FerriIridium: A Lysosome‐Targeting Iron(III)‐Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells

Reported is the Fe^III‐activated lysosome‐targeting prodrug FerriIridium for gastric cancer theranostics. It contains a meta‐imino catechol group that can selectively bond to, and be oxidized by, free Fe^III inside the cell. Subsequent oxidative rearrangement releases Fe^II and hydrolyses the amine bond under acidic conditions, forming an aminobipyridyl Ir complex and 2‐hydroxybenzoquinone. Thus, Fe^II catalyzes the Fenton reaction, transforming hydrogen peroxide into hydroxyl radicals, the benzoquinone compounds interfere with the respiratory chain, and conversion of the prodrug into the Ir complex leads to an increase in phosphorescence and toxicity. These properties, combined with the high Fe^III content and acidity of cancer cells, make FerriIridium a selective and efficient theranostic agent (IC₅₀=9.22 μm for AGS cells vs. >200 μm for LO2 cells). FerriIridium is the first metal‐based compound that has been developed for chemotherapy using Fe^III to enhance both selectivity and potency.     

FerriIridium: A Lysosome-Targeting Iron(III)-Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells

Reported is the Fe^III-activated lysosome-targeting prodrug FerriIridium for gastric cancer theranostics. It contains a meta-imino catechol group that can selectively bond to, and be oxidized by, free Fe^III inside the cell. Subsequent oxidative rearrangement releases Fe^II and hydrolyses the amine bond under acidic conditions, forming an aminobipyridyl Ir complex and 2-hydroxybenzoquinone. Thus, Fe^II catalyzes the Fenton reaction, transforming hydrogen peroxide into hydroxyl radicals, the benzoquinone compounds interfere with the respiratory chain, and conversion of the prodrug into the Ir complex leads to an increase in phosphorescence and toxicity. These properties, combined with the high Fe^III content and acidity of cancer cells, make FerriIridium a selective and efficient theranostic agent (IC₅₀=9.22 μm for AGS cells vs. >200 μm for LO2 cells). FerriIridium is the first metal-based compound that has been developed for chemotherapy using Fe^III to enhance both selectivity and potency.     

One- and Two-Photon Phototherapeutic Effects of RuII Polypyridine Complexes in the Hypoxic Centre of Large Multicellular Tumor Spheroids and Tumor-Bearing Mice**

During the last decades, photodynamic therapy (PDT), an approved medical technique, has received increasing attention to treat certain types of cancer. Despite recent improvements, the treatment of large tumors remains a major clinical challenge due to the low ability of the photosensitizer (PS) to penetrate a 3D cellular architecture and the low oxygen concentrations present in the tumor center. To mimic the conditions found in clinical tumors, exceptionally large 3D multicellular tumor spheroids (MCTSs) with a diameter of 800 μm were used in this work to test a series of new Ru^II polypyridine complexes as one-photon and two-photon PSs. These metal complexes were found to fully penetrate the 3D cellular architecture and to generate singlet oxygen in the hypoxic center upon light irradiation. While having no observed dark toxicity, the lead compound of this study showed an impressive phototoxicity upon clinically relevant one-photon (595 nm) or two-photon (800 nm) excitation with a full eradication of the hypoxic center of the MCTSs. Importantly, this efficacy was also demonstrated on mice bearing an adenocarcinomic human alveolar basal epithelial tumor.     

Sono-ReCORMs for synergetic sonodynamic-gas therapy of hypoxic tumor

Carbon monoxide (CO) gas therapy, a novel anti-tumor technique based on the cytotoxicity from the CO released in situ, has become one of the hot topics in cancer treatment. Since the technique is oxygen-independent, it displays promising therapeutic effect for hypoxic tumor where traditional photodynamic therapy shows limited efficacy and insufficient penetration depth. To fully address these limitations of PDT, we propose a synergetic sonodynamic-CO gas releasing strategy for the therapy of hypoxic tumor. In this work, two rhenium(I) tricarbonyl complexes with different substituted ligands are investigated for US-triggered ROS generation and CO release. Our results indicated that the electron-donating NMe₂-substituted complex (Re-NMe₂) exhibits stronger luminescence intensity and generates more singlet oxygen (¹O₂) than the electron-withdrawing NO₂-substituted complex (Re-NO₂). In addition, Re-NMe₂ displays release of CO triggered by US, thus showing high sono-cytotoxicity to tumor cells in-vitro and in-vivo. The strong ROS-generating capability combined with rapid CO-releasing feature from Re-NMe₂ has made it a powerful tool for the efficient treatment of hypoxic tumor.     

