ACS Medicinal Chemistry Letters最新文献

We developed a 3 mm NMR flow tube that can be insertedinto a 5mm NMR probe converting a high field NMR spectrometer into a reactionmonitoring system with a minimum reaction volume of 2 mL. The systemuses a standard LC pump to flow the reaction mixture from a reactionvial in an integrated heating block to the center of the magnet fordetection before returning the mixture back to the vial. The NMR flowtube has a temperature range of −20 to 120 °C and theNMR instrument can be switched from NMR tubes to the flow tube modein a few minutes. We report the use of this flow NMR small volumesystem to monitor the progress of two chemical reactions that resistedstudy by more common analytical techniques.

Cluster of Differentiation 38 (CD38) plays a key rolein NAD⁺ metabolism and calcium signaling, and recent reportshighlighttherapeutic opportunities for CD38 modulation in central nervous system(CNS) disorders. In this report, we describe the rational design,synthesis, and exploration of structure–activity relationships(SAR) for a novel and brain-penetrant series of tricyclic compoundsthat form an adduct with ADPR to inhibit CD38 in an uncompetitivemanner. Rigidification of the bioactive conformation via covalenttethering of a 6-membered heteroaromatic core to an imidazole warheadserved as the key design element that afforded improved biochemicalpotency against both mouse and human CD38. Incremental property-basedoptimization of core and linker motifs generated analogues with enhancedunbound brain-to-plasma ratios in mice. These efforts led to the discoveryof brain-penetrant CD38 inhibitor 16, which was evaluatedin vivo and demonstrated dose-dependent increases of NAD⁺ measured in mouse brain and lung tissue samples following oral dosesranging from 3 to 100 mg/kg.

Providedherein are novel sulfur-containing heterocycloalkyl substitutedbicyclic compounds as viral DNA polymerase inhibitors, pharmaceuticalcompositions, use of such compounds in treating viral infections,in particular, herpesvirus infections, and processes for preparingsuch compounds.

Inhibition of histone deacetylase (HDAC) metalloenzymeswith hydroxamicacid-based inhibitors is compromised by generally poor metalloenzymeselectivity and the potential for genotoxicity arising from isocyanatemetabolites. Here, we applied our previously described platform foriron(II)-activatable drug delivery to the pan-HDAC inhibitor panobinostatand its study in multiple myeloma cell line models. We demonstratesuccessful caging of HDAC activity in conjugate form, as well as mitigationof genotoxicity in a bioisosteric control. Finally, we identify thecarboxy esterase CES1 as being responsible for unexpected proteolyticinstability of the panobinostat conjugate in vitro and in vivo, identifyinga focus for future work toward the ultimate goal of mitigating hydroxamatetoxicity and mutagenicity through tumor-conditional activation.

Sesquiterpene lactones, featuring an α-methylene-γ-lactonemoiety, serve as lead compounds for anticancer drug development. Theirnitrogen-containing analogues, namely, 4-methylideneisoxazolidin-5-ones,have attracted special attention for their promising anticancer properties.Installing a fluorine atom at the exocyclic double bond of these analoguesis highly desirable for improving metabolic stability, bioavailability,and lipophilicity, yet this has not been achieved to date due to thelack of an efficient synthetic method, representing a major obstaclein drug development. Herein, we report a Ni(II)-catalyzed [3 + 2]cycloaddition/rearrangement cascade reaction of gem-difluorocyclopropenyl imides and N-Bn nitrones,providing direct access to (Z)-4-(monofluoroalkylidene)isoxazolidin-5-onesin good to high yields. The compounds 3aw and 3as show promising in vitro antiproliferative activityagainst mouse mammary carcinoma 4T1 cells (IC₅₀ = 6.85± 0.43 μM) and human lung carcinoma A549 cells (IC₅₀ = 10.34 ± 0.07 μM), respectively. Mechanisticstudies reveal that the activity occurs via a mitochondria-mediatedintrinsic apoptotic pathway.

