ChemMedChem最新文献

Antibody-based pharmaceuticals are the leading biologic drug platform (> $75B/year).^[1] Despite a wealth of information collected on them, there is still a lack of knowledge on their inter-domain structural distributions, which impedes innovation and development. To address this measurement gap, we have developed a new methodology to derive biomolecular structure ensembles from distance distribution measurements via a library of tagged proteins bound to an unlabeled and otherwise unmodified target biologic. We have employed the NIST monoclonal antibody (NISTmAb) reference material as our development platform for use with spin-labeled affinity protein (SLAP) reagents. Using double electron-electron resonance (DEER) spectroscopy, we have determined inter-spin distance distributions in SLAP complexes of both the isolated Fc domain and the intact NISTmAb. Our SLAP reagents offer a general and extendable technology, compatible with any non-isotopically labeled immunoglobulin G class mAb. Integrating molecular simulations with the DEER and solution X-ray scattering measurements, we enable simultaneous determination of structural distributions and dynamics of mAb-based biologics.

Protonation states serve as an essential molecular recognition motif for biological processes. Their correct consideration is key to successful drug design campaigns, since chemoinformatic tools usually deal with default protonation states of ligands and proteins and miss atypical protonation states. The protonation pattern for the Endothiapepsin/PepstatinA (EP/pepA) complex is investigated using different dry lab and wet lab techniques. ITC experiments revealed an uptake of more than one mole of protons upon pepA binding to EP. Since these experiments were performed at physiological conditions (and not at pH=4.6 at which a large variety of crystal structures is available), a novel crystal structure at pH=7.6 was determined. This crystal structure showed that only modest structural changes occur upon increasing the pH value. This lead to computational studies Poisson-Boltzmann calculations and constant pH MD simulation to reveal the exact location of the protonation event. Both computational studies could reveal a significant pKa shift resulting in non-default protonation state and that the catalytic dyad is responsible for the uptake of protons. This study shows that assessing protonation states for two separate systems (protein and ligand) might result in the incorrect assignment of protonation states and hence incorrect calculation of binding energy.

Aminoglycoside-phosphotransferases (APHs) are a class of bacterial enzymes that mediate acquired resistance to aminoglycoside antibiotics. Here we report the identification of small molecules counteracting aminoglycoside resistance in Enterococcus casseliflavus. Molecular dynamics simulations were performed to identify an allosteric pocket in three APH enzymes belonging to 3' and 2'' subfamilies in which we then screened, in silico, 12,000 small molecules. From a subset of only 14 high-scored molecules tested in vitro, we identified a compound, named here EK3, able to non-competitively inhibit the APH(2'')-IVa, an enzyme mediating clinical gentamicin resistance. Structure-activity relationship (SAR) exploration of this hit compound allowed us to identify a molecule with improved enzymatic inhibition. By measuring bacterial sensitivity, we found that the three best compounds in this series restored bactericidal activity of various aminoglycosides, including gentamicin, without exhibiting toxicity to HeLa cells. This work not only provides a basis to fight aminoglycoside resistance but also highlights a proof-of-concept for the search of allosteric modulators by using in silico methods.

Light induced release of cisplatin from Pt(IV) prodrugs is a promising tool for precise spatiotemporal control over the antiproliferative activity of Pt-based chemotherapeutic drugs. A combination of light-controlled chemotherapy (PACT) and photodynamic therapy (PDT) in one molecule has the potential to overcome crucial drawbacks of both Pt-based chemotherapy and PDT via a synergetic effect. Herein we report green-light-activated Pt(IV) prodrug GreenPt with BODIPY-based photosentitizer in the axial position with an incredible high light response and singlet oxygen generation ability. GreenPt demonstrated the ability to release cisplatin under low-dose green light irradiation up to 1 J/cm². The investigation of the photoreduction mechanism of GreenPt prodrug using DFT modeling and ΔG₀ PET estimation revealed that the anion-radical formation and substituent photoinduced electron transfer from the triplet excited state of the BODIPY axial ligand to the Pt(IV) center is the key step in the light-induced release of cisplatin. Green-light-activated BODIPY-based photosentitizers 5 and 8 demonstrated outstanding photosensitizing properties with an extraordinary phototoxicity index (PI)>1300. GreenPt prodrug demonstrated gradual intracellular accumulation and light-induced phototoxicity with PI>100, thus demonstrating dual action through light-controlled release of both cisplatin and a potent BODIPY-based photosensitizer.

The development of small molecule-based drugs emerged as a cornerstone of modern drug discovery. Structural activity relationship (SAR) studies in medicinal chemistry are crucial for lead optimization, where a subtle change in the substituent can significantly alter its binding affinity with the biological target. Herein, a highly efficient single-atom substitution (SAS) approach has been developed, where sulfur for oxygen strategy is utilized as a powerful molecular editing technique to identify N-vinyl Indole-thiobarbituric acid (6 a) as a novel small molecule-based scaffold with tunable photophysical and antiproliferative activities. A series of NIR-emitting indole-barbituric/thiobarbituric acid conjugates exhibiting aggregation-induced emission (AIE) were prepared, where the replacement of oxygen for sulfur strategy emerged as a magic bullet. On the evaluation of photophysical properties and chemopreventive efficacies, a significant improvement in the absorption and emission profile, cellular uptake, and antiproliferative activity was noted for sulfur counterparts. From the pool of the molecules, the lead molecule 6 a unveils a 55 nm emission shift, 142-fold increased anticancer profile, and ~4-fold elevated cellular uptake. Furthermore, the colocalization experiment unravels the nuclear localization of 6 a, where it causes severe DNA damage, arrests the cell cycle in the G2/M phase, and leads to the activation of p53-mediated apoptosis. Our experimental findings represent 6 a as a potential lead molecule possessing excellent anticancer potency in the HCT 116 cell line and HCT 116-derived 3D spheroid model.