Synthesis,in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents

New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4-d]pyrimidine scaffold. The docking analyzes have shown that 7-piperazine substituted oxazolo[4,5-d]pyrimidines 8a – 8c could be potential VEGFR2 inhibitors with high free energy of ligand–protein complex formation (ΔG: −10.1, −9.6, −9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5-d]pyrimidines 8a – 8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4-[5-(4-Chlorophenyl)-2-phenyl[1,3]oxazolo[4,5-d]pyrimidin-7-yl]piperazin-1-ium trifluoroacetate ( 8c ) exhibited a slightly higher antiproliferative effect (IC₅₀=0.21 μm ) than doxorubicin (IC₅₀=0.36 μm ) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC₅₀=1.7 μm ) and HCT-116 (IC₅₀=0.24 μm ) cells.     

Synthesis,Supramolecular Behavior,and In Vitro Photodynamic Activities of Novel Zinc(II) Phthalocyanines “Side‐strapped” with Crown Ether Bridges

Two new tetra‐ or di‐α‐substituted zinc(II) phthalocyanines 5 and 6 have been prepared through a “side‐strapped” method. In the molecules, the adjacent benzene rings of the phthalocyanine core are linked at α‐position through a triethylene glycol bridge to form a hybrid aza‐/oxa‐crown ether. The tetra‐α‐substituted phthalocyanine 5 shows an eclipsed self‐assembly property in CH₂Cl₂ and the effect on the di‐α‐substituted analogue 6 is significantly weakened. Furthermore, the crown ethers of these compounds can selectively complex with Fe³⁺ or Cu²⁺ ion in DMF, leading to formation of J‐aggregated nano‐assemblies, which can be disaggregated in the presence of some organic or inorganic ligands, such as triethylamine, tetramethylethylenediamine, CH₃COO^?, or OH^?. In addition, both compounds are efficient singlet oxygen generators with the singlet oxygen quantum yields (Φ_Δ) of 0.54‐0.74 in DMF relative to unsubstituted zinc(II) phthalocyanine (Φ_Δ=0.56). They exhibit photodynamic activities toward HepG2 human hepatocarcinoma cells, but the compound 6 , which has more than 40‐fold lower IC₅₀ value (0.08 μM ) compared to the analogue 5 (IC₅₀=3.31 μM ), shows remarkablely higher in vitro photocytotoxicity due to its significantly higher cellular uptake and singlet oxygen generation efficiency. The results suggest that these compounds can serve as promising multifunctional materials both in (opto)electronic field and photodynamic therapy.     

Nucleus‐Targeted Organoiridium–Albumin Conjugate for Photodynamic Cancer Therapy

An organoiridium–albumin bioconjugate ( Ir1‐HSA ) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1‐HSA was enhanced significantly compared to parent complex Ir1 . The long phosphorescence lifetime and high ¹O₂ quantum yield of Ir1‐HSA are highly favorable properties for photodynamic therapy. Ir1‐HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC₅₀; 0.8–5 μm , photo‐cytotoxicity index PI=40–60), while remaining non‐toxic to normal cells and normal cell spheroids, even after photo‐irradiation. This nucleus‐targeting organoiridium‐albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.     

Spin–Orbit Charge-Transfer Intersystem Crossing (ISC) in Compact Electron Donor–Acceptor Dyads: ISC Mechanism and Application as Novel and Potent Photodynamic Therapy Reagents

Spin–orbit charge-transfer intersystem crossing (SOCT-ISC) is useful for the preparation of heavy atom-free triplet photosensitisers (PSs). Herein, a series of perylene-Bodipy compact electron donor/acceptor dyads showing efficient SOCT-ISC is prepared. The photophysical properties of the dyads were studied with steady-state and time-resolved spectroscopies. Efficient triplet state formation (quantum yield Φ_T=60 %) was observed, with a triplet state lifetime (τ_T=436 μs) much longer than that accessed with the conventional heavy atom effect (τ_T=62 μs). The SOCT-ISC mechanism was unambiguously confirmed by direct excitation of the charge transfer (CT) absorption band by using nanosecond transient absorption spectroscopy and time-resolved electron paramagnetic resonance (TREPR) spectroscopy. The factors affecting the SOCT-ISC efficiency include the geometry, the potential energy surface of the torsion, the spin density for the atoms of the linker, solvent polarity, and the energy matching of the ¹CT/³LE states. Remarkably, these heavy atom-free triplet PSs were demonstrated as a new type of efficient photodynamic therapy (PDT) reagents (phototoxicity, EC₅₀=75 nm ), with a negligible dark toxicity (EC₅₀=78.1 μm ) compared with the conventional heavy atom PSs (dark toxicity, EC₅₀=6.0 μm, light toxicity, EC₅₀=4.0 nm ). This study provides in-depth understanding of the SOCT-ISC, unveils the design principles of triplet PSs based on SOCT-ISC, and underlines their application as a new generation of potent PDT reagents.     

