The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. ...All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu2+ ions at physiological pH with the same stoichiometry as carnosine. The newly synthesized compounds display highly significant copper ion sequestering ability and are capable of protecting LDL from oxidation catalyzed by Cu2+ ions, the most active compounds being the most hydrophilic ones. All the synthesized amides show quite potent carnosine-like HNE quenching activity; in particular, 7d, the member of the series selected for this kind of study, is able to cross the blood−brain barrier (BBB) and to protect primary mouse hippocampal neurons against HNE-induced death. These products can be considered metabolically stable analogues of carnosine and are worthy of additional investigation as potential neuroprotective agents.
BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF
mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, ...their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF
has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC
values in the 40-88 nM range. Selected compounds inhibited BRAF
signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds
and
, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.
A new series of compounds, structurally related to leflunomide, based on the 1,2,5-oxadiazole ring system (furazan) has been synthesised, and their ability to undergo ring scission at physiological ...pH to afford the corresponding cyano-oximes has been analyzed. The latter, together with the respective nitro derivatives obtained by oxidation, have been characterised as weak inhibitors of rat dihydroorotate dehydrogenase (DHODH).
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► 1,2,5-oxadiazole was proposed as a bioisoster of isoxazole in leflunomide analogues. ► Cyano-oximes display weak inhibitory activity on DHODH. ► The feeble inhibitory activity of cyano-oximes is amenable to their E configuration. ► Oxidation of cyano-oximes to related nitro derivatives increases DHODH inhibition.
The synthesis, physico-chemical, and biological characterisation of a short series of carnosine amides bearing NO-donor nitrooxy functionalities are described. The NO-donor carnosine analogues and ...their des-NO derivatives display carnosine-like properties, differing from the lead for their high serum stability. The newly-synthesised compounds are able to complex Cu2+ ions at physiological pH, displaying significant copper ion sequestering ability, and protect LDL from oxidation catalysed by Cu2+ ions. All products show moderately-potent HNE quenching activity. The NO-donor compounds 7c–f relaxed rat aorta strips via an NO-dependent mechanism. In vivo evaluation of organ protection in a model of cerebral ischaemia/reperfusion injury, using the selected NO-donor 7e and its des-NO analogue 7a, showed that both derivatives protect from hypoxia-induced brain damage, at lower concentrations than carnosine; 7e also decreased serum TNF-α levels. This class of NO-donor carnosine amides is worthy of further study as potential tools for treating a wide range of chronic vascular and neurodegenerative diseases in which NO-bioavailability is reduced.
NO-donor carnosine derivatives were synthesized and evaluated in vitro for their multipotent antioxidant properties and in vivo in a cerebral ischaemia/reperfusion model. Display omitted
► We synthesized and evaluated carnosine nitrooxy derivatives as antioxidant and organ protective agents. ► New compounds showed multifactorial antioxidant activity in vitro. ► Both NO and des-NO carnosine derivatives protect from ischaemia/reperfusion injury in vivo. ► One model NO-donor carnosine derivative was able to lower TNF-α in vivo.
The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated ...virtual screening hit NSC137546, a series of N‐benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT‐dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure–activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L‐glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration‐dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.
A series of N‐benzoyl amino acid derivatives was synthesized by modulation of three different molecular moieties (A, B, and C). The ability of synthesized compounds to inhibit DNMT‐dependent total DNA methylation was evaluated. The most active compound 22 inhibited both DNMT1‐ and DNMT3A‐mediated DNA methylation in a concentration‐dependent manner at micromolar concentration. Docking studies suggest putative binding at the substrate site of both DNMT isoforms studied.
The synthesis and physico-chemical properties of novel compounds obtained by conjugation of amodiaquine with moieties containing either furoxan or nitrooxy NO-donor substructures are described. The ...synthesised compounds were tested in vitro against both the chloroquine sensitive, D10 and the chloroquine resistant, W-2 strains of
Plasmodium falciparum (P. falciparum). Most of the compounds showed an antiplasmodial activity comparable to that of the parent drug. By comparing the activities of simple related structures devoid of the ability to release NO, it appears that the contribution of NO to the antiplasmodial action in vitro is marginal. All the compounds were able to relax rat aorta strips with a NO-dependent mechanism, thus showing their capacity to release NO in the vessels. A preliminary in vivo study using
Plasmodium berghei ANKA-infected mice showed a trend for prolonged survival of mice with cerebral malaria treated with compound
40, which is potent and fast amodiaquine-derived NO-donor, when compared with amodiaquine alone or with compound
31, a milder NO-donor. The two compounds showed in vivo antiplasmodial activity similar to that of amodiaquine.
Amodiaquine NO-donor antimalarials were synthesised and evaluated in vitro and in vivo in a cerebral malaria model.
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► We synthesised and evaluated amodiaquine NO-donors as antimalarial agents. ► Nitrooxy derivatives and furoxans were used as NO-donors. ► Compounds showed antiplasmodial activity in vitro. ► Amodiaquine-furoxan showed a trend to prolong survival of mice with cerebral malaria.
A new series of polyvalent drugs obtained by joining edaravone with NO-donor moieties is described. All compounds display high antioxidant power together with NO-dependent vasodilator properties. The ...analysis of a number of molecular descriptors shows that the antioxidant activity, which is tightly linked to the presence of the edaravone substructure, is principally modulated by lipophilicity. These products are potentially useful in the treatment of cardiovascular disorders in which EDRF deficiency and ROS excess are involved.
A new class of co-drugs obtained by joining antioxidant edaravone with a vasodilating substructure containing NO-donor functions, is presented. These compounds, characterized by a good ...gastrointestinal absorption, afford edaravone and the related NO-donor moieties when incubated in human serum and in rat liver homogenate. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.
A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NOx) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.
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