Bioorganic Chemistry最新文献

Neurodegenerative diseases (NDs) represent a hallmark of numerous incapacitating and untreatable conditions, the incidence of which is escalating swiftly, exemplified by Alzheimer’s disease and Parkinson’s disease. There is an urgent necessity to create pharmaceuticals that exhibit high efficacy and minimal toxicity in order to address these debilitating diseases. The structural complexity and diversity of natural products confer upon them a broad spectrum of biological activities, thereby significantly contributing to the history of drug discovery. Nevertheless, natural products present challenges in drug discovery, including time-consuming separation processes, low content, low bioavailability, and other related issues. To address these challenges, numerous analogs of natural products have been synthesized. This methodology enables the rapid synthesis of analogs of natural products with the potential to serve as lead compounds for drug development, thereby paving the way for the discovery of novel pharmaceuticals. This paper provides a summary of 127 synthetic analogues featuring various natural product structures, including flavonoids, alkaloids, coumarins, phenylpropanoids, terpenoids, polyphenols, and amides. The compounds are categorized based on their efficacy in treating various diseases. Furthermore, this article delves into the structure–activity relationship (SAR) of certain analogues, offering a thorough point of reference for the systematic development of pharmaceuticals aimed at addressing neurodegenerative conditions.

In this work, we developed a dual-targeting probe consisted of well-defined hyaluronan (HA) oligosaccharide and glucose (Glc) labeled with Rhodamine B (HGR). The probe was designed to enhance tumor targeting both in vitro and in vivo, by simultaneously targeting CD44 and Glc transporter 1 (GLUT1). The HA oligosaccharide component was crucial for accurately assessing the impact of sugar chain structure on targeting efficacy, while its unoccupied carboxyl groups could minimize interference with HA’s binding affinity to CD44. In vitro studies demonstrated that HGR possessed remarkable cytocompatibility and superior targeting abilities compared to single-targeting probes. It displayed a marked preference for CD44^high/GLUT1^high cells rather than CD44^low/GLUT1^low cells. In vivo studies using murine models further confirmed the significantly enhanced targeting efficacy and excellent biocompatibility of HGR. Therefore, this designed dual-targeting probe holds potential for clinical tumor detection.

Immunomodulatory drugs (IMiDs) represented by thalidomide exhibit benefits when combined with other chemotherapeutic drugs for patients with lung cancer, which inspired the exploration of combining pomalidomide with another agent to treat lung cancer as it is more potent than thalidomide. However, the drugs that can be combined with pomalidomide to benefit patients and related mechanisms remain unclear. Here, we performed a proteomic analysis based on the streptavidin pull-down to identify the potential target of pomalidomide in non-small cell lung cancer (NSCLC). In this work, electron transfer flavoprotein alpha subunit (ETFA), an important enzyme involved in electron transport in the respiratory chains was identified as a crucial cellular target of pomalidomide in NCI-H460 cells. Using apoptosis model and combination analyses, we found that pomalidomide directly targeted ETFA, and increased ATP generation, thereby significantly promoting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Specific knockdown of ETFA could effectively eliminate the promoting effect of pomalidomide on energy production. Furthermore, respiratory chain inhibitors can effectively block cell apoptosis induced by TRAIL and pomalidomide. These results suggested that pomalidomide may promote apoptosis by facilitating energy production by targeting ETFA and thus enhanced the anticancer effects of chemotherapeutic drugs. It is noteworthy that pomalidomide noticeably increased the anticancer efficacy of cisplatin (CDDP) in NCI-H460 xenograft model with the main mechanisms by inducing apoptosis. Collectively, our data not only provide new insights into the anticancer mechanisms of pomalidomide but also reflect translational prospects of combining pomalidomide with CDDP for NSCLC treatment.

Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems. Tetrahydrocarbazoles and 5-arylidene-4-thiazolinones have always attracted researchers for their multifaced anticancer activities and the possibility to be easily derivatized. Thereby, herein we report the combination of the two scaffolds to provide compounds 9a-j and 10a-j that were fully characterized and their tautomeric form was confirmed by crystal structure. 9a-j and 10a-j were assessed for in vitro antiproliferative activity using SRB assay against a panel of seven human cancer cell lines with doxorubicin as the standard. The results revealed that the cell lines derived from leukemia (Jurkat) and lymphoma (U937) are the most sensitive. Compounds 9d, 10e, 10g, and 10f revealed the highest potency (IC₅₀ = 3.11–11.89 μM) with much lower effects on normal lymphocytes cell line (IC₅₀ > 50 µM). The results show that modifications at 6th position of the THC and the nature of the substituent at the arylidene moiety affect the activity. To exploit the mode of action, 9d, 10e, 10f, and 10g were evaluated as VEGFR-2 and EGFR inhibitors. 10e is the most potent (IC₅₀ 0.26 and 0.14 μM) against both enzymes. It also induced G0-G1-phase cell cycle arrest and apoptosis. While 10g exhibited higher potency (IC₅₀ 9.95 μM) than vincristine (IC₅₀ 15.63 μM) against tubulin. A molecular docking study was carried out to understand the interactions between 10e, 10g and their targets. This study reveals 10e and 10g as possible candidates for developing multitarget anticancer agents against leukemia and lymphoma.

