Silva ML, Barbosa H, Silva MC
… +6 more, Costa-Silva TA, Levatti EVC, Oliveira MA, Romanelli MM, Tempone AG, Lago JHG
Bioorg Med Chem Lett
· 2026 Aug · PMID 41905674
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Previous investigations have demonstrated that n-hexacosyl p-coumarate, a natural product isolated from the Brazilian plant Baccharis sphenophylla, exhibits activity against the extracellular (trypomastigote) forms of Tr...Previous investigations have demonstrated that n-hexacosyl p-coumarate, a natural product isolated from the Brazilian plant Baccharis sphenophylla, exhibits activity against the extracellular (trypomastigote) forms of Trypanosoma cruzi. Structural modification of this compound led to the synthesis of the n-hexyl p-coumarate derivative, which showed significantly improved bioactivity, achieving an EC₅₀ value of 1.7 μM and a selectivity index of 71 against trypomastigote forms. However, when tested against intracellular amastigote forms, the compound displayed only moderate activity (EC₅₀ = 13 μM) and some cytotoxicity (CC₅₀ = 120 μM). To enhance efficacy and minimize toxicity, the double bond between C-7 and C-8 was reduced to a single bond, affording a series of phloretic acid derivatives (3a-3f). These derivatives were synthesized via Fischer esterification and evaluated for their in silico ADMET properties, which indicated improved drug-likeness profiles. Notably, phloretic acid derivatives exhibited substantially lower cytotoxicity (CC₅₀ > 200 μM) compared with the p-coumaric acid analogues, while maintaining potent activity against amastigote forms (EC₅₀ ≈ 10 μM), comparable to the reference drug benznidazole. A structure-activity relationship (SAR) analysis based on machine learning was performed using a deep neural network (DNN) model combined with SHAP interpretation, allowing identification of key molecular fragments influencing predicted EC₅₀ values, as well as their correlation with molecular flexibility and lipophilicity. Collectively, these results underscore the potential of phloretic acid derivatives as lead candidates for the development of new anti-T. cruzi agents.
Pan L, Hu Y, Tan F
… +5 more, Fang Q, Chen J, Zhang Y, Wu W, Xie H
Bioorg Med Chem Lett
· 2026 Aug · PMID 41903767
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Rearranged during transfection (RET) kinase mutations are frequently observed in the context of human thyroid and lung cancer treatment. Moreover, a considerable amount of effort has been dedicated by the scientific comm...Rearranged during transfection (RET) kinase mutations are frequently observed in the context of human thyroid and lung cancer treatment. Moreover, a considerable amount of effort has been dedicated by the scientific community to the identification of highly potent and selective RET inhibitors. In this study, we identified a series of pyrazolo[1,5-a]pyridine derivatives, and compound 9 as a candidate drug that targets both wild-type (wt) RET and RET by structure-activity relationship (SAR) study. In addition, 9 exhibited remarkable antitumor activity at a dose of 10 mg/kg/day, indicating that it completely hindered the growth of tumors induced by BAF3-KIF3B-RET-WT xenografts. In summary, 9 can be demonstrated to act as a potential RET inhibitor, as well as a treatment for RET-related cancers.
Bioorg Med Chem Lett
· 2026 Aug · PMID 41903766
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An anthraquinone derivative 2 was found to induce protein degradation under neutral conditions and without additives upon visible light irradiation. Based on this finding, a glutathione (GSH)-activatable photosensitizer...An anthraquinone derivative 2 was found to induce protein degradation under neutral conditions and without additives upon visible light irradiation. Based on this finding, a glutathione (GSH)-activatable photosensitizer 3 was designed and synthesized. 3 showed minimal photoactivity in the absence of GSH, but upon reaction with GSH, it generated a highly active species that caused selective photo-cytotoxicity toward cancer cells with elevated intracellular GSH levels. These results demonstrate the potential of anthraquinone-based systems as tunable and tumor-selective photosensitizers for photodynamic therapy.