The synthesis,structural characterization and biological evaluation of N‐(ferrocenylmethyl amino acid) fluorinated benzene‐carboxamide derivatives as potential anticancer agents

A series of N‐(ferrocenylmethyl amino acid) fluorinated benzene‐carboxamide derivatives 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i and 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i have been synthesized by coupling ferrocenylmethyl amine 3 with various substituted N‐(fluorobenzoyl) amino acid derivatives using the standard N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride, 1‐hydroxybenzotriazole protocol. The amino acids employed in this study were glycine and L‐alanine. All of the compounds were fully characterized using a combination of ¹H NMR, ¹³C NMR, ¹⁹F NMR, distortionless enhancement by polarization transfer (DEPT)‐135, ¹H–¹H correlation spectroscopy (COSY) and ¹H–¹³C COSY (heteronuclear multiple‐quantum correlation) spectroscopy. The compounds were biologically evaluated on the oestrogen‐positive MCF‐7 breast cancer cell line. Compounds 4g , 4i , 5h and 5i exhibited cytotoxic effects on the MCF‐7 breast cancer cell line. N‐(Ferrocenylmethyl‐L‐alanine)‐3,4,5‐trifluorobenzene‐carboxamide ( 5h ) was the most active compound, with an IC₅₀ value of 2.84 μm . Compounds 4i , 5h and 5i had lower IC₅₀ values than that found for the clinically employed anticancer drug cisplatin (IC₅₀ = 16.3 μm against MCF‐7). Guanine oxidation studies confirmed that 5h was capable of generating oxidative damage via a reactive oxygen species‐mediated mechanism. Copyright © 2013 John Wiley & Sons, Ltd.     

Antiprotozoal Activity and Cytotoxicity of Novel 1,7‐Dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one Derivatives from Amomum aculeatum

Cytotoxicity against the KB cancer cell line as a lead bioactivity‐guided fractionation of the petroleum ether extract of rhizomes of Amomum aculeatum Roxb. led to the isolation of three novel dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one derivatives. The structures of aculeatin A ( 1 ), aculeatin B ( 2 ), and aculeatin C ( 3 ) were established as rel‐(2R,4R,6S)‐ and rel‐(2R,4R,6R)‐4‐hydroxy‐2‐tridecyl‐1,7‐dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one ( 1 and 2 , resp.) and rel‐(2R,4R,6R)‐2‐[4‐(3‐dodecyl‐2‐heptyl‐3‐hydroxy‐6‐oxocylohexa‐1,4‐dienyl)‐2‐oxobutyl]‐4‐hydroxy‐1,7‐dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one ( 3 ) by extensive spectroscopic analyses, particularly ¹³C‐NMR, inverse‐gated ¹³C, HMQC, HMBC, NOESY, and INADEQUATE NMR experiments as well as mass spectrometry. The aculeatins represent a novel type of natural products. All compounds showed high cytotoxicity against the KB cell line: 1 , IC₅₀=1.7 μM ; 2 , IC₅₀=2.0 μM ; 3 , IC₅₀=1.6 μM . Additional testing against two Plasmodium falciparum strains as well as against trypomastigote forms of Trypanosoma brucei rhodesiense and Trypanosoma cruzi showed strong activities, particularly against P. falciparum strain K1 ( 1 , IC₅₀=0.18 μM ; 2 , IC₅₀=0.43 μM ; 3 , IC₅₀=0.37 μM ).     

Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T₁ relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)^? as expected for mono‐amide derivatives. The water proton T₁ relaxivity (r₁), bound water residence lifetime (τ_M) and rotational correlation time (τ_R) of both complexes was determined by relaxivity measurements, variable temperature ¹⁷O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r₁=6.38 mM ^?1 s^?1 at 20 MHz , τ_M=0.71 μs, τ_R=141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N₂ as evidenced by an approximately twofold decrease in T₁ measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.     

