Search Results (47)

Cancer remains one of the leading causes of morbidity and mortality worldwide, demanding the continuous search for novel and more selective chemotherapeutic agents. Quinones, particularly naphthoquinones, constitute a privileged class of redox-active compounds with well-documented antitumor activity. Likewise, thiazoles represent a heterocyclic scaffold widely explored in medicinal chemistry due to their broad pharmacophoric adaptability and diverse biological activities. In this context, this review comprehensively explores the chemical synthesis and anticancer potential of hybrid molecules combining the naphthoquinone and thiazole scaffolds. The hybridization of these pharmacophores has emerged as a powerful strategy to design multitarget antitumor agents. The review summarizes key synthetic methodologies, including Hantzsch, hetero Diels–Alder cycloaddition and multicomponent reactions, leading to structurally diverse hybrids. Particular emphasis is placed on derivatives exhibiting strong cytotoxic effects against a broad spectrum of cancer cell lines (e.g., OVCAR3, MCF-7, A549, HCT-116, HeLa, and Jurkat), low toxicity toward normal cells and well-defined mechanisms of action involving topoisomerase IIα, EGFR, STAT3, and CDK1 inhibition, as well as ROS generation and cell cycle arrest. Among these, certain hybrids displayed nanomolar potency and high selectivity indices, reinforcing their potential as promising lead compounds for anticancer drug development. Full article

Non-cephem drugs with 1,3-thiazine-derived rings are very rare, although a number of bioactive 1,3-thiazine derivatives are known. Similarly, 1,4-thiazepine-derived drugs are rare, but many 1,4-thiazepine derivatives show interesting biological activities. Therefore, our aim was the synthesis of such N,S-heterocycles using a versatile and short (1–3 steps) literature method. First, a three-component reaction of a cycloalkene, a thioamide, and an aldehyde provided 5,6-dihydro-4H-1,3-thiazines. Afterwards, Staudinger ketene–imine cycloaddition with chloroketene resulted in β-lactam-fused 1,3-thiazinanes. Finally, treatment with sodium methoxide induced ring expansion, yielding 4,5,6,7-tetrahydro-1,4-thiazepines. This synthetic pathway generates 3–5 new chiral centers with the help of pericyclic reactions, and almost every cycloaddition proceeded in a diastereoselective manner. Two-dimensional NOESY as well as single-crystal X-ray diffraction enabled unequivocal determination of the stereochemistry of all synthesized compounds. Full article

Levoglucosenone (LGO) smoothly undergoes microwave-assisted hetero-Diels–Alder reactions with thiochalcones in THF solution at 60 °C. The studied reactions are completed after 10 min, and the expected tricyclic 2,3-dihydro-4H-thiopyran derivatives are formed in a highly regio- and moderately stereoselective manner via competitive exo- and endo-attacks of the 1-thiadiene moiety onto the activated C=C bond of dienophile LGO. Although eight isomers are possible, only the formation of exo,exo- (major) and exo,endo- (minor) cycloadducts was observed. In most cases, isomeric products were separated by preparative layer chromatography and identified by means of spectroscopic methods. Some of the cycloadducts were obtained as single crystalline solids, and X-ray analyses enabled unambiguous confirmation of their structures. In order to explain the observed selectivity of the studied hetero-Diels–Alder reactions, DFT studies were carried out to determine the thermodynamic and kinetic properties of all regio- and stereoisomers. The results of these calculations predict the preferred formation of the two experimentally observed isomers. In addition, remarkable details on the electronic structure of E-1,3-diphenylprop-2-en-1-thione and on involved and hypothetical transition states could be elucidated. Full article

The relative reactivity of the nitrovinyl molecular segment characterized by the “cis” orientation of nitro group and the aryl ring was evaluated based on the experimental and Density Functional Theory quantum chemical data. It was found that, on the contrary to E-R-nitroethenes, the Z-2-Ar-1-EWG-1-nitroethene molecular segment is not planar. This fact reduces the possibility of the conjugation of π-electron systems, and as a consequence, decreases the global reactivity. Due to these conditions, the reaction of the model ethyl 4,β-dinitrocinnamate and 2-methylenecyclopentane is realized as a very difficult process; however, with full regioselectivity, it leads to the expected (4 + 2) hetero Diels–Alder cycloadduct. Bonding Evolution Theory studies show that the first new C4-C5 single bond is formed in Phase VIII by merging two pseudoradical centers. In turn, the second C6-O1 single bond is formed in last phase of the reaction, by the depopulation of V(C6), V(O1) and V’(O1) monosynaptic basins. According to this, the title reaction was classified as a process carried out according to a “one-step two-stage” mechanism. Full article

