Search Results (140)

Background/Objectives: Antibody selection is critical for advancing pretargeted PET imaging toward clinical translation. This study directly compared two clinically approved anti-HER2 antibodies—trastuzumab and pertuzumab—within an identical pretargeting system, utilizing the specific chemical ligation between tetrazine and trans-cyclooctene (TCO) via the inverse electron-demand Diels–Alder (IEDDA) cycloaddition. Methods: In HER2-positive SKOV3 tumor-bearing mice, TCO-conjugated antibodies were administered 1–13 days prior to injection of a fluorine-18-labeled tetrazine probe ([¹⁸F]PEG₁₂-Tz). Results: Both strategies enabled high-contrast imaging, overcoming the kinetic mismatch between slow-clearing antibodies and the short-lived ¹⁸F isotope. Distinct profiles were observed: pertuzumab-TCO yielded higher tumor uptake and a broader imaging window (3–13 days), whereas trastuzumab-TCO resulted in lower uptake and a narrower window (1–5 days). These differences are not affinity-driven, as both conjugates showed similar Kd values (~11–14 nM). Instead, pertuzumab-TCO’s superiority stems from a dual mechanism: (1) slower cellular internalization (65.1% vs. 94.0% at 60 min) preserves surface TCO for click reaction; and (2) markedly slower blood clearance (t_1/2β = 285.9 h vs. 106.0 h) ensures sustained bioavailability and tumor extravasation. Conclusions: This head-to-head evaluation demonstrates that epitope-dictated internalization and clearance are decisive parameters for antibody selection, providing a mechanism-based framework for optimizing pretargeted imaging. Full article

Guanidines are structurally unique, highly basic, nitrogen-containing organic compounds with strong hydrogen-bonding ability and biological activity, providing valuable functionality in medicinal chemistry, organocatalysis, and materials science. Among modern strategies for assembling guanidine-containing molecules, cycloaddition reactions have emerged as powerful tools due to their efficiency, stereoselectivity, and ability to rapidly build molecular complexity. Recent innovations have expanded cycloaddition methodologies for generating guanidine functionalities, incorporating guanidine-containing substrates, and using guanidine-based catalysts. This review summarizes these advances and highlights the current trends in guanidine-related cycloaddition chemistry. Full article

A method for the preparation of 3-substituted azafluorenones is presented. Condensation of ninhydrin with thiomethylamidrazone gives a triazine from which 3-thiomethyl-4-azafluorenone is produced after Diels–Alder cycloaddition with norbornadiene followed by two retro-Diels–Alder cycloreversions. Oxidation of the sulfide to the sulfone allows for nucleophilic substitution at the 3-position. Using different amidrazones can give other substituents at the 3-position directly. The photophysical properties of the azafluorenones are characterized and compared with computational calculations. Compounds with a substituent bearing an n-donor group show significant fluorescence. The n-donor group is prominent in the HOMOs in these systems, whereas in the compounds with weak emission, it is not. The El Sayed rules for intersystem crossing do not explain the emission intensity ordering of these compounds. Full article

The cycloaddition reaction is one of the most common reactions in organic chemistry. It has been applied in various fields. Herein, we focus on the application of cycloaddition reactions in investigating biological molecules and materials using magnetic resonance techniques. To facilitate magnetic resonance studies such as electron paramagnetic resonance (EPR) spectroscopy and paramagnetic nuclear magnetic resonance (NMR) spectroscopy, there is often a requirement to attach spin labels and paramagnetic tags to the system of interest. The cycloaddition reaction is one of the ways to tether these spin labels and paramagnetic tags. In this review, we highlight the applications of various cycloaddition reactions such as the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the strain-promoted azide–alkyne cycloaddition (SPAAC) reaction and the Diels–Alder reaction in the interdisciplinary field of magnetic resonance studies of biomolecules, including proteins, nucleic acids, carbohydrates, lipids and glycans, as well as materials. Full article

Click chemistry is highly valued in the design of polymeric biomaterials due to its ability to generate complex structures and localized surface modifications. However, prominent mechanisms in click chemistry, such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), are inefficient for the synthesis and/or modification of biomaterials because they present significant limitations for in vivo applications. The presence of residual copper in the material is toxic and requires extensive purification, increasing production costs and hindering scalability and availability for in vivo applications. To overcome these limitations and ensure the safety and biocompatibility of materials, biorthogonal reactions such as strain-promoted azide-alkyne cycloaddition (SPAAC) have been developed. Thiol-ene/thiol-yne and Diels–Alder mechanisms are also relevant for the formation of robust polymer networks with specific characteristics and attractive advantages for generating biocompatible materials. These reactions not only improve cell integration and reduce fibrosis in in vivo applications but also enable the creation of functional structures for tissue regeneration. This review provides a comprehensive analysis of advances in the synthesis of biomaterials for tissue regeneration using hydrogels designed via click chemistry, as well as the various mechanisms and structural considerations. Full article