Xu X, Wei Y, He H
… +4 more, Wan S, Li Z, Zhang J, Wu X
Bioorg Med Chem Lett
· 2026 Aug · PMID 41895535
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EGFR is a critical oncogenic driver in non-small cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation. Allosteric inhibitors targeting a site near the ATP-binding pocket h...EGFR is a critical oncogenic driver in non-small cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation. Allosteric inhibitors targeting a site near the ATP-binding pocket have emerged as a promising alternative. In our previous study, we identified the Betti-base scaffold as a promising core for EGFR inhibition. This scaffold represents a structurally unique chemotype for EGFR allosteric inhibitors, clearly distinct from previously reported EGFR allosteric ligands. In this study, a series of Betti-base derivatives was optimized through the introduction of hydrophilic groups. Particularly, compound 2b exhibited markedly improved anti-proliferative effects against both H1975 (EGFR) and Ba/F-EGFR cell lines, demonstrating IC values of 3.06 ± 0.17 μM and 1.08 ± 0.11 μM, respectively, comparable to the positive control JBJ-04-125-02. 2b could suppress the phosphorylation of EGFR and induce cell apoptosis in a dose-dependent manner in both H1975 and Ba/F-EGFR cell lines. The stable binding mode of 2b in the EGFR allosteric site, as demonstrated by molecular docking and dynamics simulations, provided a structural basis for its efficacy. These findings collectively suggested that 2b was a highly promising lead compound for combating NSCLC resistance driven by the C797S mutation.
Sun C, Zhang J, Yu F
… +6 more, Zhu W, He Y, Liang C, Luo K, Liu Y, Pei S
Bioorg Med Chem Lett
· 2026 Aug · PMID 41895534
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The escalating threat of antibiotic resistance has become an urgent issue in global public health, and this study designed and synthesized 28 novel thiophene amide derivatives to address this challenge. In vitro antibact...The escalating threat of antibiotic resistance has become an urgent issue in global public health, and this study designed and synthesized 28 novel thiophene amide derivatives to address this challenge. In vitro antibacterial activity tests showed that most of the derivatives exhibited broad-spectrum inhibitory activity against gram-negative and gram-positive bacteria, and Z10 was the most significant. The minimum inhibitory concentration (MIC) of compound Z10 against key strains was 1.40 to 2.33 μM, which was comparable to that of the positive control ciprofloxacin, and it showed low cytotoxicity to normal human liver cells (L02). Time-kill curve analysis confirmed its concentration-dependent bactericidal effect. Molecular docking simulations conducted using Schrodinger software show that the pyridine group of Z10 tightly binds to the carboxyl group, Lys-465 residue, and Leu-480 residue of the predicted MsbA protein target, thereby elucidating its antibacterial mechanism. Theoretical prediction of ADME properties by ADMET lab 3.0 platform confirmed that all compounds met the pharmacokinetic criteria of potential drugs. Structure-activity relationship analysis showed that the antibacterial activity was significantly enhanced when the R substituent was ethyl and the R substituent was an electron-donating heterocycle with small steric hindrance. In summary, thiophene amide derivatives (especially compound Z10) show broad prospects in the development of new antibacterial drugs.
Huang Y, Wang Y, Wang Y
… +4 more, Cheng H, Yang H, Wang C, Xu Y
Bioorg Med Chem Lett
· 2026 Aug · PMID 41881316
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ASK1 is a key regulator in the molecular mechanisms underlying multiple neurological diseases, where it drives oxidative stress, inflammation, and apoptotic pathways. ASK1 has emerged as a potential therapeutic target in...ASK1 is a key regulator in the molecular mechanisms underlying multiple neurological diseases, where it drives oxidative stress, inflammation, and apoptotic pathways. ASK1 has emerged as a potential therapeutic target in a range of neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In the study, we designed and synthesized [F]ASK1-IN-6 as the first fluorine-18 ASK1 radioligand with high purity (>95%). In in vitro autoradiography studies, [F]ASK1-IN-6 showed good binding specificity to ASK1 protein and exhibited high binding in various brain regions of mice. Furthermore, the binding specificity of the [F]ASK1-IN-6 in brain slice of wild-type mice and AD model (5 × FAD) mice were explored, the results showed [F]ASK1-IN-6 have higher binding in AD model mice, indicating that the compound has great potential for brain imaging in AD patients. Further study will focus on improving the synthesis yield of the compound and investigate its in vivo imaging in mice.
Acharya A, Gupta V, Nagpure M
… +1 more, Guchhait SK
Bioorg Med Chem Lett
· 2026 Jul · PMID 41871730
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This perspective demonstrates a critical analysis of natural products-conserved scaffolds, the molecular architectures that are produced in the common T-point of naturally evolved various biosynthetic pathways. It presen...This perspective demonstrates a critical analysis of natural products-conserved scaffolds, the molecular architectures that are produced in the common T-point of naturally evolved various biosynthetic pathways. It presents structure and functional correlation of T-point molecules with preclinical agents and drug molecules and molecule-to-medicinal properties (pharmacodynamic, physicochemical, ADMET and pharmacokinetic). Cheminformatic analysis reinforces the scaffolds' structural and functional relevance. This analysis is valuable to serve as a guiding model for development of "Nature-to-new" therapeutic molecular space.
