Organic & Biomolecular Chemistry最新文献

Oxime ethers are extensively present as key components in numerous active pharmaceutical ingredients and many other synthetically viable organic compounds. Herein, we present a metal, base and additive free mild C-O bond formation strategy for the synthesis of oxime ethers from various oxime derivatives and tertiary and secondary aryl alcohols. The reaction is carried out in the presence of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the green solvent at 30 °C. The reaction tolerates both aldoximes and ketoximes including ketoximes bearing heteroatoms, furnishing high yields (up to 99%). The formation of a triphenylmethyl carbocation as an intermediate is supported via UV-Vis spectroscopy. Successful gram-scale synthesis of the oxime ether, low energy input and simple reaction conditions further highlight the potential of this reaction to effectively transition from the laboratory scale to industrial production. A broad substrate scope compatibility was also observed.

Since the discovery of penicillin, the forerunner of the most widely used class of antibiotics (i.e. β-lactams), natural compounds and their derivatives represented a major source of antibacterial therapeutic products whose availability enabled modern medical practices (invasive surgery, organ transplant, etc.). However, the relentless emergence of resistant bacteria is challenging the long-term efficacy of antibiotics, also decreasing their economic attractiveness for big pharma, leading to a significant decay in antibacterial development in the 21^st century and an increased use of last-resort drugs such as carbapenems or colistin. Indeed, bacteria evolved an arsenal of resistance mechanisms, leading to the emergence of totally-drug resistant isolates, already sporadically isolated among Gram-negative bacterial species. To face this deadly peril, it is fundamental to explore new ground-breaking approaches. In view of the significance of both β-lactam antibiotics and the production of one or more β-lactamases as the major resistance mechanism (especially in Gram-negative bacteria), we implemented an original approach to selectively deliver antibacterial zidovudine (AZT) exploiting the β-lactamase-mediated hydrolysis of a β-lactam-conjugate prodrug. The synthesis of the targeted pronucleosides was performed in 5-7 steps and based on an original Pd-catalyzed cross-coupling reaction. Enzymatic and microbiological evaluations were performed to evaluate the synthesized pronucleosides, yielding new insights into molecular recognition of β-lactamase enzymes. This approach would potentially allow a targeted and selective eradication of antibiotic-resistant β-lactamase-producing (opportunistic) pathogens, as the inactive prodrug is unable to harm the commensal microbial flora.

A series of novel derivatives of Poliacetylene Glycosides (PAGs) were synthesized, and their antiproliferative and antiviral properties were evaluated. Starting from D-(+)-glucose pentaacetate as a precursor, a commercially available and low-cost starting material, three different strategies were attempted to synthesize the new PAGs, and the desired compounds were obtained in high overall yields after only three steps. The synthesized PAGs exhibited antitumoral activity in concentrations ranging from 68-878 μM and antiviral activities in concentrations ranging from 71-794 μM. Some preliminary structure-activity relationships are also discussed.

Antisense oligodeoxynucleotides can bind to target RNAs and cleave them using RNase H. Despite the high activity of antisense oligodeoxynucleotides modified with locked nucleic acids (LNA) at several bases at both the 5' and 3' ends (LNA gapmer), toxicity has been reported, necessitating additional backbone modifications to reduce toxicity. In this study, we introduced a sulfonamide linkage into the LNA gapmer to elucidate its fundamental properties such as hybridization, base recognition, and induction of RNase H activity. A new chemically stable sulfonyltriazole was used as a synthetic intermediate to introduce a sulfonamide linkage between the two nucleosides. We studied the properties of the duplex of the sulfonamide-linked gapmer and target RNAs, such as melting temperature, circular dichroism, and cleavage of RNA strands by RNase H. We found that the gapmers had a lower but tolerable duplex stability with base-pair specificity and the ability to induce RNase H activity.

C-P bond formation reactions have garnered significant attention due to the widespread presence of organophosphorus compounds in pharmaceuticals, phosphine-containing ligands, pesticides, and materials science. Consequently, various efficient methodologies have been established in recent decades for constructing C-P bonds. This review article traces the historical evolution of C-P bond research and explores the prospects of C-P bond formation. It contrasts biotechnological approaches with chemical synthesis, emphasizing the critical importance of precision and innovation in developing novel C-P structures. A forward-looking perspective is provided on the role of computational tools and machine learning in optimizing C-P bond synthesis and discovering new compounds. The article explores prospective avenues for reactions that form C-P bonds and advocates for enhanced interdisciplinary collaboration to propel scientific and technological advancements.