Achieving adequate oral absorption for proteolysis-targetingchimeras(PROTACs) remains challenging due to their size, polarity, and conformationalcomplexity. While existing approaches often rely on physicochemicalproperty space or chameleonicity-driven models, a generalizable frameworkfor guiding compound design prior to synthesis is lacking. Here, weintroduce comPASS, a fully computational scoring function derivedfrom molecular dynamics-based descriptors that is designed to capturethe balance between molecular extension and exposed polarity throughnormalized radius of gyration and three-dimensional polar surfacearea of PROTACs. Across mouse and rat data sets, comPASS shows consistentpredictive performance and may facilitate prioritization of compoundsat early design stages. We further show that within the data setsstudied, extended molecular geometries are associated with improvedabsorption, when increased elongation is not driven solely by increasesin molecular size. To assess the potential benefit of incorporatingexperimental information, we also developed an enhanced variant, ePASS,which incorporates experimental polar surface area (EPSA) and lipophilicityterms consistent with prior approaches and shows promising predictiveperformance relative to similar literature methods. Together, theseresults establish practical guidance for presynthetic prioritizationof PROTACs and provide a potential framework for guiding the designof orally absorbed PROTACs.

Although the gastrin-releasingpeptide receptor (GRPR)is an establishedtheranostic target across multiple cancers, many GRPR-targeting peptidesundergo rapid renal clearance, limiting tumor uptake and therapeuticexposure. Albumin-binding moieties (ABMs) reversibly interact withserum albumin, prolonging systemic exposure and increasing the opportunityfor tumor uptake. To examine how ABM structure and placement affectthis behavior, we prepared four DOTA-functionalized GRPR-targetingconjugates, varying both ABM lipophilicity and position relative tothe DOTA chelator. The conjugates were radiolabeled with lutetium-177in radiochemical yields and purities of >98%. All radioconjugatesretained GRPR-mediated uptake in PC-3 cells, exhibited subnanomolarreceptor affinity and enhanced blood retention. [¹⁷⁷Lu]Lu-CA6356,bearing a 4-(p-iodophenyl)butyric acid-derived ABM,achieved the highest tumor uptake in PC-3 xenografts at 4 h pi (12± 2% IA/g), which increased by approximately 30% 24 h pi. Thesefindings show that ABM identity and placement can modulate systemicexposure and tumor uptake in GRPR-targeting radioligands.

The increasing emergenceof antimicrobial resistance (AMR) is reducingthe effectiveness of existing antibiotics against bacterial infections,including tuberculosis (TB), a deadly disease caused by Mycobacteriumtuberculosis (M.tb). Approximately 90% of infected individuals developlatent tuberculosis infection, for which current treatment optionsare limited. Latent tuberculosis infection is characterised by theformation of hypoxic granulomas, which restrict oxygen and drug penetration,highlighting the need for therapies effective under hypoxic conditions.In this study, a hypoxia-activated prodrug (HAP) strategy wasemployed to improve selective drug delivery of promising anti-tuberculosisdrugs bedaquiline, TBAJ-587 and TBAJ-876 (sorfequiline) to hypoxicTB granulomas. Thirty-six nitroimidazole-based hypoxia-activatedprodrugs (HAPs) were successfully synthesized and evaluated for antitubercularactivity. The HAPs exhibited potent in vitro activityunder both oxic and hypoxic conditions, with consistently lower MICvalues observed in the hypoxic assays. Assessment of hypoxic selectivitydemonstrated enhanced trigger cleavage under hypoxic conditions, providingstrong evidence for the hypoxia-selective activation of these compounds. Collectively, these findings highlight the therapeutic potentialof hypoxia-mediated strategies for the treatment of latent tuberculosis,particularly within hypoxic niches that drive disease persistenceand prolonged treatment regimens.

In recent years, the role of interleukin-11 (IL-11) inrenal fibrosishas garnered considerable interest and is regarded as a promisingtherapeutic target for this condition. Herein, we explored the effectsof replacing the oxidation-sensitive thioether moiety with a lactambridge. By screening linker length and performing further optimization,we developed an analog, 4L6–16. This compoundexhibited a high binding affinity for IL-11, with a K_D valueof 134 nM, along with enhanced antagonistic activity. Moreover, 4L6–16 demonstrated significant renoprotective effectsin both in vitro and in vivo modelsof renal fibrosis, supporting its potential for further optimizationto develop novel IL-11-targeted therapeutic agents.