Sulfur-containing heterocyclic structures play an important role in modern biotechnology. Their synthesis is made possible by means of the hetero Diels–Alder reaction involving unsaturated sulfur compounds. In the framework of this paper, the molecular mechanism of the cycloaddition reactions between tioanalogs of the butadiene generated in situ with the participation of the Lawesson reagent and the E-2-phenyl-1-nitroethene was evaluated on the basis of the DFT quantum chemical calculations. It was found that the most favored reaction path is realized according to a stepwise mechanism with the participation of the zwitterionic intermediate. To study this further, the molecular mechanism of the deamination process of the primary cycloadducts was also analyzed. It was found that this mechanism is substantially different to the case of other known β-elimination processes and is achieved via a stepwise scheme. In addition to these investigations, the LA catalysis of the deamination process was also explored. Full article

Tocopheramines are a class of antioxidants which are distinguished from tocopherols (vitamin E) by the presence of an amino group instead of the phenolic hydroxyl group. α-Tocopheramine is intensively studied for biomedical applications but also as a stabilizer for synthetic and natural polymers, in particular for cellulose solutions and spinning dopes for cellulosic fibers. This study addresses a fundamental difference in the oxidation chemistry of α-tocopheramine and its tocopherol counterpart: while the formation of the ortho-quinone methide (o-QM) involving C-5a is one of the most fundamental reactions of α-tocopherol, the corresponding ortho-iminoquinone methide (o-IQM) derived from α-tocopheramine has been elusive so far. Synthesis of the transient intermediate succeeded initially via 5a-hydroxy-α-tocopheramine, and its occurrence was confirmed by dimerization to the corresponding spiro-dimer and by trapping with ethyl vinyl ether. Eventually, suitable oxidation conditions were found which allowed for the generation of the o-IQM directly from α-tocopheramine. The underlying oxidation chemistry of α-tocopherol and α-tocopheramine is concisely discussed. Full article

The regioselectivity and the molecular mechanism of the Diels–Alder reactions between N-(2,2,2-trichloroethylidene)carboxamides and dicyclohexylcarbodiimide were explored based on the ωB97xd/6-311G(d) (PCM) calculations. It was found that the reaction course is determined by polar local interactions. It is interesting that the most favored reaction channel is realized not via classical single-step Diels–Alder mechanism, but according to the stepwise scheme with the intervention of the zwitterionic intermediate. The details of the electron density redistribution along the reaction coordinate were explained using the ELF technique. Full article

Due to the importance of biaryls as natural products, drugs, agrochemicals, dyes, or organic electronic materials, a green alternative biaryl synthesis has been developed based on easy-to-prepare and cheap copper(I)-exchanged zeolite catalysts. Cu^I-USY proved to efficiently catalyze the direct homocoupling of either phenols or aryl boronic acids under simple and practical conditions. The Cu^I-USY-catalyzed oxidative homocoupling of phenols could conveniently be performed under air either in warm methanol or water with good to high yields. In methanol, a small amount of Cs₂CO₃ was required, while none was necessary in water. The homocoupling of aryl boronic acids was best performed also in warm methanol, without an additive. These mild conditions showed good functional-group tolerance, leading to a variety of substituted (hetero)biaryls (28 examples). The heterogeneous Cu^I-USY catalyst could readily be recovered and reused. Interestingly, the homocoupling of vinyl boronic acids was successfully coupled to a Diels–Alder reaction, even in a one-pot process, allowing access to highly functionalized cyclohexenes. Full article

The hetero-Diels–Alder (HDA) reaction between the ambident heterodiene 3-methylene-2,4-chromandione (MCDO) and non-symmetric methyl vinyl ether (MVE) is investigated using the molecular electron density theory (MEDT) at the B3LYP/6-311G(d,p) computational level. The aim of this study is to gain insight into its molecular mechanism and to elucidate the factors that control the selectivity found experimentally. DFT-based reactivity indices reveal that MCDO exhibits strong electrophilic characteristics, while MVE displays a strong nucleophilic character. Meanwhile, the Parr function explains the ortho regioselectivity of this HDA reaction. The highly polar nature of this HDA reaction, supported by the high global electron density transfer (GEDT) taking place at the transition state structures (TSs), accounts for the very low activation energy associated with the most favorable TS-4on. The ambident nature of MCDO allows for the formation of two constitutional isomeric cycloadducts. In the case of MVE, pseudocyclic selectivity is attained using a thermodynamic control. This polar HDA reaction displays an endo stereoselectivity and a complete ortho regioselectivity. A comparative relative interacting atomic energy (RIAE) analysis of the two diastereomeric structures TS-4on and TS-6on indicates a high degree of likeness, which explains the low pseudocyclic selectivity under kinetic control. Full article

