Diels-Alder Adducts Research Articles

Orvinol-based opioid receptor antagonist fluorinated at C(20)-pharmacophore.

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the antagonist activity of the N-allyl substituted orvinol derivative fluorinated within the pharmacophore associated with C(20) and its surrounding. This compound was prepared via a novel synthetic sequence from 18,19-dihydrothevinone bearing an allyl substituent at N(17) and three fluorine atoms at C(21). Preliminary trials reported earlier demonstrated that the compound exhibited no analgesic activity. However, in vivo experiments conducted in an acute pain model (tail-flick test in mice) demonstrated that this fluorinated compound, when administered at doses of 5-10mg/kg (sc) 30min before morphine, exhibited antagonistic activity at the level of naloxone (1mg/kg, sc) for a longer duration (at least 120min) compared to naloxone (60min). Together with the analgesic activity that has been reported for the C(21)-trifluorinated relatives bearing methyl or cyclopropylmethyl substituent at N(17), this result highlights C(21)-fluorinated thevinols and orvinols as the family of opioid receptor ligands (structurally related to buprenorphine, diprenorphine, etc.) covering the full range of activity profiles from agonists to antagonists, which is promising for tuning of their pharmacological properties via a substitution of hydrogen atoms within the pharmacophore associated with C(20) and its surrounding for fluorine.

Syntheses and Structures of Functionalized Macrocyclic Carbon Nanohoops Bearing a [9]Cycloparaphenylene or a Higher Homological Unit.

The Diels-Alder reactions between (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene and dienophiles and the use of the resulting adducts for macrocyclization and aromatization were established. Several functionalized macrocyclic structures bearing a functionalized [9]cycloparaphenylene or a higher homological unit were isolated. The distribution of the macrocyclic structures was found to be governed by the structures of the starting Diels-Alder adducts. An empirical correlation between the angles of the two 4-bromophenyl groups of the X-ray structures of the Diels-Alder adducts and the macrocyclization steps was observed.

Photo-crosslinked Diels-Alder and thiol-ene polymer networks.

Compositions of ethylene glycol dicyclopentenyl ether methacrylate (EGDEMA), a vegetable oil based alkyl methacrylate (C13MA), and furfuryl methacrylate (FMA) were terpolymerized for dual-crosslinked networks with tailored mechanical and thermal properties. Specifically, initiators for continuous activator regeneration (ICAR) atom transfer radical polymerization (ATRP) afforded materials with tailored glass transition temperature (T g) and incorporation of furan and norbornene functionalities within a single chain. The terpolymer with high furan and norbornene functionality (Ter2: F FMA = 0.42, F EGDEMA = 0.46, F C13MA = 0.12) is crosslinked to form single-crosslinked reversible networks with 1,1'-(methylenedi-4,1-phenylene)bismaleimide (BM) via Diels-Alder (DA) chemistry and dual-crosslinked networks incorporating additional non-reversible thiol-ene crosslinks. The reactions were photo-initiated using 254 nm UV light with BM : FMA molar ratios of 0.1 and 0.2 for both systems. FTIR analyses for crosslinked Ter2 samples confirmed the successful formation of DA and thiol-ene adducts, while DSC confirmed the reversibility of the DA reaction. A terpolymer with higher C13MA composition (Ter3: F C13MA = 0.75, F FMA = 0.17, F EGDEMA = 0.08) was similarly crosslinked in single and dual crosslinked networks with BM : FMA of 0.1 and 0.2. Crosslinking efficiency was evaluated for both single and dual crosslinked networks with a BM : FMA = 0.1 by comparing thermal and UV curing methods, with UV curing proving more effective for dual-crosslinked systems, leading to increased gel content (71% with UV compared to 61% thermally) and improved material properties. FTIR and DSC results confirmed the formation of the DA adducts and the reversibility of the DA reaction. The terpolymers were further analyzed for adhesive applications through rheological testing. These studies demonstrated that the incorporation of thiol-ene crosslinking alongside Diels-Alder crosslinking offers a balanced combination of reversible and permanent bonds, resulting in materials with enhanced mechanical strength, thermal stability, and functional versatility that are suitable for applications such as recyclable adhesives.

