Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease

Rabal, Obdulia; Sánchez‐Arias, Juan A.; Cuadrado‐Tejedor, Mar; Miguel, Irene de; Pérez-González, Marta; García‐Barroso, Carolina; Ugarte, Ana; Mendoza, Ander Estella-Hermoso de; Sáez, Elena; Espelosin, María; Ursúa, Susana; Haizhong, Tan; Wu, Wei; Xu, Min; García‐Osta, Ana; Oyarzábal, Julen

doi:10.1016/j.ejmech.2018.03.005

Cited by 62 publications

(57 citation statements)

References 61 publications

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“…Among them, 86 (Figure ) displayed the best enzyme inhibitory activity (IC 50 HDAC6 = 15 nM; IC 50 PDE5A = 11 nM), was able to cross the BBB and to achieve its functional response, reducing the levels of AD‐related markers such as pTau and human amyloid precursor protein in Tg2576 neurons, and increasing the markers of the physiological neuron response in mouse hippocampus following the administration of 40 mg/kg dose. However, this treatment did not induce a significant improvement in memory after 2 weeks …”

Section: The Mtdl Approachmentioning

confidence: 83%

“…The effect of the HDAC6‐selective inhibitor tubastatin A in combination with PDE5Ai has been evaluated against SH‐SY5Y neuroblastoma cell lines, with the aim to highlight the role of this specific HDAC isoform in such disease. A marked increase of H3K9 acetylation has been registered compared to cells treated with tubastatin A alone . From these findings, Rabal et al recently identified new sildenafil 85 ‐based dual PDE5A/HDAC6 inhibitors.…”

Section: The Mtdl Approachmentioning

confidence: 99%

“…A marked increase of H3K9 acetylation has been registered compared to cells treated with tubastatin A alone. 347 From these findings, Rabal et al 347 recently identified new sildenafil 85-based dual PDE5A/HDAC6 inhibitors. Among them, 86 (Figure 9) displayed the best enzyme inhibitory activity (IC 50 HDAC6 = 15 nM; IC 50 PDE5A = 11 nM), was able to cross the BBB and to achieve its functional response, reducing the levels of AD-related markers such as pTau and human amyloid precursor protein in Tg2576 neurons, and increasing the markers of the physiological neuron response in mouse hippocampus following the administration of 40 mg/kg dose.…”

mentioning

confidence: 99%

“…However, this treatment did not induce a significant improvement in memory after 2 weeks. 347 Both HDACs and transglutaminases (TGs) play a pivotal role in neurodegeneration, and several evidence showed their induction in the presence of toxic stimuli. Moreover, the inhibition of both targets induces a protective effect in different neurodegenerative diseases restoring the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), a well-known neurotrophin implicated in neuronal vitality, development, and synaptic plasticity.…”

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confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Section: The Mtdl Approachmentioning

confidence: 83%

Section: The Mtdl Approachmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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“…Analyzing the pharmacological results obtained for 22, 23, and 24 in SH-SY5Y cells or in the in vivo Tg2576 mice model, it is difficult to rationalize which kind of HDACi profile is the most promising one; 22, for F I G U R E 1 MTDLs as PDE5/HDACis designed for the treatment of Alzheimer's disease. HDAC, histone deacetylase; MTDL, multitarget-directed ligandexample, is from 3.4-to 5.4-fold more potent for HDAC6 inhibition than class I HDACs 168 ; 23 is not completely selective for HDAC6 over class I HDACs (IC 50 HDAC1 = 345 nM), which can be noticed by its capability to increase the AcH3K9 levels (12.1-fold over basal) at 1 µM concentration, since the inhibition of HDAC6 alone should not, in principle, increase it169 ; and 24 features a nonlinear inhibition profile for class I…”

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confidence: 99%

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

Rodrigues

Pinheiro

Sagrillo

et al. 2020

Medicinal Research Reviews

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Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented.

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Suzuki–Miyaura Cross‐Coupling

Pagett

Lloyd‐Jones

2019

Organic Reactions

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The Suzuki–Miyaura cross coupling reaction uses a metal catalyst to create carbon–carbon bonds from organoboron reagents and organo(pseudo)halides. By careful adjustment of the ligand system, solvents, and other additives, this reaction can couple a diverse range of sp‐, sp 2 ‐, and sp 3 ‐hybridized organoboron and organo(pseudo)halide reactants. The Suzuki–Miyaura cross coupling reaction has become preeminent in both small‐ and large‐scale synthesis owing to its mild reaction conditions, predictable stereochemical outcomes, chemoselectivity, functional‐group compatibility, and use of relatively non‐toxic and air‐stable starting materials. This chapter describes the theoretical and practical aspects of the palladium‐catalyzed Suzuki–Miyaura cross‐coupling reaction. A broad overview of the reaction mechanism and scope is described, with selected examples of how mechanistic insights have enabled progress in the development of this coupling reaction. Examples include early reaction discovery as well as modern applications in synthesis using a diverse array of organoboron and organo(pseudo)halide reactants, and on scales that range from milligram to multi‐kilogram. Tabular surveys are organized by the structure of the transferable group attached to boron as the primary rubric (alkyl, alkenyl, aryl, alkynyl, then heterocyclic), with the structure of the electrophile as the secondary rubric. Selected literature is covered from the seminal paper in 1979 to mid‐2018.

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Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease

Cited by 62 publications

References 61 publications

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

Suzuki–Miyaura Cross‐Coupling

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