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Abstract
Among the different types of breast cancer (BC), the estrogen receptor positive (ER+) subtype, which requires estrogens for its growth and proliferation, is the most common, while triple negative BC, characterized by the absence of ER, progesterone receptor and human epidermal growth factor receptor 2, often leads to poor prognosis.
First-line therapies for the treatment of ER+ BC act either by suppressing estrogen production, through the inhibition of aromatase (AR) enzyme, or by blocking estrogen prooncogenic activity, via the modulation/degradation of ERs. The serious side effects and the intrinsic or acquired resistance phenomena that arise with prolonged use of these drugs limit their therapeutic application, stimulating the search for new strategies to face this disease. In this context, the development of dual acting aromatase inhibitors, able to target both the orthosteric and the recently identified allosteric pockets of AR could be an opportunity to fight ER+ BC. Another promising strategy could be the development of multitarget compounds, targeting both AR and ERs.
In this scenario, here we designed and synthesized two series of new xanthones or more flexible benzophenones as potential dual acting aromatase inhibitors. Moreover, inspired from tamoxifen metabolites and a literature compound endowed with activity on both AR and ER, different structurally related series of potential multitarget compounds were developed. The biological results showed that some of the new molecules were promising candidates for further development.
It was recently observed that the lately discovered histamine H4 receptor is expressed in human breast tissue, displaying a key role in biological processes mediated by histamine such as cell proliferation, senescence, and apoptosis in malignant cells, representing a potential target in triple negative BC. Thus, a broad series of methyl quinazoline sulfonamides, carrying different functional groups on the sulfonamide moiety, were designed and synthesized as potential H4 receptor ligands.
Abstract
Among the different types of breast cancer (BC), the estrogen receptor positive (ER+) subtype, which requires estrogens for its growth and proliferation, is the most common, while triple negative BC, characterized by the absence of ER, progesterone receptor and human epidermal growth factor receptor 2, often leads to poor prognosis.
First-line therapies for the treatment of ER+ BC act either by suppressing estrogen production, through the inhibition of aromatase (AR) enzyme, or by blocking estrogen prooncogenic activity, via the modulation/degradation of ERs. The serious side effects and the intrinsic or acquired resistance phenomena that arise with prolonged use of these drugs limit their therapeutic application, stimulating the search for new strategies to face this disease. In this context, the development of dual acting aromatase inhibitors, able to target both the orthosteric and the recently identified allosteric pockets of AR could be an opportunity to fight ER+ BC. Another promising strategy could be the development of multitarget compounds, targeting both AR and ERs.
In this scenario, here we designed and synthesized two series of new xanthones or more flexible benzophenones as potential dual acting aromatase inhibitors. Moreover, inspired from tamoxifen metabolites and a literature compound endowed with activity on both AR and ER, different structurally related series of potential multitarget compounds were developed. The biological results showed that some of the new molecules were promising candidates for further development.
It was recently observed that the lately discovered histamine H4 receptor is expressed in human breast tissue, displaying a key role in biological processes mediated by histamine such as cell proliferation, senescence, and apoptosis in malignant cells, representing a potential target in triple negative BC. Thus, a broad series of methyl quinazoline sulfonamides, carrying different functional groups on the sulfonamide moiety, were designed and synthesized as potential H4 receptor ligands.
Tipologia del documento
Tesi di dottorato
Autore
Caciolla, Jessica
Supervisore
Dottorato di ricerca
Ciclo
33
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Aromatase inhibitors,
allosteric modulators,
SERMs,
SERDs,
Estrogen receptors,
dual acting ligands,
breast cancer,
multitarget,
tamoxifen derivatives,
small molecules,
drug discovery,
H4 receptor,
H4R ligands,
Benzophenone,
Xanthone,
Bisphenol,
Sulfonamide
URN:NBN
DOI
10.48676/unibo/amsdottorato/9876
Data di discussione
21 Maggio 2021
URI
Altri metadati
Tipologia del documento
Tesi di dottorato
Autore
Caciolla, Jessica
Supervisore
Dottorato di ricerca
Ciclo
33
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Aromatase inhibitors,
allosteric modulators,
SERMs,
SERDs,
Estrogen receptors,
dual acting ligands,
breast cancer,
multitarget,
tamoxifen derivatives,
small molecules,
drug discovery,
H4 receptor,
H4R ligands,
Benzophenone,
Xanthone,
Bisphenol,
Sulfonamide
URN:NBN
DOI
10.48676/unibo/amsdottorato/9876
Data di discussione
21 Maggio 2021
URI
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