Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms also are implicated in the insurgence and development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. In particular, HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function.1 Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Unfortunately, most of them are pan-inhibitors towards the different isoforms of HDACs and may lead to several side-effects. The primary purpose of this work is to synthesize new HDACIs that sum up the best chemical features of the HDACIs reported in literature in the hope of achieving as much as possible potency and selectivity.2 In this regard, we selected: i) a hydroxamic acid as the most fruitful metal-binding moiety due to the fact that all HDACs involved in cancer development Zn2+ proteases; ii) an aromatic capping group (i.e. substituted pyrazole nucleus) that interacts with the external domain of the catalytic site and may differentiate among HDAC isoforms; iii) a cinnamoyl linker that connects the metal-binding moiety and the capping group by means of an amide function (Fig. 1).

SYNTHESIS OF PYRAZOLE DERIVATIVES DESIGNED AS POTENTIAL INHIBITORS OF DIFFERENT HDAC ISOFORMS

IRRERA, ALESSIO BRJAN;SCALA, ANGELA;PIPERNO, Anna;GRASSI, Giovanni;MICALE, Nicola
2016-01-01

Abstract

Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms also are implicated in the insurgence and development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. In particular, HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function.1 Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Unfortunately, most of them are pan-inhibitors towards the different isoforms of HDACs and may lead to several side-effects. The primary purpose of this work is to synthesize new HDACIs that sum up the best chemical features of the HDACIs reported in literature in the hope of achieving as much as possible potency and selectivity.2 In this regard, we selected: i) a hydroxamic acid as the most fruitful metal-binding moiety due to the fact that all HDACs involved in cancer development Zn2+ proteases; ii) an aromatic capping group (i.e. substituted pyrazole nucleus) that interacts with the external domain of the catalytic site and may differentiate among HDAC isoforms; iii) a cinnamoyl linker that connects the metal-binding moiety and the capping group by means of an amide function (Fig. 1).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3102416
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