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

The multicomponent synthesis of a novel and highly symmetric polyheterocycle based on the pyrrolo[3,4-b]pyridin-5-one core incorporating the privileged tetrahydroisoquinoline moiety is described. The target compound was synthesized as an inseparable mixture of stereoisomers through a pseudo-repetitive Ugi–Zhu five-component reaction (PR-UZ-5CR) coupled to a double post-transformation sequence involving an intermolecular aza Diels–Alder cycloaddition, an intramolecular N-acylation, and a final tandem aromatization step. The product was prepared in 63% overall yield, and with an excellent atom economy of 85%, within a total reaction time of 85 min, and a temperature range from 25 to 65 °C. Structural elucidation and molecular mass confirmation were successfully achieved through NMR and FT-IR spectroscopy, and high-resolution mass spectrometry (HRMS), respectively. Full article

We investigated the Diels-Alder cycloaddition of methylcyclopentadiene with conjugated nitroalkenes and examined the influence of solvent polarity and substituent effects on the reaction mechanism. In nonpolar media (toluene), pathways A and C proceed via a pre-reactive molecular complex (MC), two transition states, and a heterocyclic intermediate, whereas pathways B and D follow a single-transition-state route directly to the norbornene product. Moderate increases in solvent polarity (acetone) do not qualitatively alter the energy profiles or mechanistic patterns, whereas highly polar solvents (methanol, acetonitrile, water, nitromethane) induce a fundamental transformation in pathway B, which adopts a stepwise, zwitterionic mechanism. NPA, MEP, and NCI analyses confirm the polar, charge-separated nature of the zwitterionic intermediate, while BET analysis elucidates the sequential electronic reorganization, highlighting early polarization toward the nitro fragment and stepwise formation of the C-C bonds. Substituent effect studies using Hammett σ parameters reveal that electron-withdrawing groups lower activation barriers, whereas electron-donating groups increase them, indicating that electronic effects dominate over steric factors. Overall, the study demonstrates a general, solvent- and substituent-dependent Diels-Alder mechanism, with pathway B proceeding through a polar, highly asynchronous, stepwise route involving a zwitterionic intermediate. Full article

Vinylallenes have been used in Diels–Alder reactions with a variety of dienophiles. However, vinylallenes activated at the allenic part of the molecule have been reacted only with carbon–carbon double bonds. We prepared siloxy vinylallenes by the base-induced equilibrium of silyl-protected allyl-propargyl alcohols. We found that these systems react with imines to form cycloadducts with total regio and facial selectivity, but only moderate endo:exo selectivity. The cycloadducts obtained were transformed into indolizidine derivatives. The reaction was studied computationally using DFT and compared to the reaction of siloxydienes. It was found that the main difference between those systems is the higher nucleophilicity of the siloxydienes compared to the siloxy vinylallenes. 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

This work reports progress in the semi-synthetic modification of cassane-type diterpenes isolated from Coulteria platyloba, a plant of ethnopharmacological relevance. The approach involves a sequence of transformations, including oxidative aromatization, ring opening, and Knoevenagel condensation, to generate key intermediates for further diversification. Preliminary studies demonstrated the feasibility of organocatalytic reactions under trienamine activation, including a successful Diels–Alder cycloaddition. The initial steps were achieved with good yields and high purity, underscoring the potential of this strategy to access novel molecular scaffolds through efficient and sustainable methods aligned with the principles of Diversity-Oriented Synthesis (DOS). Full article

The substantial ring strain and activated double bonds render methylenecyclopropanes (MCPs) potential substrates for Diels–Alder (DA) reactions. In this work, we present a thermally induced intramolecular Diels–Alder (IMDA) reaction utilizing furan-tethered MCPs. The reactions were carried out smoothly with respect to a wide variety of substrates with good functional group compatibility, affording the desired products in moderate to excellent yields. The synthetic utility of these products was successfully demonstrated. Mechanistic studies involving radical scavenger control experiments and density functional theory (DFT) calculations revealed a concerted mechanism involving an asynchronous one-step pathway. 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

Click chemistry has become a powerful and flexible approach for designing hydrogels used in tissue engineering thanks to its high specificity, fast reaction rates, and compatibility with biological systems. In this review, we introduce the core principles of click chemistry, including efficiency, orthogonality, and modularity, and highlight the main types of reactions commonly used in hydrogel formation, such as azide-alkyne c-cloadditions, thiol-ene/yne reactions, Diels–Alder cycloadditions, and tetrazine–norbornene couplings. These chemistries allow researchers to create covalently crosslinked hydrogels that are injectable, responsive to environmental stimuli, biodegradable, or multifunctional. We also explore strategies to enhance bioactivity, such as incorporating peptides, growth factors, or extracellular matrix components, and enabling precise spatial and temporal control over biological cues. Click-based hydrogels have shown promise across a wide range of tissue engineering applications, from cartilage and skin repair to neural regeneration, corneal healing, and cardiovascular scaffolds, as well as in 3D bioprinting technologies. Despite the many advantages of click chemistry such as mild reaction conditions and customizable material properties, some challenges remain, including concerns around copper toxicity, the cost of specialized reagents, and scalability. Finally, we discuss the status of clinical translation, regulatory considerations, and future directions, including integration with advanced bio fabrication methods, the design of dual-click systems, and the emerging role of in vivo click chemistry in creating next-generation biomaterials. Full article