Ren S, Wang H, Liu Y
… +6 more, Chen Y, Kang CS, Liu D, Li M, Sagastume E, Chong HS
Bioorg Med Chem Lett
· 2026 Aug · PMID 41871729
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We report the synthesis and evaluation of pyridine-based chelators for Zr with applications in positron emission tomography (PET) imaging. A series of pyridine-containing small molecule ligands were screened for spectros...We report the synthesis and evaluation of pyridine-based chelators for Zr with applications in positron emission tomography (PET) imaging. A series of pyridine-containing small molecule ligands were screened for spectroscopic Zr(IV) complexation kinetics and radiolabeling with Zr. Among these ligands, dipicolinic acid (DPA) was identified as the most effective donor system for Zr(IV). Two DPA units were linked using a tetraethylene glycol (TEG) spacer to generate an acyclic chelator TEG-DPA that can form a neutral complex with Zr(IV). The chelator TEG-DPA rapidly bound Zr at room temperature, and the resulting Zr-labeled TEG-DPA complex exhibited high serum stability. In vivo biodistribution studies showed renal excretion of the hydrophilic Zr-TEG-DPA complex, resulting in rapid blood clearance and low uptake in normal tissues including liver, muscle, and bone in healthy mice. In summary, we demonstrate for the first time the potential of DPA-based donor systems for Zr radiolabeling and identify TEG-DPA as a lead chelator for further structural optimization and applications in Zr PET imaging.
Uddin N, Roy S, Baruah R
… +3 more, Nareda A, Dutta GK, Chatterjee PN
Bioorg Med Chem Lett
· 2026 Aug · PMID 41864439
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Bis(indolyl)methanes (BIMs) are significant molecular scaffolds comprising nitrogen heterocycles that exhibit notable biological and pharmacological properties. This work represents an alternative and novel method for th...Bis(indolyl)methanes (BIMs) are significant molecular scaffolds comprising nitrogen heterocycles that exhibit notable biological and pharmacological properties. This work represents an alternative and novel method for the synthesis of BIMs via a Sc(OTf)-catalyzed tandem C-O and C-C bond-breaking reactions in β-hydroxyketone substrates. Our developed method involves the release of a unique yet unusual ketone leaving group. Anti-bacterial activity of some of the representative BIMs was evaluated against the bacterial strain Escherichia coli (E. coli), and the results were compared with those of the standard, the broad-spectrum antibiotics ciprofloxacin and tetracycline. Most of the tested BIMs exhibited anti-bacterial activity with quantitative values. Notably, BIM 3l showed the highest anti-bacterial activity among all tested BIMs, with a zone of inhibition (ZI) value of 18.33 ± 1.52 mm, as compared to the standard antibiotics ciprofloxacin (25 ± 0.57) and tetracycline (28 ± 0.57).
Bioorg Med Chem Lett
· 2026 Aug · PMID 41864438
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In daily life, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs that elicit analgesic, antipyretic, anti-inflammatory, and antithrombotic activities. However, gastric ulceration is a serious side eff...In daily life, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs that elicit analgesic, antipyretic, anti-inflammatory, and antithrombotic activities. However, gastric ulceration is a serious side effect of these drugs, which results from cyclooxygenase-1 (COX-1) inhibition by oral NSAIDs in normal human gastric mucosa. Thus, COX-2-selective inhibitors should be developed to address this problem. Carbostyril (2-quinolinone and 2-quinolone) is a time-proven structural skeleton in pharmaceutical agents and physiologically active substances. The replacement of two fused-ring skeletons of lead or model compounds with carbostyril skeletons as bioisosteres without losing activities offers various advantages. Thus, promising pharmaceutical agents without serious pharmacodynamic and pharmacokinetic toxicities can be obtained using this strategy to incorporate carbostyrils into COX inhibitors. Herein, we report the synthesis and biological evaluation of carbostyril derivatives with integrated side chains, which form L-shaped structures like representative COX-2-selective inhibitors such as celecoxib.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41861920
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Salidroside (SAL) is a natural glycoside compound with various biological activities. Recent studies have shown that SAL exhibits certain therapeutic effects on triple-negative breast cancer (TNBC). To enhance the anti-T...Salidroside (SAL) is a natural glycoside compound with various biological activities. Recent studies have shown that SAL exhibits certain therapeutic effects on triple-negative breast cancer (TNBC). To enhance the anti-TNBC activity, 15 SAL-furoxan hybrids were designed and synthesized. The anti-proliferative activities of all target compounds against four tumor cell lines (MDA-MB-231, MCF-7, BGC-823, and A549) and a normal human cell line (MCF-10A) were evaluated using the MTT assay. A12 demonstrated the most potent inhibitory activity on MDA-MB-231 cells (IC₅₀ = 14 nM), and lower toxicity compared to DOX (SI = IC/IC: 129.57 vs 1.01). Further research indicated that the anti-tumor mechanism of A12 involves the high amount of NO released in MDA-MB-231 cells and thereby induction of cells apoptosis.
