Development of [18F]Thiazolylacylaminopyridine-Based Glycogen synthase Kinase-3ß ligands for positron emission tomography imaging.

Glycogen synthase kinase-3ß (GSK-3ß) regulates numerous of CNS-specific signaling pathways, and is particularly implicated in various pathogenetic mechanisms of Alzheimer's disease (AD). A noninvasive method for detecting GSK-3ß in AD brains via positron emission tomography (PET) imaging could enhance the understanding of AD pathogenesis and aid in the development of AD therapeutic drugs. In this study, an array of fluorinated thiazolyl acylaminopyridines (FTAAP) targeting GSK-3ß were designed and synthesized. These compounds showed moderate to high affinities (IC50 = 6.0 - 426 nM) for GSK-3ß in vitro. A potential GSK-3ß tracer, [18F]8, was successfully radiolabeled. [18F]8 had unsatisfactory initial brain uptake despite its suitable lipophilicity, molecular size and good stability. Further structural refinement of the lead compound is needed to develop promising [18F]-labeled radiotracers for the detection of GSK-3ß in AD brains.

A new class of CYP1B1 inhibitors derived from bentranil.

Cytochrome P450 1B1 (CYP1B1) is highly expressed in a variety of tumors and implicated to drug resistance. More and more researches have suggested that CYP1B1 is a new target for cancer prevention and therapy. Various CYP1B1 inhibitors with a rigid polycyclic skeleton have been developed, such as flavonoids, trans-stilbenes, and quinazolines. To obtain a new class of CYP1B1 inhibitors, we designed and synthesized a series of bentranil analogues, moreover, IC50 determinations were performed for CYP1B1 inhibition of five of these compounds and found that 6o and 6q were the best inhibitors, with IC50 values in the nM range. The selectivity index (SI) of CYP1B1 over CYP1A1 and CYP1A2 was 30-fold higher than that of α-naphthoflavone (ANF). The molecular docking results showed that compound 6q fitted better into the CYP1B1 binding site than other compounds, which was consistent with our experimental results. On the basis of 6o and 6q, it is expected to develop CYP1B1 inhibitors with stronger affinity, higher selectivity and better solubility.

Design, Synthesis, and Evaluation of 18F-Labeling CYP1B1 PET Tracer Based on 2-Phenylquinazolin.

Cytochrome P450 (CYP)1B1 has been identified to be specifically overexpressed in several solid tumors, thus it's a potential target for the detection of tumors. Based on the 2-Phenylquinazolin CYP1B1 inhibitors, we designed and synthesized several positron emission computed tomography (PET) imaging probes targeting CYP1B1. Through IC50 determinations, most of these probes exhibited good affinity and selectivity to CYP1B1. Considering their affinity, solubility, and their 18F labeling methods, we chose compound 5c as the best candidate. The 18F radiolabeling of [18F] 5c was easy to handle with good radiolabeling yield and radiochemical purity. In vitro and in vivo stability study indicated that probe [18F]5c has good stability. In cell binding assay, [18F]5c could be specifically taken up by tumor cells, especially HCT-116 cells. Although the tumor-blood (T/B) and tumor-muscle (T/M) values and PET imaging results were unsatisfied, it is still possible to develop PET probes targeting CYP1B1 by structural modification on the basis of 5c in the future.

Strategies toward Aryne Multifunctionalization via 1,2-Benzdiyne and Benzyne.