Self‐Healing Biobased Thermoreversible Polymer Networks by Photo‐Diels‐Alder Chemistry

ABSTRACTPoly(furfuryl methacrylate) (poly(FMA)) homopolymers with controlled molecular weights made via ICAR ATRP undergo photo‐crosslinking (λ = 254 nm) with 1,1′‐(methylenedi‐4,1‐phenylene)bismaleimide (BM) by Diels‐Alder (DA) chemistry, and are compared to the same DA reaction under non‐UV initiated, ambient conditions (RT‐DA). FTIR and DSC analysis confirm DA adduct formation and the retro‐DA reaction. Co‐ and terpolymers of FMA with C13MA (alkyl methacrylate with average side length = 13) and isobornyl methacrylate (IBOMA) are prepared to enhance mechanical properties. Poly(C13MA‐co‐FMA) samples are used to study curing condition effects and BM loading on crosslinking density and thermal behavior. Varying BM loading (0.05–0.2 BM: FMA) in samples cured by photo‐DA and RT‐DA, UV cured samples showing higher gel content (50% versus 25% for 0.2 BM loading) and two endothermic peaks in the first heating run, unlike RT cured samples which display a single peak. Subsequently, poly(C13MA‐co‐IBOMA‐co‐FMA) are crosslinked with BM via photo‐DA with resulting networks indicating self‐healing/recyclability. FTIR and DSC results confirm DA and retro‐DA reactions, while scratched samples of crosslinked terpolymers exhibit self‐healing upon heating. Microscopic images show complete scratch healing in just 20 min due to furan‐maleimide adduct formation, facilitated by the presence of flexible low Tg poly (C13MA) segments and rigid poly (IBOMA) repeating units.

Unveiling the potential of dual-extrinsic/intrinsic self-healing lignin-based coatings for anticorrosion applications

The development of self-healing ecofriendly coatings for anticorrosion applications provides stronger protection than passive coatings and mitigates the environmental pollution resulting from petroleum-derived coatings. Due to its intrinsic anticorrosion characteristics, lignin is a viable precursor for the formulation of self-healing anticorrosion coatings. However, the structural rigidity of lignin and the lack of self-healing functionalities in pristine lignin-based coatings hinder the comprehensive application of lignin in this field. Accordingly, we introduced Diels-Alder (DA)-based self-healing functions in the lignin-based coatings and meanwhile, the coatings were chemically conjugated with corrosion inhibitors to further improve the anticorrosion performance. A thin layer (16μm) of the coating increased the Ecorr from -480mV (for bare steel) to +91mV and reduced the corrosion rate (CR) >4000 times. The dual self-healing properties of the coating are attributed to the synergistic action of the DA adduct and the conjugated corrosion inhibitor. Practically, in response to the emergence of microcracks in the coating structure, trace amounts of the corrosion inhibitor are released into the microcracks to form a protective layer on the unveiled metal surface. Simultaneously, DA adducts undergo reversible reactions at specific temperatures (50-120°C) promoting complete restoration of the microcrack.

Diels-Alder adduct of levoglucosenone and isoprene in the syntheses of the key synthon for loganin

Based on the hemiketal obtained by the carbonyl eneketalization of the Diels-Alder adduct of levoglucosenone and isoprene with acetaldehyde, two methods have been suggested for incorporating the carboxy group of loganin at the pyran ring. The first method involved one-pot conversion employing ozonolytic cleavage of the double bond, ozonide reduction, <em>in situ</em> aldehyde oxidation and esterification. An alternative five-step sequential conversion of the ketal, with isolation and identification of intermediate compounds, involved ketalization, Wagner <em>vic</em>-hydroxylation of the double bond, periodate cleavage of diols, <em>in situ</em> oxidation of the aldehyde to an acid, and esterification.

Diels–Alder Adducts of <i>N</i>-Substituted 2-Pyridones with Maleinimides. Synthesis and Antiviral Activity

Adducts of N-substituted 2-pyridones [pyridine-2(1H)-ones] and N-substituted maleic acid imides were synthesized under thermal conditions of the Diels–Alder reaction with yields from 68 to 97%. Cytotoxicity and antiviral activity of the obtained compounds were studied using a model of adenovirus infection [human adenovirus type 5 (AdV5)] in MA-104 cell culture. It was shown that the synthesized adducts have low toxicity and medium antiviral activity. Only 9-hexyl-2-phenyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole-1,3,8-trione has the most pronounced viral inhibitory properties with a selectivity index of 7.

