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Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

Butts A, Martin JA, DiDone L, Bradley EK, Mutz M, Krysan DJ - PLoS ONE (2015)

Bottom Line: Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity.Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules.Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.

ABSTRACT
Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

No MeSH data available.


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Summary of structure-activity relationships.
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pone.0125927.g007: Summary of structure-activity relationships.

Mentions: From our set of commercially available SERMs and tamoxifen derivatives from the AstraZeneca archive (Fig 3), we have identified four important features of the relationship between the structure of triphenylethylene-based SERMs and anti-cryptococcal activity; these are summarized in Fig 7. First, aliphatic substituents longer than one carbon at the 2-position of the double bond improve activity substantially. Second, the presence of a basic group such as an amine tethered to the one of the aromatic rings is required for activity. Ospemiphene (Fig 2, molecule 9) is a potent estrogen receptor antagonist but has no antifungal activity and, thus, it appears that the structural requirements for these two activities are distinct. Third, our data indicate that electronegative substituents on the aromatic rings increase the anti-cryptococcal activity relative to analogs without such functionality. Fourth, previous studies by our group have shown that extending the length of the aliphatic linker between the C ring phenoxy group and the alkylamino moiety improves anti-cryptococcal activity [12]. Although the set of analogs is not extensive, these data provide the first insights into which specific features of the tamoxifen scaffold are important for antifungal activity and, thereby, represent regions where further optimization can be focused.


Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

Butts A, Martin JA, DiDone L, Bradley EK, Mutz M, Krysan DJ - PLoS ONE (2015)

Summary of structure-activity relationships.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4446328&req=5

pone.0125927.g007: Summary of structure-activity relationships.
Mentions: From our set of commercially available SERMs and tamoxifen derivatives from the AstraZeneca archive (Fig 3), we have identified four important features of the relationship between the structure of triphenylethylene-based SERMs and anti-cryptococcal activity; these are summarized in Fig 7. First, aliphatic substituents longer than one carbon at the 2-position of the double bond improve activity substantially. Second, the presence of a basic group such as an amine tethered to the one of the aromatic rings is required for activity. Ospemiphene (Fig 2, molecule 9) is a potent estrogen receptor antagonist but has no antifungal activity and, thus, it appears that the structural requirements for these two activities are distinct. Third, our data indicate that electronegative substituents on the aromatic rings increase the anti-cryptococcal activity relative to analogs without such functionality. Fourth, previous studies by our group have shown that extending the length of the aliphatic linker between the C ring phenoxy group and the alkylamino moiety improves anti-cryptococcal activity [12]. Although the set of analogs is not extensive, these data provide the first insights into which specific features of the tamoxifen scaffold are important for antifungal activity and, thereby, represent regions where further optimization can be focused.

Bottom Line: Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity.Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules.Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.

ABSTRACT
Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

No MeSH data available.


Related in: MedlinePlus