Fan Y, Jiang M, Hu J
… +3 more, Su W, Shan T, Wang L
Bioorg Med Chem Lett
· 2026 Jul · PMID 41845974
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To address the crisis of multidrug-resistant microbial infections, this study used matrine, a natural product, as the lead compound to design and synthesize a series of novel N-substituted methyl matrinecarboxylate deriv...To address the crisis of multidrug-resistant microbial infections, this study used matrine, a natural product, as the lead compound to design and synthesize a series of novel N-substituted methyl matrinecarboxylate derivatives. Antimicrobial evaluation showed that multiple compounds exhibited potent inhibitory activity against Candida albicans. Among them, the minimum inhibitory concentration (MIC) of compound 4r reached 1.6 μg/mL, and it could effectively inhibit and destroy the biofilm of Candida albicans. The mechanism study indicated that compound 4r could bind stably to the target protein, and molecular dynamics simulations confirmed the stability of the complex. Further analysis of the 3D-QSAR model revealed that steric and hydrophobic interactions were the key factors affecting the activity. This work provides valuable design ideas and experimental basis for the development of novel antifungal lead compounds based on natural products.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41833828
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Celastrol (CEL), a natural product, has attracted great attention because of its remarkable antitumor potential. Its unique quinone methide (QM) moiety covalently binds to the thiol groups of cysteine residues, thereby e...Celastrol (CEL), a natural product, has attracted great attention because of its remarkable antitumor potential. Its unique quinone methide (QM) moiety covalently binds to the thiol groups of cysteine residues, thereby exerting antitumor activity. To enhance the antitumor activity of CEL, we designed and synthesized 30 CEL thiazole derivatives with improved covalent binding capacity. Most of these derivatives exhibited enhanced anti-proliferative activity against four human cancer cell lines (MCF-7, MDA-MB-231, A549, and BGC-823) compared to CEL. Among them, compound 28 exhibited the most potent antiproliferative activity against MDA-MB-231 cells (IC = 0.29 ± 0.02 μM). Further pharmacological studies showed that compound 28 exhibited more extensive and stable binding to dithiothreitol (DTT, a thiol-containing model molecule) than CEL, which might account for its enhanced antiproliferative activity. Moreover, compound 28 effectively induced apoptosis in MDA-MB-231 cells and arrested cells in the G2/M phase. In conclusion, compound 28 warrants further investigation for cancer therapy.
Wang X, Zhang L, He Z
… +3 more, Li X, Bai J, Zhong Q
Bioorg Med Chem Lett
· 2026 Jul · PMID 41825650
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Tropomyosin receptor kinase (TRK) plays a critical role in tumorigenesis, and its aberrant activation is strongly implicated in cancer progression and metastasis. In this study, a series of novel indoline-2-one derivativ...Tropomyosin receptor kinase (TRK) plays a critical role in tumorigenesis, and its aberrant activation is strongly implicated in cancer progression and metastasis. In this study, a series of novel indoline-2-one derivatives were designed and synthesized using a 3D-QSAR-guided approach targeting TRK. The antitumor potential of these compounds was evaluated through a panel of in vitro bioassays. Several derivatives were found to reduce TRK phosphorylation levels in a cellular context and exhibited pronounced anti-proliferative and anti-migratory effects. Among them, compound IIIc demonstrated potent activity against HepG2 hepatocellular carcinoma cells, with an IC₅₀ value of 2.06 μM. Furthermore, ELISA-based phosphorylation assays revealed that treatment with compound IIIc resulted in decrease in TRK phosphorylation, yielding an IC₅₀ of 0.19 μM, highlighting its therapeutic promise. Collectively, this study provides experimental evidence and a structural basis for the development of lead compounds capable of modulating TRK signaling in cancer therapy.