Progressive Endergonic Synthesis of Diels–Alder Adducts Driven by Chemical Energy

AbstractThe overwhelming majority of artificial chemical reaction networks respond to stimuli by relaxing towards an equilibrium state. The opposite response—moving away from equilibrium—can afford the endergonic synthesis of molecules, of which only rare examples have been reported. Here, we report six examples of Diels–Alder adducts formed in an endergonic process and use this strategy to realize their stepwise accumulation. Indeed, systems respond to repeated occurrences of the same stimulus by increasing the amount of adduct formed, with the final network distribution depending on the number of stimuli received. Our findings indicate how endergonic processes can contribute to the transition from responsive to adaptive systems.

Progressive Endergonic Synthesis of Diels-Alder Adducts Driven by Chemical Energy.

The overwhelming majority of artificial chemical reaction networks respond to stimuli by relaxing towards an equilibrium state. The opposite response-moving away from equilibrium-can afford the endergonic synthesis of molecules, of which only rare examples have been reported. Here, we report six examples of Diels-Alder adducts formed in an endergonic process and use this strategy to realize their stepwise accumulation. Indeed, systems respond to repeated occurrences of the same stimulus by increasing the amount of adduct formed, with the final network distribution depending on the number of stimuli received. Our findings indicate how endergonic processes can contribute to the transition from responsive to adaptive systems.

Diels-Alder Cycloaddition of 2,5-Bis(hydroxymethyl)furan (BHMF) and N-Phenylmaleimide Derivatives.

Currently, amidst atmospheric menace where natural calamities such as wildfire and floods are becoming more frequent than ever, biobased derivatives offer a sustainable alternative to conventional ways, for instance, petrochemical commodities. Biobased products, obtained from agricultural waste, including 5-(hydroxymethyl)furfural (HMF), 2,5-bis(hydroxymethyl)furan (BHMF), and 2,5-furandicarboxylic acid (FDCA) are promising chemical platforms in the biorefinery, which is yet to be explored. The Diels-Alder cycloaddition of BHMF and N-phenylmaleimide derivatives under optimal reaction conditions is investigated in this report. First, HMF is reduced to BHMF in the presence of NaBH4, and then the Diels-Alder reaction of BHMF and N-phenylmaleimide derivatives is investigated to produce Diels-Alder adducts. All novel compounds are synthesized in acceptable yields and effectively characterized by employing important techniques such as one-dimensional (1D) NMR spectroscopy (1H, 13C, DEPT-90, and DEPT- 135), two-dimensional (2D) NMR spectroscopy (1H-1H COSY, 1H-13C HSQC, and 1H-13C HMBC), IR spectroscopy, elemental analysis, mass spectrum (QTOF), and single-crystal X-ray diffraction (SC-XRD). Furthermore, this study underlines the necessity of sustainable synthetic methodologies and gives critical insights into the progress of ecologically friendly methodologies, providing a new avenue as a tunable precursor for the challenging functionalized polymer in the future.