Polysubstituted arenes are prevalent in numerous natural products, medicines, agrochemicals, and organic functional materials. Among methods to prepare polysubstituted arenes, pathways involving benzyne intermediates are particularly attractive given they can readily assemble highly diverse vicinal difunctionalized benzenes in a step-economical manner under transition-metal-free conditions. In order to incorporate more than two substituents on a benzene ring via a benzyne intermediate, methodologies involving benzdiyne and benztriyne have been developed, which significantly expand the current difunctionalization strategies in benzyne chemistry. In the past years, our group has been focusing on pushing the frontier of traditional benzyne chemistry and exploring new applications. In an aim to efficiently and conveniently construct polysubstituted arenes, we developed several aryne multifunctionalization strategies. The first strategy is through the 1,2-benzdiyne processes, which can be divided into a domino aryne approach and stepwise 1,2-benzdiyne approach. In our domino aryne study, we developed three domino aryne reagents as "sesquibenzyne" synthons, which are complementary in terms of reactivity and could adapt different modes of cascade transformations. By employing these domino aryne precursors, we were able to accomplish several cascade transformations, including double nucleophilic reactions, i.e., the reaction with carbonyl protected benzothioamides, 1,2-diamination, and 1,3-diamination. In addition, two cascade processes involving nucleophilic and pericyclic reactions, namely, domino aryne annulation via nucleophilic-ene cascade and domino aryne nucleophilic, Diels-Alder process, were successfully achieved as well. Meanwhile, with our desire to expand the scope of 1,2-benzdiyne transformations, we employed stepwise 1,2-benzdiyne tactics to access polysubstituted arenes. Depending on the property of the substituent on the C3-position of a benzyne intermediate, either an electron-withdrawing or electron-donating group, the incoming ortho groups were chosen accordingly. Consequently, we realized a [2 + 2] cycloaddition-Grob fragmentation process using 3-triflyloxybenzyne and a 1,2-benzdiyne process using 3-(trimethylsilyl)benzyne. Our second research strategy is to use single benzyne to access trisubstituted arenes, which represents a more atom- and step-economical protocol. With our deliberate design, we discovered a tandem benzyne S═O bond insertion/C-H functionalization process using single benzyne and aryl allyl sulfoxides, furnishing three chemical bonds of different types in a single process. This transformation is the first 1,2,3-trisubstitution example using single benzyne intermediate. At last, we developed an oxidative dearomatization strategy on Kobayashi benzyne precursors, which led to the preparation of various cyclohexenynone precursors with diverse substituents in highly efficient manner. In this study, we also demonstrated a new reaction mode of these cyclohexenynones with allyl sulfoxides, which involves a deeper utilization of the cyclohexyne triple bond. This work is the first example of successful connection of precursors of benzyne with cyclohexyne together, revealing a new research direction in the field of cyclohexyne.

Arene Trifunctionalization with Highly Fused Ring Systems through a Domino Aryne Nucleophilic and Diels-Alder Cascade.

A convenient and efficient domino aryne process was developed under transition-metal-free conditions to generate a range of tetra- and pentacyclic ring systems. This transformation was realized via a 1,2-benzdiyne through a nucleophilic and Diels-Alder reaction cascade using styrene as the diene moiety. Three new chemical bonds, namely one C-N and two C-C bonds, and two benzofused rings could be constructed concomitantly, which was made possible by distinct chemoselective control at both the 1,2-aryne and 2,3-aryne stages. Moreover, in-depth studies were carried out on the domino aryne precursors and controlling the diastereoselectivity.

Cyclohexenynone Precursors: Preparation via Oxidative Dearomatization Strategy and Reactivity.

A unique approach toward the preparation of cyclohexenynone equivalents was successfully developed via oxidative dearomatization of aryne precursors, featuring multiple functionalities on the target rings. Upon activation, these in situ formed cyclohexenynone intermediates exhibit good to excellent reactivity with various trapping agents. Moreover, an unprecedented cascade was discovered with aryl allyl sulfoxides, revealing a deeper utilization of the alkyne bond by concomitantly introducing one nucleophile and two electrophiles.

Domino Aryne Annulation via a Nucleophilic-Ene Process.

1,2-Benzdiyne equivalents possess the unique property that they can react with two arynophiles through iteratively generated 1,2- and 2,3-aryne intermediates. Upon rational modification on the second leaving group of these aryne precursors, a domino aryne annulation approach was developed through a nucleophilic-ene reaction sequence. Various benzo-fused N-heterocyclic frameworks were achievable under transition metal-free conditions with a broad substrate scope.

Selective Aryne Formation via Grob Fragmentation from the [2+2] Cycloadducts of 3-Triflyloxyarynes.

A chemoselective ring-opening protocol of the formal [2+2] cycloadducts of 3-triflyloxyarynes was developed to generate 2,3-aryne intermediate via Grob fragmentation. A variety of 1,3-di- and 1,2,3-trisubstituted arenes could be readily accessed through this [2+2] cycloaddition-2,3-aryne formation sequence. The regioselectivity in these transformations originates from the steric repulsion of the aliphatic chain.

Aryne 1,2,3-Trifunctionalization with Aryl Allyl Sulfoxides.

An aryne 1,2,3-trisubstitution with aryl allyl sulfoxides is accomplished, featuring an incorporation of C-S, C-O, and C-C bonds on the consecutive positions of a benzene ring. The reaction condition is mild with broad substrate scope. Preliminary mechanistic study suggests a cascade formal [2 + 2] reaction of aryne with S═O bond, an allyl S → O migration, and a Claisen rearrangement.

Domino aryne precursor: efficient construction of 2,4-disubstituted benzothiazoles.

An aryne precursor with a potential to perform domino aryne chemistry was proposed and synthesized. The reaction of this reagent with benzothioamide derivatives could afford 2,4-disubstituted benzothiazole with sequential incorporation of C-S, C-N, and C-C bonds on the consecutive three positions of the aryne precursor.

Design of Novel 2-Phenylquinazolin-4-amines as Selective CYP1B1 Inhibitors for Overcoming Paclitaxel Resistance in A549 Cells.

