RESUMEN
Two conflicting mechanisms have emerged for the direct arylation of allylic C-H bonds enabled by the combined use of thiol and photoredox catalysis. In the original report (Nature, 2015, 519, 74-77), a radical coupling step-between a radical anion of an arene and an allylic radical-is proposed to be the key C-C bond-forming step. A recent mechanistic study (J. Org. Chem. 2022, 87, 223-230) has suggested that the C-C bond formation occurs via radical anion capture by the olefin followed by an H atom transfer (HAT) event to deliver the allylic C-H arylation product. Utilizing cyclohexene-4,4,5,5-d 4 as a mechanistic probe to distinguish between otherwise indistinguishable regioisomeric allylic C-H arylation products in the reaction of cyclohexene and dicyanobenzene, we establish that the radical anion capture-HAT mechanism is not operative. Furthermore, experimental k H/k D studies and DFT calculations lend strong support to the radical coupling mechanism proceeding via irreversible HAT to form the allylic radical of cyclohexene, followed by regioselectivity-determining radical coupling (for unsymmetrical olefins) and facile decyanation.
RESUMEN
Abnormal assembly of amyloid ß (Aß) in the brain is implicated in Alzheimer's disease (AD) and is associated with cognitive impairments. Since Aß accumulation occurs in advance of the onset of clinical symptoms, identifying preventable drug candidates regulating Aß accumulation is regarded as a promising approach in AD therapeutic. Herein, we synthesized eight Yonsei Institute of pharmaceutical sciences Alzheimer's Drug (YIAD) compounds based on 5-benzyl-6-phenylbenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine structures. Subsequently, YIAD-0203 and YIAD-0205 were selected as effective candidates via thioflavin T assays and gel electrophoresis. The potential therapeutic effect of YIAD-0203 and YIAD-0205 on Aß aggregates was investigated through an AD transgenic mouse model with five familial AD mutations (5XFAD) by oral gavage. Significant amounts of Aß plaque and oligomer reduction were observed in the hippocampus region of both 4.3-month-old (early stage of AD) and 6.0-month-old (mid stage of AD) YIAD-0205-treated 5XFAD mice brains when compared to the nontreated brains. The ability of YIAD-0205 to ameliorate Aß aggregates in the early and mid stages of AD progression supports the notion that YIAD-0205 could be utilized as a reliable scaffold for the development of preventive AD drug candidates.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Ratones Transgénicos , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Amiloide , Imidazoles , Modelos Animales de Enfermedad , Placa Amiloide , Precursor de Proteína beta-Amiloide/metabolismoRESUMEN
Cerebral amyloid-ß (Aß) deposition is a representative hallmark of Alzheimer's disease (AD). Development of Aß-clearing small molecules could be an advantageous therapeutic strategy for Aß clearance considering the advantages in terms of side effects, cost-effectiveness, stability, and oral bioavailability. Here, we report an Aß-dissociating small molecule, YIAD-0121, a derivative of 4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazine. Through a series of anti-Aß screening assays, YIAD-0121 was identified to inhibit Aß aggregation and dissociate preformed Aß fibrils in vitro. Furthermore, the administration of YIAD-0121 in 5XFAD transgenic AD mice inhibited the increase of cerebral Aß aggregation and progression of hippocampus-dependent cognitive decline, with ameliorated neuroinflammation.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Animales , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Hipocampo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
Experimental 13C kinetic isotope effects (KIEs) provide unprecedented mechanistic insight into three intermolecular anti-Markovnikov alkene hydrofunctionalization reactionsâhydroesterification, hydroamination, and hydroetherificationâenabled by organophotoredox catalysis. All three reactions are found to proceed via initial oxidation of the model alkenes to form a radical cation intermediate, followed by sequential nucleophilic attack and hydrogen-atom transfer to deliver the hydrofunctionalized product. A normal 13C KIE on the olefinic carbon that undergoes nucleophilic attack provides qualitative evidence for rate-limiting nucleophilic attack in all three reactions. Comparison to predicted 13C KIE values obtained from density functional theory (DFT) calculations for this step reveals that alkene oxidation has partial rate-limiting influence in hydroesterification and hydroamination, while the nucleophilic attack is solely rate-limiting in the hydroetherification reaction. The basic additive (2,6-lutidine) activates the nucleophile via deprotonation and is an integral part of the transition state for nucleophilic attack on the radical cation, providing an important design principle for the development of asymmetric versions of these reactions. A more electron-rich pyridine base (2,6-dimethoxypyridine) exhibits considerable rate enhancements in both inter- and intramolecular hydrofunctionalization reactions.
Asunto(s)
Alquenos , Hidrógeno , Carbono , Catálisis , Cationes , PiridinasRESUMEN
A new domino mode of assembly was discovered from the one-pot three-component reactions of pyrrole derivatives, active methylene compounds (malononitrile, methyl cyanoacetate, or ethyl cyanoacetate), and sodium cyanide in the presence of piperidinium acetate in EtOH at room temperature, leading to a novel tricyclic skeleton in excellent yield under mild and eco-friendly conditions. This well-choreographed domino process enabled formation of multiple bonds (three C-C and one C-O) for consecutive construction of two rings (pyrrolidine and dihydrofuran) in a diastereoselective manner.