СИНТЕЗЫ ЭЛЕУТЕЗИДОВ

The review is devoted to research in the field of "marine" diterpene metabolites of the 4,7-oxaeunicellan type, which have a taxol-like mechanism of cytotoxic action. The known most effective chemical syntheses are presented, as well as the results of our own research, on the basis of which, based on (+)-δ-cadinol, the formal synthesis of eleuthesides was realized, and the synthesis of analogs of sorcrdictyin A and eleutherobin was carried out from the Diels-Alder adduct of levogluclsenone and piperylene. In the course of the research, the features of the chemical behavior of the little-studied sesquiterpene (+)-δ-cadinol, isolated from the resin of the Siberian cedar Pinus sibirica R.Mayer, were revealed, which caused certain difficulties at the initial stage of research when developing a scheme for the synthesis of eleuthesides. Thus, the ozonolytic cleavage of the double bond, regardless of the reaction conditions, was accompanied by α-ketol rearrangement and aldol cyclization. Both problems were solved by protecting the aldehyde group into dimethyl acetal, and the hydroxyl groups by intramolecular oxacyclization into 1,4-epoxide. After the construction of the "upper" and "lower" side chains, the reverse transition from the 1,4-epoxide to the linear structure was carried out by the action of BF3·Et2O-Ac2O to obtain a diacetate derivative corresponding to the key synthon of the synthesis scheme of Nicolau et al., which completed the formal synthesis of eleuthesides. Based on the analysis of literature data on the properties of N-methylurocanoic acid and its role in sarcodictyins, an assumption was made about the manifestation of cytotoxic properties by more accessible esters of the little-studied N-methylurocanoic acid. In this regard, methods have been developed for obtaining esters of urocanic acid from histidine and glucose and its N-methylation. Then, esters of N-methylurocanoic acid were synthesized with a number of alcohols, including those of natural origin. Using a similar strategy, a scheme was developed for the synthesis of the structural core of an eleutheside analog with a 14-methylcyclohexene ring A starting from the Diels-Alder adduct of levoglucosenone and piperylene. The key step of the scheme is the intramolecular acetylenealdehyde cyclization into a 10-membered carbocycle, which completes the construction of the eleutheside core. Trichloroacetimidate, a glycosylation agent in the synthesis of eleutherobin, was obtained. Synthetic studies have been completed by obtaining analogs of sarcodictin A with a 14-methylcyclohexene ring A and an analog of eleutherobin with a similar ring A and an orthoester arabinose substituent.

A super strong polyurethane elastomer with efficient self-healing performance enabled by partially mixing reversible hard domains

A super strong polyurethane elastomer with efficient self-healing performance enabled by partially mixing reversible hard domains

Chalcomoracin promotes apoptosis and endoplasmic reticulum stress in hepatocellular carcinoma cells.

Chalcomoracin (CMR), a Diels-Alder adduct obtained from mulberry leaves, demonstrated wide-spectrum anti-cancer activity. Herein, we aimed to explore the function of CMR and how it works in hepatocellular carcinoma (HCC). Human HCC cell lines Hep3B and SNU-387 were cultured and treated with various concentrations of CMR (1.5, 3, and 6 µM). Subsequently, the effects of CMR on cell viability, colony formation, apoptosis, migration, and invasion abilities were studied in vitro. Furthermore, the levels of endoplasmic reticulum (ER) stress-related proteins and mitogen-activated protein kinase (MAPK) pathway-related proteins in cells under CMR exposure were detected using western blot. Experiments in vivo were conducted to examine the effects of CMR on tumor growth in HCC. CMR administration inhibited the viability and clonogenic, migration, and invasion abilities, as well as promoted cell apoptosis and ER stress in Hep3B and SNU-387 cells. In addition, CMR treatment reduced the phosphorylation levels of ERK, P38, and JNK in the MAPK pathway. Moreover, an in vivo study showed that CMR administration could inhibit tumorigenesis and MAPK pathway activity in HCC. Our data indicate that CMR has the potential to inhibit the development of HCC, potentially through the inhibition of the MAPK pathway. These findings suggest that CMR may have promising applications as an anticancer agent in future therapeutics for HCC.

Structural Effects on Mechanochemical Reactivity of Anthracene–Maleimide Diels–Alder Adducts

Structural Effects on Mechanochemical Reactivity of Anthracene–Maleimide Diels–Alder Adducts

Multiple Force-Triggered Downconverted and Upconverted Emission in Polymers Containing Diels-Alder Adducts.

Fluorescent mechanophores can indicate the deformation or damage in polymers. The development of mechanophores with multi-triggered response is of great interest. Herein, Diels-Alder (DA) adducts are incorporated into linear poly(methyl acrylate) PMA-BA and network poly(hexyl methacrylate) (PHMA) as mechanophores to detect the stress caused by ultrasound, freezing, and compression. The DA mechanophores undergo retro-DA reaction to release 9-styrylanthracene chromophore upon applying force, resulting in cyan fluorescence. The dissociation ratio of the DA mechanophore after pulsed ultrasonication of PMA-BA solution for 240 minutes is estimated to be 52 % by absorption spectra and 1H NMR. Additionally, the rate constant of mechanical cleavage is calculated to be 1.2×10-4 min-1⋅kDa-1 with the decrease in molecular weight from 69 to 22 kDa measured by gel permeation chromatography. Freezing of PHMA gels as well as compression of PHMA bulk samples turn-on the DA mechanophores, revealing the microscale fracture. Photon upconversion responses toward various force stimuli are also achieved in both polymer solutions and bulk samples by doping platinum octaethylporphyrin (PtOEP) or palladium meso-tetraphenyltetrabenzoporphyrin (PdTPTBP) sensitizers with multiple excitation wavelengths.

