Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (P2, P9, P13) showed favorable stability, permeability, and pharmacokinetics. Notably, P2 and P13 significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from P2 and P13, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate's cellular permeability and oral bioavailability, paving the way for clinical translation.
- MeSH
- aplikace orální MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- objevování léků MeSH
- prekurzory léčiv * chemie farmakologie chemická syntéza farmakokinetika MeSH
- sukcináty * chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Platinum(IV) compounds possess distinct properties that set them apart from platinum(II) compounds. Often designed as prodrugs, they are reduced within cancer cells to their active platinum(II) form, enabling their cytotoxic effects. Their versatility also lies in their ability to be functionalized and conjugated with bioactive molecules to enhance cancer cell targeting. This report introduces new prodrugs that combine antitumor cisplatin with axially coordinated eugenol, leveraging their synergistic action to target cancer stem cells. A third bioactive ligand, 4-phenylbutyrate or octanoate, was added to further enhance biological activity, creating 'triple action' prodrugs. These new platinum(IV) prodrugs offer a novel approach to cancer therapy by improving targeting, increasing efficacy, overcoming drug resistance, and reducing tumor invasiveness while sparing healthy tissue.
- MeSH
- cisplatina * farmakologie MeSH
- eugenol * farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky * účinky léků patologie MeSH
- nádory tračníku * farmakoterapie patologie MeSH
- prekurzory léčiv * farmakologie chemie MeSH
- protinádorové látky * farmakologie chemie MeSH
- synergismus léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design.
- MeSH
- amfotericin B * farmakologie MeSH
- antifungální látky * farmakologie chemie chemická syntéza MeSH
- Aspergillus účinky léků MeSH
- Candida účinky léků MeSH
- larva účinky léků MeSH
- mikrobiální testy citlivosti * MeSH
- molekulární struktura MeSH
- můry účinky léků MeSH
- prekurzory léčiv * farmakologie chemie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chemické transformace kompatibilní s biologickými systémy slouží jako neocenitelné nástroje pro zkoumání biomolekul, sloučenin léčiv a biologických procesů v jejich přirozeném prostředí. Složité prostředí živých organismů vyžaduje, aby tyto reakce byly vysoce selektivní a účinné, což představuje pro oblast organické chemie obrovskou výzvu. V poslední době se objevila řada chemických reakcí, které tyto podmínky splňují, a poskytují proto výzkumným pracovníkům rozmanitou sadu nástrojů. Tento rukopis představuje komplexní přehled současných bioortogonálních reakcí s důrazem na jejich aplikace v zobrazování, diagnostice a medicíně.
Chemical transformations compatible with biological systems serve as invaluable tools for probing biomolecules, drug compounds, and biological processes in their native environments. The complex environment of living organisms requires these reactions to be highly selective and efficient, posing a formidable challenge to the field of organic chemistry. A number of chemical reactions have recently emerged to meet this challenge, providing a diverse toolkit for researchers. This manuscript presents a comprehensive survey of current bioorthogonal reactions, emphasizing their applications in bioimaging, diagnostics, and medicine.
Obor medicinální chemie se často potýká s problémem suboptimálních vlastností aktivních látek. Za účelem zlepšení těchto vlastností byla vyvinuta řada důmyslných přístupů tvorby proléčiv. Proléčivo je inaktivovaná forma léčiva, která dočasně modifikuje jeho vlastnosti. V těle je pak proléčivo (nejčastěji enzymaticky) transformováno zpět na aktivní léčivo. Proléčiva mohou upravit řadu vlastností jako např. absorpci, rozpustnost, či cílené doručení do tkáně. Poměr proléčiv mezi schválenými léky v posledních letech stoupá, což podtrhuje význam této strategie pro medicinální chemii i klinické využití.
The field of medicinal chemistry is often struggling with suboptimal properties of active compounds. To address this issue, many sophisticated prodrug approaches have been developed. Prodrug is an inactive form of a drug which temporarily alters its properties. In the body, the prodrug is (most often enzymatically) transformed back to the parent active drug. Prodrugs can modify variety of properties such as absorption, solubility, or tissue targeted delivery. The number of prodrugs among approved drugs has been rising in the past years which underlines the importance of prodrugs for medicinal chemistry and clinical use.
Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.
- MeSH
- cisplatina * farmakologie MeSH
- dasatinib * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny farmakologie chemie chemická syntéza MeSH
- prekurzory léčiv * farmakologie chemie chemická syntéza MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- screeningové testy protinádorových léčiv MeSH
- synergismus léků * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.
- MeSH
- diazooxonorleucin * farmakologie terapeutické užití MeSH
- glutamin metabolismus MeSH
- lidé MeSH
- nádory * farmakoterapie metabolismus MeSH
- prekurzory léčiv * farmakologie terapeutické užití MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The development of new antiviral agents such as nucleoside analogues or acyclic nucleotide analogues (ANPs) and prodrugs thereof is an ongoing task. We report on the synthesis of three types of lipophilic triphosphate analogues of (R)-PMPA and dialkylated diphosphate analogues of (R)-PMPA. A highly selective release of the different nucleotide analogues ((R)-PMPA-DP, (R)-PMPA-MP, and (R)-PMPA) from these compounds was achieved. All dialkylated (R)-PMPA-prodrugs proved to be very stable in PBS as well as in CEM/0 cell extracts and human plasma. In primer extension assays, both the monoalkylated and the dialkylated (R)-PMPA-DP derivatives acted as (R)-PMPA-DP as a substrate for HIV-RT. In contrast, no incorporation events were observed using human polymerase γ. The dialkylated (R)-PMPA-compounds exhibited significant anti-HIV efficacy in HIV-1/2 infected cells (CEM/0 and CEM/TK-). Remarkably, the dialkylated (R)-PMPA-MP derivative 9a showed a 326-fold improved activity as compared to (R)-PMPA in HIV-2 infected CEM/TK- cells as well as a very high SI of 14,000. We are convinced that this study may significantly contribute to advancing antiviral agents developed based on nucleotide analogues in the future.
- MeSH
- adenin MeSH
- HIV-2 MeSH
- látky proti HIV * chemie MeSH
- lidé MeSH
- nukleotidy MeSH
- organofosfonáty * chemie MeSH
- prekurzory léčiv * chemie MeSH
- tenofovir farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.
- MeSH
- diazooxonorleucin farmakokinetika MeSH
- estery terapeutické užití MeSH
- glutamin MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- prekurzory léčiv * chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