Isocyanates play a crucial role as key building blocks in the production of thermoplastic foams, elastomers, adhesives, agrochemicals, and pharmaceuticals. These compounds are essential in the manufacture of various polymeric products, such as polyurethane foams, synthetic rubbers, and surface coatings. Given their significance, and the fact that many isocyanates are highly reactive and toxic, there is an increasing demand for innovative and sustainable methods for their synthesis and detection that emphasize safety, efficiency, and selectivity. Developing processes for isocyanate production that avoid hazardous reagents like phosgene is particularly critical. While several methods exist for the in situ generation of isocyanates, the search for an eco-friendly and sustainable approach for their direct synthesis and isolation continues. Recent advances in isocyanate synthesis promise innovative and efficient strategies with broad industrial and environmental benefits. This review highlights various methods for synthesizing di- and monoisocyanates, emphasizing their isolation and conversion into ureas and carbamates in line with the principles of sustainable and green chemistry.

A novel extended tetrathiafulvalene was prepared by introducing the large pentaleno[1,2-b:4,5-b']difluorene as a central polycyclic aromatic hydrocarbon moiety. This compound behaved as a multi-redox system that could take reversibly six redox states (-1, 0, +1, +2, +3, +4). The compound exhibited strong absorptions in the visible region with an end-absorption almost reaching to 700 nm.

Herein, N-N bond cleavage of sulfonylhydrazides was observed and applied in the synthesis of N-sulfonated quinolin-2-(1H)-one-3-carboxamides. More than 30 examples were forged in 52%-97% yields. Further transformation delivered a 3,4-dihydro-quinolin-2(1H)-one derivative.

Nitrogen-containing heterocyclic cores are of immense importance due to their high abundance in naturally occurring or synthetic molecules having wide applications in different fields of basic and applied sciences. The functionalities introduced in an N-heterocyclic core play an important role in regulating the physiochemical behavior of the particular N-heterocycles to alter their chemical and biological reactivity. Suitably functionalized N-heterocycles demonstrate their widespread applications in pharmaceuticals, agronomy, materials sciences, synthetic chemistry, pigments, etc. During the last decade, electrochemistry has emerged as a sustainable alternative to conventional synthetic approaches by minimizing reagent uses and chemical waste. Synthetic chemists have extensively utilized the tool to functionalize N-heterocycles. This is evidenced by the appearance of more than a hundred methods on the topic over recent years, signifying the importance of the synthetic area. This review is focused on the accumulation of synthetic methods based on the electrochemical functionalization of N-heterocycles developed over the recent decade. Literature reports on the C-/N-H-functionalization and functional modifications of N-heterocycles that are accessible through the available search engines are included in the review. Relevant mechanistic details in support of the reported reactions are discussed to present a clear picture of the reaction pathways. The review aims to provide a clear picture of the possible pathways of electron transfer, the electrochemical behavior of different N-heterocyclic cores, functionalization reagents, and the chemical processes that occur during the electrochemical functionalization/modification of N-heterocycles.

This study focuses on the stereoselective syntheses of 1-deoxysphingosine analogues as potential inhibitors of sphingosine kinase (SphK), particularly targeting its isoforms SphK1 and SphK2, which are implicated in cancer progression and therapy resistance. The research builds on previous work by designing a series of analogues featuring systematic structural modifications like the incorporation of a triazole ring, varying degrees of fluorination, and different head groups (e.g., guanidino, N-methylamino, and N,N-dimethylamino). These modifications aimed to enhance polar and hydrophobic interactions especially with SphK2. The synthesized compounds were evaluated for their inhibitory activity, revealing that certain derivatives, particularly those with guanidino groups and heptafluoropropyl fragments at the lipidic tail, exhibited significant potency and selectivity towards SphK2. Docking studies supported these findings by showing favorable binding interactions within the SphK2 active site, which were less pronounced in SphK1, correlating with the observed selectivity. This work contributes to the development of novel 1-deoxysphingosine analogues targeting SphK inhibition, as well as to the knowledge of the differential topology of the active sites in SphK1 and SphK2.