Synthesis and biological evaluation of salpichrolide analogs as antiestrogenic agents

Sonego, Juan Manuel; Rivero, Ezequiel Mariano; Gargiulo, Lucía; Lüthy, Isabel Alicia; Álvarez, Lautaro D.; Veleiro, Adriana S.; Burton, Gerardo

doi:10.1016/j.ejmech.2014.05.067

Cited by 3 publications

(8 citation statements)

References 25 publications

(41 reference statements)

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“…A central aspect of the molecular basis of antiestrogenic activity of d ‐aromatic steroid analogs resides in the orientation that these molecules may assume within the ERs. To obtain a preliminary insight on the binding mode of compound 3 , we have previously docked compound 3 into the crystal structure of ERα/estradiol complex (pdb: 1qku) and found that it can acquire three globally different orientations inside the ERα LBP. Two of them (poses A and B) correspond to an inverse binding mode in which ring D points toward the polar pocket flanked by Glu353 and Arg394 [Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The difference between both inverse modes resides in that pose B exhibits a second 180° inversion along the long axis of the molecule. The statistical analysis of the docking solutions revealed that pose A was both the more frequent and the more energetically favorable, suggesting that this could be a relevant binding mode of d ‐aromatic analogs. Based on these findings and to further investigate the molecular basis of the interaction between 3 and the ERα LBP, we constructed three ERα/ 3 complexes using the best solution of each docking pose and the ERα/estradiol crystal structure (ERα/ 3 ‐A, ERα/ 3 ‐B, and ERα/ 3 ‐C systems).…”

Section: Resultsmentioning

confidence: 99%

“…To build the ERα/estradiol system the co‐crystallized estradiol molecule was conserved. All ERα/ 3 systems were constructed from our previous docking study, using ligand coordinates from the best solutions found in clusters A, B, and C to obtain the corresponding ERα/ 3 ‐A, ERα/ 3 ‐B, and ERα/ 3 ‐C systems. The ERα/ 2 system was constructed from the 20 ns snapshot of the ERα/ 3 ‐A system and the HF/631G** optimized structure of 2 , which was introduced by overlapping skeleton carbon atoms with the corresponding atoms in 3 .…”

Section: Methodsmentioning

confidence: 99%

“…) have a six‐membered aromatic D ring, an unusual structural modification of the steroid nucleus. To further investigate this new type of ER ligands, we have synthesized salpichrolide analogs with a simplified side chain, and tested the antiestrogenic activity in the ER+ human breast cancer cells MCF‐7 . It is noteworthy that a very simple salpichrolide analog such as compound 3 [Fig.…”

Section: Introductionmentioning

confidence: 99%

“…This result suggested that the aromatic D ring is a key structural motif for the observed activity. Combining docking and molecular dynamics (MD) simulation methods we also performed a preliminary analysis of the ligand‐binding mode of compound 3 in the ER LBP, finding that an inverse orientation might be stable . As this new scaffold could represent an opportunity to design novel antiestrogens with an improved therapeutic profile, we have now investigated in detail the binding mode of this type of compounds and explored the molecular basis of action of compounds 2 and 3 through MD simulations.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens

2015

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Salpichrolides are natural plant steroids that contain an unusual six-membered aromatic ring D. We recently reported that some of these compounds, and certain analogs with a simplified side chain, exhibited antagonist effects toward the human estrogen receptor (ER), a nuclear receptor whose endogenous ligand has an aromatic A ring (estradiol). Drugs acting through the inhibition or modulation of ERs are frequently used as a hormonal therapy for ER(+) breast cancer. Previous results suggested that the aromatic D ring was a key structural motif for the observed activity; thus, this modified steroid nucleus may provide a new scaffold for the design of novel antiestrogens. Using molecular dynamics (MD) simulation we have modeled the binding mode of the natural salpichrolide A and a synthetic analog with an aromatic D ring within the ERα. These results taken together with the calculated energetic contributions associated to the different ligand-binding modes are consistent with a preferred inverted orientation of the steroids in the ligand-binding pocket with the aromatic ring D occupying a position similar to that observed for the A ring of estradiol. Major changes in both dynamical behavior and global positioning of H11 caused by the loss of the ligand-His524 interaction might explain, at least in part, the molecular basis of the antagonism exhibited by these compounds. Using steered MD we also found a putative unbinding pathway for the steroidal ligands through a cavity formed by residues in H3, H7, and H11, which requires only minor changes in the overall receptor conformation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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