Taoda Y, Hirai K, Sugiyama S
… +12 more, Tanaka S, Tomida Y, Akiyama T, Nakahara K, Unoh Y, Tachibana Y, Uehara S, Sako Y, Yamamoto S, Kawashima S, Nobori H, Kato T
Bioorg Med Chem Lett
· 2026 Jul · PMID 41819156
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COVID-19, an infectious disease caused by SARS-CoV-2, first identified in Wuhan, China, in 2019 and rapidly spread around the world. In response to this worldwide crisis, the research and development of antiviral drugs a...COVID-19, an infectious disease caused by SARS-CoV-2, first identified in Wuhan, China, in 2019 and rapidly spread around the world. In response to this worldwide crisis, the research and development of antiviral drugs advanced together with vaccines, and several medications are currently being used for treatment. This study aimed to explore the structure-activity relationships (SAR) of non-covalent inhibitors of the SARS-CoV-2 3CL protease (3CL) and to develop more potent inhibitors starting from ensitrelvir, a potent non-peptide small-molecule 3CL inhibitor discovered by Shionogi & Co., Ltd. Although a previously reported dihydrofuran-ring-fused tricyclic compound 1 exhibited high antiviral activity, there were issues with its metabolic stability and solubility. Therefore, we focused on compound 2, which has a pyridopyrimidinedione scaffold, and tried to optimize its structure. Here we report compounds that have improved antiviral activity while maintaining enzyme inhibitory activity and enhanced solubility. In particular, compound 18f demonstrated a balance of potent activity, high solubility, and excellent metabolic stability. Its favorable pharmacokinetics were also confirmed in rat PK tests, suggesting that this compound offers promise as a new therapeutic agent.
Hu Y, Liu W, Sun R
… +7 more, Li M, Sun S, Li R, Zuo Z, Liu J, Zhou L, Wang S
Bioorg Med Chem Lett
· 2026 Jul · PMID 41812927
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Hyperuricemia is a major risk factor for gout and is closely associated with metabolic and cardiovascular disorders. Urate-lowering drugs targeting the urate transporter 1 (URAT1) represent an effective therapeutic strat...Hyperuricemia is a major risk factor for gout and is closely associated with metabolic and cardiovascular disorders. Urate-lowering drugs targeting the urate transporter 1 (URAT1) represent an effective therapeutic strategy; however, the clinical application of benzbromarone is limited by its hepatorenal toxicity. In this study, a series of novel pyridine-triazole derivatives were designed through a scaffold-hopping strategy based on benzbromarone, aiming to improve safety while retaining urate-lowering efficacy. Among the derivatives, analog HYJ-2 showed marginally stronger inhibition of URAT1-mediated urate transport in vitro (IC = 368 nM) than benzbromarone. In a hyperuricemic mouse model, HYJ-2 demonstrated effective serum uric acid-lowering activity without inducing apparent hepatic or renal injury. In addition, HYJ-2 showed markedly reduced cytotoxicity toward hepatic and renal cell lines and did not significantly induce apoptosis or mitochondrial dysfunction in hepatic cells. Computational docking suggested favorable interactions between HYJ-2 and key residues within the URAT1 binding pocket. Overall, these results identified HYJ-2 as a promising URAT1 inhibitor with potential application in the treatment of hyperuricemia and gout.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41791615
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Immune activity is markedly modulated by glycolipid antigens through CD1d-dependent recognition, resulting in selective induction by NKT cells. In this study, we developed a novel and effective GalCer labeling method to...Immune activity is markedly modulated by glycolipid antigens through CD1d-dependent recognition, resulting in selective induction by NKT cells. In this study, we developed a novel and effective GalCer labeling method to apply to the anti-inflammatory α-GalCer-Bz amide that possesses Th2-biased cytokine induction ability. Using these fluorescent-labeled antigen probes, the uptake of the synthesized KRN7000-type and α-GalCer-Bz amide-type labeled compounds into CD1d-expressing cells was observed by confocal microscopy. The antigen presentation on the cell surface was also tracked with visualizing the complex of CD1d and glycolipid antigens. The intracellular behavior of α-GalCer-Bz amide-type showed that its efficient cellular uptake is highly dependent on the presence of CD1d, while it rapidly presented on the cell surface as the CD1d-complex. The findings on the characteristic cellular behavior of the glycolipid antigens provide basis for further understanding of the immune modulation.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41791614