Self-healing of epoxy nanocomposites using Diels-Alder adduct grafted graphitic nanoplatelets

Self-healing of epoxy nanocomposites using Diels-Alder adduct grafted graphitic nanoplatelets

Synthesis of 25-Hydroxy-provitamin D3 by Direct Hydroxylation of Protected 7-Dehydrocholesterol.

A new synthetic route to 25-hydroxy-provitamin D3 was elaborated. The synthesis consists of direct hydroxylation at C-25 of 7-dehydrocholesterol hetero Diels-Alder adducts. The adducts were prepared by [4 + 2] cycloaddition of azadienophiles to the steroidal diene. The hydroxylation reactions of adducts were carried out with different dioxiranes or with chromyl trifluoroacetate. The byproducts of these reactions were isolated and identified. The strengths and weaknesses of hydroxylation methods with different oxidizing agents were discussed.

Natural compound Sanggenon C inhibits porcine reproductive and respiratory syndrome virus replication in piglets

Porcine reproductive and respiratory syndrome virus is one of the main pathogens threatening the global pig industry, and there is still a lack of effective therapeutic drugs. Sanggenon C is a flavanone Diels-Alder adduct compound extracted from the root bark of the mulberry genus, which has blood pressure-reducing, anti-atherosclerotic, anti-oxidative, and anti-inflammatory effects. In our previous study, Sanggenon C was confirmed to significantly inhibit PRRSV replication in vitro. However, its antiviral potential to inhibit PRRSV infection in vivo has not been evaluated in piglets. Here, the antiviral effect of Sanggenon C was evaluated in PRRSV-challenged piglets based on assessments of rectal temperature, viral load, pathological changes of lung tissue and secretion of inflammatory cytokines. The results showed that Sanggenon C treatment relieved the clinical symptoms, reduced the viral loads in the lungs and bloods, alleviated the pathological damage of lung tissue, decreased the secretion of inflammatory cytokines, and shorten the excretion time of virus from the oral and nasal secretions and feces of piglets after PRRSV infection. The results indicated that Sanggenon C is a promising anti-PRRSV drug, which provides a new strategy for the prevention and control of PRRS in clinical practice.

The study of designing a controlled drug release using oxaliplatin-loaded hydrogel for ovarian cancer treatment

The study of designing a controlled drug release using oxaliplatin-loaded hydrogel for ovarian cancer treatment

'Donor-acceptor', 'interpenetrating polymer network' and 'electrostatic self-assembly' work in tandem to achieve extraordinary specific shielding effectiveness.

The exploration of 'electrostatic self-assembly' on solid surfaces has garnered significant interest across various fields. With the sophistication of gadgets, managing electromagnetic interference (EMI) from stray signals, especially in stealth applications, necessitates materials that can absorb microwaves. A promising approach involves integrating lightweight self-healing polymeric materials. This study employs electrostatic self-assembly to design a carbon nanotube structure on an interpenetrating polymer network (IPN) made of PVDF and bismaleimide (BMI)-grafted dopamine hydrochloride, enhancing mechanical integrity through well-formed IPNs. Graphene oxide (GO) is introduced before IPN formation to facilitate an 'acceptor-donor' interaction via the Diels-Alder adduct between BMI and GO, which binds with multi-walled carbon nanotubes (MWCNTs). MWCNTs, modified with PQ7 or PDDA for a positive charge, self-assemble onto the IPN-GO construct, creating a lightweight and chemically stable structure capable of absorbing electromagnetic radiation. The 21 μm thick construct exhibits enhanced microwave absorption within the X-band (8.2-12.4 GHz), with a specific shielding effectiveness of 8637 dB cm2 g-1 and a green index (gs ≈ 1.41). The construct is coated with self-healable polyetherimide (PEI) containing exchangeable disulfide bonds to address maintenance challenges, providing heat-triggered self-healing properties. These innovative structures offer solutions for 5G and IoT applications where lightweight, durable, and multifunctional properties are essential for effectively shielding electronic devices from stray signals.