In this paper, an alternative and efficient copper(I)-catalyzed synthesis of 2-sulfonyliminocoumarins is developed through a three-component reaction of ortho-hydroxybenzyl alcohol, alkynes, and p-toluenesulfonyl azide. The proposed route for access to the 2-iminocoumarin ring involves a [4 + 2] hetero-Diels-Alder reaction between ortho-quinone methide and ketenimine intermediates generated in situ. Full article

Radiolabeled peptides are valuable tools for diagnosis or therapies; they are often radiofluorinated using an indirect approach based on an F-18 prosthetic group. Herein, we are reporting our results on the F-18 radiolabeling of three peptides using two different methods based on click reactions. The first one used the well-known CuAAC reaction, and the second one is based on our recently reported hetero-Diels–Alder (HDA) using a dithioesters (thia-Diels–Alder) reaction. Both methods have been automated, and the ¹⁸F-peptides were obtained in similar yields and synthesis time (37–39% decay corrected yields by both methods in 120–140 min). However, to obtain similar yields, the CuAAC needs a large amount of copper along with many additives, while the HDA is a catalyst and metal-free reaction necessitating only an appropriate ratio of water/ethanol. The HDA can therefore be considered as a minimalist method offering easy access to fluorine-18 labeled peptides and making it a valuable additional tool for the indirect and site-specific labeling of peptides or biomolecules. Full article

An investigation of phenolic glycosides extracted from Salix germplasm revealed that arbusculoidin (benzyl 1-O-β-d-glucopyranosyl-1-hydroxy-6-oxo-2-cyclohexenyl carboxylate) and its enolic 6-glycoside isomer, isoarbusculoidin, are widespread across the Salix family. An analysis of natural hybrid species and progeny from a willow breeding programme demonstrated that the putative biosynthetic pathway leading to the salicinoid family of phenolic glycosides runs in parallel to a “benzyl”-based pathway to arbusculoidin. The introduction of a known Diels–Alder reaction trait from Salix dasyclados, as well as an acylation trait, into progeny containing both salicyl- and benzyl- pathways caused the formation of all possible hetero-cyclodimers from mixtures of reactive dienone (acyl)glycosides that participated in cross-over reactions. In addition to providing access to new analogues of the anti-cancer dimer miyabeacin, the analysis of the breeding progeny also indicated that these dienone (acyl)glycosides are stable in planta. Although the immediate biosynthetic precursors of these compounds remain to be defined, the results suggest that the (acyl)glycosylation reactions may occur later in the pathway than previously suggested by in vitro work on cloned UGT enzymes. Full article

Thiochalcones undergo cycloaddition reactions in THF solution at 60 °C with the synthetically unexplored 1-phenyl-4H-phosphinin-4-one 1-oxide in a highly regio- and stereoselective manner, yielding hitherto unknown bicyclic P,S-heterocycles containing fused thiopyran and phosphinine rings. The stereochemical structures of two of the obtained (4+2)-cycloadducts were unambiguously assigned by means of the X-ray single-crystal analysis. Based on these assignments, a concerted mechanism of the hetero-Diels–Alder reaction via the preferred endo approach of the heterodiene from the less hindered P=O side of the phosphininone molecule is postulated to explain the established rac-(4RS,8SR,9SR,10SR)-configured (4+2)-cycloadducts isolated as major products. Full article

This paper developed a method for preparing ultrasound-responsive microgels based on reversible addition fragmentation chain transfer-hetero Diels–Alder (RAFT-HAD) dynamic covalent bonding. First, a styrene cross-linked network was successfully prepared by a Diels–Alder (DA) reaction between phosphoryl dithioester and furan using double-ended diethoxyphosphoryl dithiocarbonate (BDEPDF) for RAFT reagent-mediated styrene (St) polymerization, with a double-ended dienophile linker and copolymer of furfuryl methacrylate (FMA) and St as the dienophile. Subsequently, the microgel system was constructed by the HDA reaction between phosphoryl disulfide and furan groups using the copolymer of polyethylene glycol monomethyl ether acrylate (OEGMA) and FMA as the dienophore building block and hydrophilic segment and the polystyrene pro-dienophile linker as the cross-linker and hydrophobic segment. The number of furans in the dienophile chain and the length of the dienophile linker were regulated by RAFT polymerization to investigate the effects of the single-molecule chain functional group degree, furan/dithioester ratio, and hydrophobic cross-linker length on the microgel system. The prepared microgels can achieve the reversible transformation of materials under force responsiveness, and their preparation steps are simple and adaptive to various potential applications in biomedical materials and adaptive electrical materials. Full article

The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels–Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure–activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific. Full article