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiates viral entry through binding of its spike (S) protein receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2). Curcumin, a...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiates viral entry through binding of its spike (S) protein receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2). Curcumin, a turmeric-derived curcuminoid with broad antiviral properties, shows potential as a SARS-CoV-2 S:ACE2 inhibitor. However, its poor bioavailability, which results in low plasma concentrations, limits effective delivery to infected sites. Structural modifications, such as converting the 1,3-diketone backbone to a monoketone and varying the aromatic ring substituents, offer strategies to enhance both bioavailability and inhibitory activity. Here, fifteen (15) aryl-functionalized mono- and diketone curcumin derivatives were synthesized and evaluated for their inhibitory activity against SARS-CoV-2 S:ACE2 binding using an ELISA-type assay. Their absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) profiles were predicted using SwissADME and ProTox 3.0. Four monoketone derivatives showed >50% inhibition and dose-dependent responses (2d, IC = 13.45 μM; 3c, IC = 23.84 μM; 3d, IC = 1.24 μM; 3e, IC = 10.15 μM). Active derivatives also exhibited favorable ADME properties and low toxicity, demonstrating their potential as lead candidates for SARS-CoV-2 S:ACE2 inhibitors.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41791613
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2-(Ferrocenylmethyl)pentanoic acid (Fc-VPA), a ferrocenyl analog of valproic acid (VPA), was synthesized, fully characterized and its effect on glutamate decarboxylase (GAD) evaluated in mouse brain homogenates using an...2-(Ferrocenylmethyl)pentanoic acid (Fc-VPA), a ferrocenyl analog of valproic acid (VPA), was synthesized, fully characterized and its effect on glutamate decarboxylase (GAD) evaluated in mouse brain homogenates using an HPLC assay. Fc-VPA produced robust, concentration-dependent GAD inhibition (IC = 51 ± 4 μM), comparable to 3-mercaptopropanoic acid (3-MPA; IC = 38 ± 2 μM), whereas VPA showed weak/biphasic effects under identical conditions. Blind docking to human GAD (PDB 2OKK) supported the trend: Fc-VPA achieved a modestly higher XSCORE than VPA (5.287 vs 4.887) and engaged a broader interaction network within the active site. These findings show that ferrocenyl substitution markedly reprograms VPA's enzyme interaction profile from weak modulation to potent inhibition. The pharmacological desirability of GAD inhibition by Fc-VPA remains to be established in cellular and in vivo models.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41786055
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Gallium-68 labeled peptide radiotracers have attracted significant attention in positron emission tomography (PET) imaging of various diseases. While Ga-DOTA radiolabeling protocols are well-established, two classes of p...Gallium-68 labeled peptide radiotracers have attracted significant attention in positron emission tomography (PET) imaging of various diseases. While Ga-DOTA radiolabeling protocols are well-established, two classes of peptides, disulfide-directed multicyclic peptides (DDMPs) and amphiphilic antimicrobial peptides (AAMPs), presented challenges in achieving satisfactory radiolabeling efficiency using existing methods. This study therefore aimed to establish optimized Ga-DOTA radiolabeling protocols specifically tailored to these peptides, in order to achieve high radiochemical purity (RCP) and radiochemical yield (RCY) suitable for clinical translation. By systematically varying key labeling conditions and purification methods such as pH, GaCl concentration, reaction time, purification cartridge and eluent types, and sterile filtration, two new radiolabeling protocols were developed for DDMP- and AAMP-based radiotracers. Detailed optimization identified an optimal pH of 3.6 combined with the use of concentrated GaCl for efficient radiolabeling of DDMPs, achieving RCY > 60% and RCP > 95%. For AAMPs, extended reaction time, hydrophilic-lipophilic balanced (HLB) cartridges, and ethanol/HCl elution improved RCY to > 60% with RCP > 90%. These results demonstrate that precise pH control and concentrated GaCl are essential for high labeling efficiency of DDMPs, whereas optimized purification methods are key for AAMPs. Importantly, this work provides efficient radiolabeling strategies for these two clinically promising classes of peptides and offers insights for optimizing labeling protocols for other peptides. The established methods will support subsequent Good Manufacturing Practice (GMP)-compliant manufacturing and facilitate the clinical translation of high-value radiopharmaceuticals with favorable in vivo performance.