Cytochrome P450 1B1 (CYP1B1) contributes to the metabolic inactivation of chemotherapeutics when overexpressed in tumor cells. Selective inhibition of CYP1B1 holds promise for reversing drug resistance. In our pursuit of potent CYP1B1 inhibitors, we designed and synthesized a series of 2-phenylquinazolin-4-amines. A substantial proportion of these newly developed inhibitors demonstrated inhibitory activity against CYP1B1, accompanied by improved water solubility. Remarkably, compound 14b exhibited exceptional inhibitory efficacy and selectivity toward CYP1B1. Molecular docking studies suggested that the expansion of the π-system through aromatization, the introduction of an amine group, and iodine atom augmented the binding affinity. Furthermore, inhibitors 14a, 14b, and 14e demonstrated the ability to significantly reduce the resistance in A549 cells to paclitaxel, while also inhibiting the migration and invasion of these cells. Finally, radioiodine labeling experiments shed light on the metabolic pathway of compound 5l in mice, highlighting the potential of 125I-5l as a radioactive probe for future research endeavors.

Maresin-1 improves LPS-induced depressive-like behavior by inhibiting hippocampal microglial activation.

Maresin-1 is an antiphlogistic agonist synthesized by macrophages from docosahexaenoic acid (DHA). It has both anti-inflammatory and pro-inflammatory properties and has been found to enhance neuroprotection and cognitive function. However, there is limited knowledge of its effects on depression and the potential mechanism remains unclear. In this study, the effects of Maresin-1 on lipopolysaccharide (LPS)-induced depressive symptoms and neuroinflammation were investigated in mice and the possible cellular and molecular mechanisms were further clarified. Maresin-1 treatment (5 µg/kg, i.p.) led to improved tail suspension times, as well as distances moved in an open-field test but it did not improve reductions in sugar-water consumption in mice with depressive-like behaviors induced by LPS (1 mg/kg, i.p.); TSPO PETCT scanning showed that Maresin-1 reduced the standardized uptake value (SUV) of [18 F] DPA-714 in brain regions associated with depression (e.g., hippocampus and pre-frontal cortex), while immunofluorescence of hippocampal and indicated that Maresin-1 inhibited microglial activation reducing the expression of the pro-inflammatory cytokine IL-1ß and NLRP3. The RNA sequencing of mouse hippocampi showed that genes expressed differentially between Maresin-1-treated and LPS-treated tissue were associated with tight connections between cells and the stress-activated MAPK cascade negative regulatory pathways. Overall, this study demonstrates that peripheral application of Maresin-1 could partially relieve LPS-induced depressive-like behaviors and showed for the first time that this effect was related to its anti-inflammatory action on microglia, thus providing new clues for the pharmacological mechanism underlying the anti-depression properties of Maresin-1.

Engineering manganese ferrite shell on iron oxide nanoparticles for enhanced T1 magnetic resonance imaging.

Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T1 relaxivity of IO nanoparticle in recent years; however, the high T2 relaxivity of MnIO nanoparticle hampers its T1 contrast efficiency and remains a hurdle when developing contrast agent for early and accurate diagnosis. Herein, we engineered the interfacial structure of IO nanoparticle coated with manganese ferrite shell (IO@MnIO) with tunable thicknesses. The Mn-doped shell significantly improve the T1 contrast of IO nanoparticle, especially with the thickness of ∼0.8 nm. Compared to pristine IO nanoparticle, IO@MnIO nanoparticle with thickness of ∼0.8 nm exhibits nearly 2 times higher T1 relaxivity of 9.1 mM-1s-1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T2 relaxivity to T1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T1 relaxation rates but obvious lower T2 relaxivities and r2/r1 ratios to MnIO nanoparticles with similar sizes. The desirable T1 contrast endows IO@MnIO nanoparticle to provide sufficient signal difference between normal and tumor tissue in vivo. This work provides a detailed instance of interfacial engineering to improve IO-based T1 contrast and a new guidance for designing effective high-performance T1 contrast agent for early cancer diagnosis.

Vicinal Diamination of Arenes with Domino Aryne Precursors.

Vicinal diamination of domino aryne precursors was achieved with sulfamides. The reaction proceeds through a two-aryne pathway, accepting two N-nucleophiles at the 1,2-positions of an arene ring. Symmetrical and unsymmetrical diaminobenzenes were readily obtained.

Diamination of Domino Aryne Precursor with Sulfonamides.

The reaction of a domino aryne precursor with sulfonamides efficiently afforded both 1,3-diaminobenzenes and trisubstituted 1,3-diaminobenzenes by simply varying the reaction conditions. Mechanistic study supports the sequential formation of two transient aryne intermediates involved in the reaction.