudoring A′ has been changed from an oxygen (1) to a nitrogen that is either unsubstituted (5a) or substituted with small alkyl groups (a methyl in 5b, or an ethyl in 5c). The importance of hydrogen-bonded pseudocycle A′ in the binding process was confirmed by the fact that benzaldoxime 4 showed a greatly reduced binding affinity compared to salicylaldoxime 1. Moreover, the binding affinity improved considerably when the A′-ring contained either an unsubstituted nitrogen (5a) or an N-Me group (5b). On the other hand, the N-Et-substituted anthranyl derivative 5c showed a marked drop in binding affinity. Molecular modeling docking studies on ERα confirmed that compounds 5a and 5b fit nicely in the ligand binding pocket, with an especially comfortable fit for the N-Me group of 5b in a small hydrophobic pocket surrounded by nonpolar residues. The limited size of this pocket does not allow accommodation of N-substituents larger than a methyl group, which is consistent with the low binding affinity of the N-Et compound 5c.

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