The complex nature of Alzheimer’s disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-β (Aβ) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3β is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of Aβ plaques, making GSK-3β an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4-tetrahydropyrimidine based derivatives as inhibitors of GSK-3β, tau phosphorylation, and Aβ accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3β and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3β inhibition by the most potent compound 44. The in- vitro drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3β inhibitor was tested using AD transgenic Caenorhabditis elegans (C. elegans) strain CL2006 for quantification of Aβ plaques and BR5706 C. elegans strain for tau pathology evaluation. We then evaluated the blood–brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3β inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.

Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with ¹³¹I to obtain the chemically and biologically identical radiopharmaceutical [¹³¹I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [¹³¹I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [¹³¹I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [¹³¹I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.

A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both in vitro and in vivo. Among them, compound III-4 demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC₅₀ value of 2.9 nM and a K_D value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3⁺ T cells assay, III-4 relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 μg/mL). Moreover, compound III-5, an ester prodrug derived from III-4, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound III-5 holds promise as an inhibitor of the PD-1/PD-L1 interaction for cancer immunotherapy.

Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson’s and Alzheimer’s. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC₅₀ of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma T_max: 1 h, C_max: 51.10 ± 13.51 ng/ml; Brain T_max: 0.5 h, C_max: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.

Diabetes mellitus can induce liver injury and easily progress to liver fibrosis. However, there is still a lack of effective treatments for diabetes-induced hepatic fibrosis. Cordycepin (COR), a natural nucleoside derived from Cordyceps militaris, has demonstrated remarkable efficacy in treating metabolic diseases and providing hepatoprotective effects. However, its protective effect and underlying mechanism in diabetes-induced liver injury remain unclear. This study utilized a high-fat diet/streptozotocin-induced diabetic mouse model, as well as LX-2 and AML-12 cell models exposed to high glucose and TGF-β1, to explore the protective effects and mechanisms of Cordycepin in liver fibrosis associated with diabetes. The results showed that COR lowered blood glucose levels, enhanced liver function, mitigated fibrosis, and suppressed HSC activation in diabetic mice. Mechanistically, COR attenuated the activation of the Wnt/β-catenin pathway by inhibiting β-catenin nuclear translocation, and β-catenin knockdown further intensified this effect. Meanwhile, COR significantly inhibited SOX9 expression in vivo and in vitro. Knockdown of SOX9 downregulated Wnt3a and β-catenin expression at the protein and gene levels to exacerbate the inhibitory action of COR on HG&TGF-β1-induced HSCs activations. These results indicate SOX9 is involved in the mechanism by which COR deactivates the Wnt/β-catenin pathway in hepatic fibrosis induced by diabetes. Moreover, prolonged half-life time, slower metabolism and higher exposure of COR were observed in diabetes-induced liver injury animal model via pharmacokinetics studies. Altogether, COR holds potential as a therapeutic agent for ameliorating hepatic injury and fibrosis in diabetes by suppressing the activation of the SOX9-mediated Wnt/β-catenin pathway.

In most organisms, the tri-carboxylic acid cycle (TCA cycle) is an essential metabolic system that is involved in both energy generation and carbon metabolism. Its uni-directionality, however, restricts its use in synthetic biology and carbon fixation. Here, it is describing the use of the modified TCA cycle, called the Tri-carboxylic acid Hooked to Ethylene by Enzyme Reactions and Amino acid Synthesis, the reductive tricarboxylic acid branch/4-hydroxybutyryl-CoA/ethylmalonyl-CoA/acetyl-CoA (THETA) cycle, in Escherichia coli for the purposes of carbon fixation and amino acid synthesis. Three modules make up the THETA cycle: (1) pyruvate to succinate transformation, (2) succinate to crotonyl-CoA change, and (3) crotonyl-CoA to acetyl-CoA and pyruvate change. It is presenting each module’s viability in vivo and showing how it integrates into the E. coli metabolic network to support growth on minimal medium without the need for outside supplementation. Enzyme optimization, route redesign, and heterologous expression were used to get over metabolic roadblocks and produce functional modules. Furthermore, the THETA cycle may be improved by including components of the Carbon-Efficient Tri-Carboxylic Acid Cycle (CETCH cycle) to improve carbon fixation. THETA cycle’s promise as a platform for applications in synthetic biology and carbon fixation.