Bioorganic & Medicinal Chemistry最新文献

Vitamin A and its primary active derivative, all-trans retinoic acid (RA), are endogenous signaling molecules essential for numerous biological processes, including cell proliferation, differentiation, and immune modulation. Owing to its differentiation-inducing effect, RA was the first differentiating agent approved for the clinical treatment of acute myeloid leukemia. While the classical mechanisms of RA signaling involve nuclear receptors, such as retinoic acid receptors (RARs), emerging evidence suggests that RA also engages in non-covalent and covalent interactions with a broader range of proteins. However, tools for thoroughly characterizing these interactions have been lacking, and a comprehensive understanding of the landscape of RA-modified and RA-interacting proteins remains limited. Here, we report the development of two RA-based chemical reporters, RA-yne and RA-diazyne, to profile RA-modified and RA-interacting proteins, respectively, in live cells. RA-yne features a clickable alkyne group for metabolic labeling of RA-modified proteins, while RA-diazyne incorporates a photoactivatable diazirine and an alkyne handle for crosslinking and capturing RA-interacting proteins. Using quantitative proteomics, we demonstrate the high-throughput identification of these proteins, revealing that non-covalent interactions are more prevalent than covalent modifications. Our global profiling also uncovers a large number of RA-interacting proteins mainly enriched in pathways related to mitochondrial processes, ER homeostasis, and lipid metabolism. Overall, this work introduces new RA-derived chemical reporters, expands the resource for studying RA biology, and enhances our understanding of RA-associated pathways in health and disease.

Infectious diseases caused by drug-resistant bacteria represent one of the most significant global public challenges of this century. There is an urgent need for the treatment of drug-resistant Gram-negative bacterial infections. A series of 3,4-dihydro-2H-[1,3]oxazino[5,6-h]quinoline derivatives were synthesized and evaluated for their antibacterial activity against Gram-negative bacteria including strains from ATCC and clinical isolates, initially revealing the structure-activity relationship. Among them, 22 compounds demonstrated inhibitory activity (MICs: 3.125-12.5 μg/mL) against Escherichia coli (E. coli) ATCC 25922 and Acinetobacter baumannii (A. baumannii) ATCC 19606. Among these, 7 compounds exhibited good inhibitory activity against MDR A. baumannii clinical isolates, with MICs ranging from 3.125 to 12.5 μg/mL. Most of these compounds also showed lower cytotoxicity than IMB-881. Notably, 2 compounds, 4n1 and 4b3, significantly extended the survival of Galleria mellonella larvae infected with E. coli. Mechanism studies have revealed that compounds 4n1 and 4b3 might disrupt the interaction between LptA and LptC, showing moderate affinity for LptA protein. These compounds also induce abnormal bacterial morphology and cause outer membrane damage. This finding provides a novel class of antibiotic sensitizers with the potential to effectively fight against E. coli and A. baumannii.

Thiols have interesting bio-chemical properties and can be found in a number of approved drugs. However, some thiols exhibited poor plasma stability and microsomal stability, leading to poor in vivo activity and poor oral bio-availability, in spite of their potent activity in vitro. Prodrug is a classic strategy to improve drug pharmacokinetics. In this study, we designed and synthesized 25 prodrug derivatives of a potent thiol-based HDAC inhibitor, IYS-15, to explore the structure-plasma stability relationships and structure-microsomal stability relationships in these series. We also tried to identify the main metabolic enzymes participated in the metabolism of some representative thiol-based prodrug derivatives. This work thus presents a comparison between different prodrugs based on the same model thiol, giving insights into the stability profile of the synthesized prodrug derivatives in human plasma and human liver microsomes, and more importantly, might also provide structural guidance to medicinal chemists in the design of thiol-based prodrugs and other novel prodrugs with thiol-based linkers.