The C−X-C chemokine receptor 4 (CXCR4) is highly upregulated in most cancers, making it an ideal target for delivering radiation therapy to tumors. We previously demonstrated the feasibility of targeting CXCR4 in vivo using a radiolabeled derivative of EPI-X4, an endogenous CXCR4 antagonist, named DOTA−K-JM#173. However, this derivative showed undesirable accumulation in the kidneys, which would limit its clinical use. In this study, we identified that removing a positive charge from the peptide sequence significantly reduced renal uptake. We evaluated a series of optimized derivatives lacking this positive charge, in vitro and in vivo in a xenografted athymic nude mice model, after radiolabeling with ¹⁷⁷Lu. The most promising derivatives were further assessed in vivo after ⁶⁸Ga labeling. Among them, we identified DOTA-JM#173 and D-L¹-DOTA-JM#173, where the D-Ile¹ was replaced by D-Leu¹, two optimized derivatives with a lysine residue removed. These two molecules represent the most advanced DOTA-conjugated ligands derived from EPI-X4 for CXCR4-directed theranostic applications, offering enhanced potential for targeted cancer treatment.

In this research, a series of novel hydrazone derivatives based on pyrazolopyridothiazinylacetohydrazide were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human colon cancer cells (HTC116, HT-29, and LoVo). After MTT and SRB assays four of the most active derivatives: hydrazide GH and hydrazones GH7, GH8, and GH11, were chosen for further investigation. Hydrazone GH11 had the highest cytotoxic activity (IC₅₀ values of c.a. 0.5 μM). Additionally, the impact of novel derivatives on the oxidative stress level, apoptosis induction, and modulation of inflammation in colon cancer cells was examined. In all studies, the activity of the derivatives increased in order GH < GH7 < GH8 < GH11. At the same time, most of the research was conducted on compounds combined with apple pectin (PC). The most interesting observation was that all the studied derivatives applied together with PC showed significantly higher activity than observed in the case of using PC, hydrazide, or hydrazones separately. Finally, computational chemistry methods (molecular modeling and Density Functional Theory – DFT) were used to complement the experimental studies.

New concepts to treat eye diseases have emerged that elegantly combine unnatural light exposure with chemical biology approaches to achieve superior cellular specificity and, as a result, improvement of visual function. Historically, light exposure without further molecular eye treatment has offered limited success including photocoagulation to halt pathological blood vessel growth or low light exposure to stimulate retinal cell viability. To add cellular specificity to such treatments, researchers have introduced various biological or chemical light-sensing molecules and combined those with light exposure. (Pre-)clinical trials describe the use of optogenetics and channelrhodpsins, i. e. light-sensitive ion channels, in patient vision restoration. In the chemical arena, pharmacological agents, rendered light-sensitive by reversible modification with photosensitive protecting compounds (“caging”), have been applied to eyes of living mice to photo-release specific cellular activities. Among these were successful proof-of-principle experiments that were conducted to establish photo-sensitive gene therapies in the eye. For light-mediated treatment in combination with chemical biology, we wish to describe here the current frontiers of research in vision restoration with an eye on differences between biological and chemical light-sensing molecules, patient requirements, and future outlooks.

Gemcitabine (GEM), a chemotherapeutic agent, is widely used to treat various neoplastic conditions, such as pancreatic, lung, breast, and ovarian cancer. However, its therapeutic effectiveness is often hindered by its short half-life and susceptibility to enzymatic degradation. To address these limitations, in this research, five new conjugates of GEM were synthesized by conjugating its N-4 amino group with five different acids [4-decenoic acid (4Dec), lipoic acid (Lipo), lauric acid (Laur), 5-benzyl N-(tert-butoxycarbonyl)- L-glutamate (Glu), and decanoic acid (Dec)]. The anticancer potential of these conjugates was evaluated using CCK-8 assay. Among the synthesized conjugates, 4Dec-GEM demonstrated comparable cytotoxic activity to native GEM. The mechanistic insight of 4Dec-GEM was investigated using annexin-V FITC/propidium iodide staining, reactive oxygen species generation, and mitochondrial membrane potential loss assays. To further enhance its therapeutic efficacy, 4Dec-GEM was encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles using single-emulsion method using high-pressure homogenization. The developed nanoparticles were characterized by various techniques (TEM, FT-IR, DSC, p-XRD) and demonstrated successful entrapment of 4Dec-GEM inside PLGA nanoparticles. Finally, the cytotoxicity of developed nanoparticles demonstrated improved anticancer activity as compared to native GEM in cancerous cell lines. Our study demonstrated that the combination of prodrug and nanoparticle approach can be a promising approach to augment the therapeutic efficacy of GEM.

Correction to “α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML”

Maria Luisa Introvigne, Lorenza Destro, Luca Mologni, Valentina Crippa, Paolo Zardi, Francesco Fini, Fabio Prati, Emilia Caselli, Alfonso Zambon, “α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML”, ChemMedChem 2024, 19, e202400622 DOI: https://doi.org/10.1002/cmdc.202400622

The full first names of the authors of this paper were omitted upon initial publication, and Fabio Prati was incorrectly entered as “L. F. Prati”. All author names are correct and complete as shown.