Asunto(s)
Pirroles , Estructura MolecularRESUMEN
A highly efficient synthetic route to a new 1,4-diazepene skeleton, 2-acyl-4-aryl-5H-pyrrolo[1,2-d][1,4]diazepine, was established where Knoevenagel condensation of readily available two fragments, N-substituted pyrrole-2-carboxaldehyde and α-azidoketone, followed by intramolecular aza-Wittig reaction under Staudinger azide reduction conditions permitted facile access to a poly-substituted 1,4-diazepine ring system for the first time. Successful application of this protocol to construct new 1-alkoxy-3-acylisoquinolines and 1-alkoxy-3-acyl-ß-carbolines is also demonstrated.
RESUMEN
A new one-pot, sequential three-component access to 3,4-diacylpyrrolo[1,2-a]pyrazine was achieved from the reaction of an α-haloketone, azide, and N-substituted pyrrole-2-carboxaldehyde under mild reaction conditions, through which a polysubstitution pattern on the pyrazine moiety of the scaffold was realized. The formation of multiple bonds (one C-C and two C-N) was enabled by this domino process involving the in situ generation of α-iminoketones, intermolecular Mannich reaction, intramolecular imine formation, and aromatization. Construction of the relevant 3,4-diacylpyrazino[1,2-a]indole and further expansion of this chemical space via synthetic elaboration of the resulting products were demonstrated as well. Preliminary biological screening of the synthesized derivatives against oral adenosquamous carcinoma cells (CAL-27) and triple negative human breast cancer cells (MDA-MB-231) led us to identify a potent hit compound (7o) having â¼3 times stronger in vitro anticancer activity than that of the anticancer agent, capecitabine.
RESUMEN
A modular approach to polycyclic N-fused heteroaromatics is described. Acid-catalyzed reactions of various 1-(2-oxo-2-arylethyl)-1H-pyrrole-2-carbaldehydes with several o-phenylenediamines provided facile access to a number of new benzo[d]imidazole-pyrrolo[1,2-a]pyrazine hybrid structures through double cyclodehydration and aromatization. Optical characterization of the synthesized compounds revealed unique emission properties, with deep blue emission in the aggregated and solid states, and a dramatic substituent effect was observed. Fusion of an additional benzene ring into the benzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine scaffold resulted in a remarkable increase in the intensity of blue fluorescence from the solution along with good cell permeability and negligible phototoxicity, indicating the potential for bioimaging applications.
RESUMEN
Efficient construction of new chemical space by way of strategic use of tandem reactions is highly important in drug discovery. Described herein is an atom-economical [4+1+1] annulation approach to 3-(hetero)aryl-4-acyl-3,4-dihydropyrrolo[1,2- a]pyrazines, a new chemical space, via a one-pot three-component reaction under mild reaction conditions. Formation of multiple bonds (one C-C and two C-N) was achieved by a cascade reaction sequence consisting of generation of a Schiff base, a diastereoselective Mannich reaction, and intramolecular imine formation. This modular and environment-friendly process allowed rapid access to a wide range of 4-acylated 3,4-dihydropyrrolo[1,2- a]pyrazines and their analogues, opening opportunity to explore biological activity associated with this scaffold.
RESUMEN
Excellent stereoselective (up to ≤96 : 4 Z/E ratio) construction of pharmaceutically interesting functionalized pyrano[3,2-c]chromenes, pyranonaphthoquinones and related pyrano-fused heterocycles has been achieved in good to high yields (72-89%) through a domino Michael/hydroalkoxylation reaction involving several enolizable cyclic ß-keto esters/1,3-dicarbonyls and α-arylacetylenyl-ß-nitrostyrenes as binucleophiles in EtOH at room temperature using DABCO as an organocatalyst. Moreover, syn-2-benzyl-4-aryl-3,4-dihydropyrano[3,2-c]chromenes were obtained in high yields (81-86%) via a stereoselective denitrohydrogenation of the corresponding 2-benzylidene-3,4-dihydropyrano[3,2-c]chromenes using a catalytic amount of 10% Pd/C.
Asunto(s)
Alquenos/química , Benzopiranos/síntesis química , Compuestos Heterocíclicos/síntesis química , Naftoquinonas/síntesis química , Nitrocompuestos/química , Piperazinas/química , Piranos/síntesis química , Benzopiranos/química , Catálisis , Compuestos Heterocíclicos/química , Modelos Moleculares , Estructura Molecular , Naftoquinonas/química , Piranos/química , EstereoisomerismoRESUMEN
Interaction of hen egg white lysozyme with different liposomes made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) was studied by circular dichroism (CD), steady state and time resolved fluorescence spectroscopy. We used anticancer drug ellipticine and studied its entrapment and release from liposomes upon interaction with lysozyme. The molecular docking study revealed that ellipticine preferably binds to the hydrophobic pocket of lysozyme (Kbinding = 1.09 × 10(6) M(-1)). The binding was also supported by spectroscopic evidence. Addition of lysozyme to the ellipticine impregnated liposomes caused quenching of the fluorescence intensity of ellipticine as lysozyme induces hydration and phospholipid rearrangement in the bilayers leading to the leakage of drug molecules. The extent of quenching depends on the prehydration level of liposomes. Maximum quenching took place in the DPPC liposome as it is the least hydrated while minimum quenching was observed in the DOPC liposome having the highest hydration level among all the lipids. The time resolved studies revealed that both the fast and slow lifetime components of ellipticine decrease significantly with addition of lysozyme. This fact is attributed to lysozyme induced hydration and rupture of bilayers. It is revealed that upon addition of lysozyme to liposomes, the amplitude of the fast component increases and that of the slow component decreases which imply that the drug molecules are released from liposomes and subsequent migration takes place to the aqueous phase. Molecular docking studies and fluorescence measurements indicate that ellipticine after removal from the liposome binds to the hydrophobic binding site of lysozyme.