This study reports the design, synthesis, and characterization of a novel series of benzene sulfonamide-triazole hybrid derivatives, to evaluate their anticancer potential against colorectal cancer. The synthesized compounds were characterized using NMR and HRMS spectroscopic techniques. In vitro cytotoxicity assessments revealed that compounds 5g and 5j exhibited significant anticancer effects. 5g showed the highest potency in the DLD-1 cell line (IC₅₀ = 11.84 µM), while 5j demonstrated robust activity in the HT-29 cell line (IC₅₀ = 9.35 µM). Apoptotic analysis indicated that compound 5g effectively induced early and total apoptosis, surpassing the chemotherapeutic agent 5-fluorouracil (5-FU), highlighting its therapeutic potential. Molecular docking studies showed strong binding interactions with key proteins involved in colorectal cancer progression, such as TGFβ2 and VEGFR1. 5j displayed a high binding affinity for TGFβ2 (MM-GBSA ΔG = -92.52 kcal/mol) and 5g showed promising interactions with VEGFR1 (ΔG = -70.63 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes, indicating potential as targeted therapeutic agents. Compounds 5g and 5j demonstrate significant promise for further development in colorectal cancer treatment.

Technetium-99m (Tc-99m) is the most employed radionuclide in nuclear imaging diagnostics worldwide for many diseases. The ideal physiochemical properties of Tc-99m (such as half-life and pure gamma energy) make it favorable for Single Photon Emission Computed Tomography (SPECT). In this study, we aim to expand the utilization of Tc-99m radiopharmaceutical toward prostate cancer diagnostics which is currently no FDA approved products and has been intensively examined for a potential candidate. The new formulation for Tc-99m complexation with PSMA-617, a current ligand for radionuclide therapy of prostate cancer with lutetium-177 (Lu-177), has been investigated. Co-complexation with citrate was utilized to improve the labeling efficiency by over 97 %. The stability of the new radiopharmaceutical was in vitro evaluated confirming that the Tc-99m labeled PSMA-617 remained stable for over a single half-life of Tc-99m in normal saline solution and in human serum. The in vivo study in the LNCaP xenografted mouse model confirmed a high selectivity of the new tracer toward prostate cancer.

Sphingosine-1-phosphate-5 receptors (S1P₅) are predominantly expressed in oligodendrocytes and as a result have been proposed as an important target in Multiple Sclerosis (MS). Selective S1P₅ radiotracers could enable in vivo positron emission tomography (PET) imaging of oligodendrocytes activity. Here we report the synthesis, radiolabelling and first preclinical evaluation of the pharmacokinetics and binding properties of a lead 6-arylaminobenzamide derivative, 6-(mesitylamino)-2-methoxy-3-methylbenzamide (also named as TEFM180), as a potential core scaffold for development of novel S1P₅ PET radiotracers. Following intravenous bolus injection, TEFM180 was found to quickly enter the brain with good brain:blood ratios and subsequent rapid clearance. Autoradiography studies showed that [³H]TEFM180 had a high affinity for its target (K_D = 2.8 nM), with moderate levels of non-displaceable binding. Distribution of [³H]TEFM180 in the brain was found to be consistent with S1P₅ expression and showed a binding potential (BP) of >2-3 in white matter rich regions. Overall, TEFM180 offers a good initial platform for development of future radiotracers targeting S1P₅.

Cyclooxygenase-2 (COX-2) is a key enzyme in the biosynthesis of prostaglandins and plays a special role in the process of inflammatory response. COX-2 is a target of non-steroidal anti-inflammatory drugs (NSAIDs), which can effectively relieve inflammation, pain and fever responses by inhibiting COX-2. Despite the significant study progress of inhibitors targeting COX-2, the development of COX-2 degraders remains insufficient. Proteolysis targeting chimaeras (PROTACs) have recently emerged as a fascinating technology for targeted protein degradation and drug discovery. In this report, we present the design, synthesis and detection of aspirin-based PROTACs that demonstrate effective ubiquitin-proteasome pathway degradation of COX-2 in lipopolysaccharide-stimulated RAW264.7 cells, and the aspirin-based negative PROTACs does not promote the degradation of COX-2. Moreover, we show AspPROTACs could significantly affect proteasome degradation and inflammatory signaling pathways through quantitative proteomic data analysis. These COX-2 degraders offer valuable chemical tools and novel insights for research in anti-inflammatory drugs.

