Epoxide containing molecules: A good or a bad drug design approach

Gomes, Ana R.; Varela, Carla; Silva, E. J. Tavares da; Roleira, Fernanda M.F.

doi:10.1016/j.ejmech.2020.112327

Cited by 60 publications

(38 citation statements)

References 153 publications

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“…Here, we replaced the metabolically labile C-17-spiro oxirane ring in BNN27 with the more stable cyclopropane moiety [46]. In this way, the potential epoxide ring-opening that can result in activity loss may be avoided [47]. Thereby we synthesized the congener compound of BNN27, ENT-A010, and show that it demonstrates neuroprotective properties and modulates microglial function in a TRKA-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

et al. 2022

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Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders.

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Section: Introductionmentioning

confidence: 99%

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

et al. 2022

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“…The modification of the natural compounds with various functional groups is one of the main strategies used in drug discovery and development. Epoxide (oxirane, oxacyclopropane)—cyclic ether with an oxygen atom in a saturated three-membered ring—is an important functional group in organic and medicinal chemistry [ 1 , 2 , 3 ]. Despite its structural simplicity, epoxide is a very versatile moiety with a suitable synthetic balance between stability and reactivity, often used as a synthetic intermediate and valuable pharmacophoric agent.…”

Section: Introductionmentioning

confidence: 99%

“…On the one hand, epoxides have been identified for many years as biologically hazardous compounds due to their ability to bind covalently to the nucleophilic centers of proteins and nucleic acids [ 4 , 5 ]. On the other hand, due to their high reactivity, epoxides are used as alkylating or cross-linking agents, indicating their high biological potential as anticancer agents [ 3 ]. Mechanistic studies have shown that apoptosis seems to be the most common type of cell death induced by the epoxy-containing derivatives [ 6 , 7 , 8 ]; however, such compounds can also induce necrosis [ 3 ], and thus comprehensive evaluation of the molecular mechanisms underlying their cytotoxicity is required.…”

Section: Introductionmentioning

confidence: 99%

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

Salomatina

Sen’kova

Moralev

et al. 2022

IJMS

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It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.

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“…Figure2. Comparison of the solution-and solid-state structures of 2 a and 18 as determined by1 H NMR and single-crystal X-ray diffraction.…”

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confidence: 99%

“…Chiral oxiranes, or epoxides, are common heterocyclic structural motifs found in bioactive natural products, synthetic drugs, [1] as well as likely biogenetic precursors to various naturally occurring molecules. [2] These strained heterocycles are among the most versatile intermediates in organic synthesis, characterized by their ability to undergo regio-and stereoselective functionalization with nucleophiles to produce chiral alcohols of diverse structural patterns.…”

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confidence: 99%

Enantioselective Synthesis of Spiro‐oxiranes: An Asymmetric Addition/Aldol/Spirocyclization Domino Cascade

2021

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Enantioenriched spiro-oxiranes bearing three contiguous stereocenters were synthesized using a rhodium-catalyzed asymmetric addition/aldol/spirocyclization sequence. Starting from a linear substrate, the cascade enabled the formation of a spirocyclic framework in a single step. sp 2 -and sp-hybridized carbon nucleophiles were found to be competent initiators for this cascade, giving arylated or alkynylated products, respectively. Derivatization studies demonstrated the synthetic versatility of both the epoxide and the alkyne moieties of the products. DFT calculations were used to reconcile spectroscopic discrepancies observed between the solution-and solid-state structures of the products.

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Epoxide containing molecules: A good or a bad drug design approach

Cited by 60 publications

References 153 publications

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

Enantioselective Synthesis of Spiro‐oxiranes: An Asymmetric Addition/Aldol/Spirocyclization Domino Cascade

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