Betulinic acid (BA) is a kind of naturally occurring lupane pentacyclic triterpenoid, possessing various biological activities including antiviral, anti-inflammatory and antitumor activity. Covalent inhibitors, characterized by electrophilic warheads that form covalent bonds with specific amino acid residues of target proteins, have garnered enormous attention in anticancer agent discovery over the past decade owing to their exceptional selectivity and efficacy. In this study, BA was structurally modified with electrophilic groups, and 23 derivatives of BA were synthesized. Most of these BA derivatives exhibited improved antiproliferative activity against MCF-7, HeLa, MDA-MB-231 cells in MTT assay, especially the compound 15b (IC₅₀ = 1.09 μM against MCF-7 cells). Further study demonstrated that 15b inhibited the migration and clone formation of MCF-7 cells, induced the apoptosis, autophagy and cycle arrest at G2/M phase in MCF-7 cells, and promoted the production of intracellular reactive oxygen species (ROS). Western blot analysis showed that 15b inhibited AKT/mTOR signaling pathway in MCF-7 cells. In addition, 15b reversed the resistance of JIMT-1 cells to trastuzumab, which might be related to the inhibition of AKT/mTOR pathway. Finally, 15b significantly inhibited the growth of tumor in the breast cancer xenograft mouse model with 36 % inhibition rate of tumor growth and without significant reduction of mouse body weight.

The NMDA receptor has long attracted researchers' attention due to its potential as a drug target and its central role in the central nervous system. The NMDA receptor is a ligand-gated and voltage-dependent ion channel widely distributed in the central nervous system. In this study, we employed a drug design strategy combining "molecular assembly" and "combinatorial chemistry." By reducing the carbonyl group of germacrone to a hydroxyl group and esterifying it with alanine and linarinic acid, we successfully obtained nine novel germacrone derivatives through two rounds of structural optimization. We evaluated the neuroprotective activity of these nine derivatives using the MTT assay. The results revealed that compound C1 exhibited particularly outstanding activity, achieving a cell protection rate of 29.63 ± 1.56 % at a concentration of 0.05 μM, outperforming the positive control drug, ifenprodil. Further experiments on NMDA-induced Ca²⁺ influx verified that the action site of compound C1 was the NMDA receptor, and demonstrated its superior antagonistic effect on the NMDA receptor compared to germacrone and ifenprodil. Additionally, molecular docking studies and ADMET property predictions were conducted for compound C1. The results showed that compound C1 tightly bound to the active site of the NMDA receptor and possessed favorable pharmacokinetic properties. In conclusion, compound C1, characterized by a germacrone-linarinic acid structure, not only exhibits strong antagonistic effects on the NMDA receptor but also demonstrates excellent pharmacokinetic properties, indicating its potential for further development as a therapeutic drug for central nervous system diseases.

Six pyridine analogs of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid-or CD3254 (11)-in addition to two novel analogs of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (CBt-PMN or 23) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), an FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Treatment with 1 often elicits side-effects by disrupting or provoking other RXR-dependent nuclear receptors and cellular pathways. All analogs were assessed through modeling for their ability to bind RXR and then evaluated in human colon and kidney cells employing an RXR-RXR mammalian-2-hybrid (M2H) system and in an RXRE-controlled transcriptional assay. The EC₅₀ values for these analogs, and their corresponding effectiveness in activating both LXR/LXRE and the Sterol Regulatory Element Binding Protein (SREBP) promoter in comparison to 1, suggests that these compounds likely display a range of therapeutic potential and differential side effect profiles. Several analogs also exhibited reduced retinoic-acid-receptor (RAR) cross-signaling implying that they possess enhanced selectivity towards activation of cellular RXR versus RAR pathways. These results show that modifying potent rexinoids such as CD3254 or partial agonists such as CBt-PMN can result in improved target receptor selectivity and enhanced potency, such as compounds 26, 27 and 28 in this study, compared with approved therapeutics such as compound 1, where these three compounds exhibited similar potency as 1, but 26 and 27 lower RAR and SREBP activation than 1.