Initiator-Loaded Gold Nanocages as a Light-Induced Free-Radical Generator for Cancer Therapy

Tumor hypoxia greatly suppresses the therapeutic efficacy of photodynamic therapy (PDT), mainly because the generation of toxic reactive oxygen species (ROS) in PDT is highly oxygen-dependent. In contrast to ROS, the generation of oxygen-irrelevant free radicals is oxygen-independent. A new therapeutic strategy based on the light-induced generation of free radicals for cancer therapy is reported. Initiator-loaded gold nanocages (AuNCs) as the free-radical generator were synthesized. Under near-infrared light (NIR) irradiation, the plasmonic heating effect of AuNCs can induce the decomposition of the initiator to generate alkyl radicals (R^.), which can elevate oxidative-stress (OS) and cause DNA damages in cancer cells, and finally lead to apoptotic cell death under different oxygen tensions. As a proof of concept, this research opens up a new field to use various free radicals for cancer therapy.     

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives embedded with benzimidazole moiety as potent antioxidants

Fourteen novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives bearing benzimidazole moiety ( 7a-n ) have been synthesized using the one-pot nitro reductive cyclization method. All the synthesized compounds were confirmed by ¹H nuclear magnetic resonance (¹H NMR), ¹³C NMR, fourier-transform infrared (FT-IR), mass spectrum, and elemental analyses. All the title compounds were subjected to in vitro antioxidant activity. The free radical scavenging activity of the compounds was examined using DPPH, nitric oxide, and superoxide radical scavenging methods. The results demonstrated that compound 3-(2-(3,4-dimethoxyphenyl)-1-propyl-1H-benzo[d]imidazol-5-yl)-6-4-tolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine ( 7c ) was potent in scavenging both DPPH and nitric oxide radical with IC₅₀ values of 13.57 and 18.55 μg/ml when compared to the standard with IC₅₀ values of 23.75 and 23.14 μg/ml, respectively, which was due to the presence of electron-donating groups. The activity was found to decline when electron-donating groups were replaced by electron-withdrawing groups. Moderate scavenging activity was observed for the superoxide radical. Structure activity relationship and physiochemical properties were studied for all the derivatives.     

A New Nonconjugated Naphthalene Derivative of Meso-tetra-(3-hydroxy)-phenyl-porphyrin as a Potential Sensitizer for Photodynamic Therapy

A new 5,10,15,20-tetra-(phenoxy-3-carbonyl-1-amino-naphthyl)-porphyrin was prepared by an isocyanate condensation reaction and its photophysical properties fully evaluated, both in terms of photostability and singlet oxygen production. It shows considerably enhanced photostability when compared with the parent 5,10,15,20-tetra-(3-hydroxy-phenyl)-porphyrin, with the photodegradation quantum yields for T(NAF)PP and T(OH)PP being 4.65 × 10⁻⁴ and 5.19 × 10⁻³, respectively. Its photodynamic effect in human carcinoma HT-29 cells was evaluated. The new porphyrin showed good properties as a sensitizer in photodynamic therapy with an in vitro cytotoxicity IC₅₀ value of 6.80 μg mL⁻¹ for a 24 h incubation. In addition to the potential of this compound, the synthetic route used provides possibilities of extension to a wide range of new sensitizers.     

Immunotoxicity of Organic Arsenic Compounds in Marine Animals

In the present study, we demonstrated for the first time the immunotoxic effects of organic arsenic compounds in marine animals, namely arsenocholine [AsCho; trimethyl(2-hydroxyethyl)arsonium cation], arsenobetaine [AsBe; the trimethyl(carboxymethyl)arsonium zwitterion] and the tetramethylarsonium ion (TetMA), to murine principal immune effector cells (macrophages and lymphocytes), comparing them with the effects of inorganic arsenicals in vitro . Inorganic arsenicals (arsenite and arsenate) showed strong cytotoxicity to both macrophages and lymphocytes. The concentration of arsenite that reduced the number of surviving cells to 50% of that in untreated controls (IC₅₀) was 3–5 μmol dm⁻³, and the cytotoxicity of arsenate (IC₅₀=100 μ-1 m mol dm⁻³) was lower than that of arsenite. Compared with these findings, trimethylarsenic compounds in marine animals, AsCho and AsBe, were less toxic even at a concentration over 10 mmol dm⁻³ to both macrophages and lymphocytes; however, TetMA had weak, but significant, cytotoxicity to these cells (IC₅₀ was about 6 mmol dm⁻³).     

(Metallo)porphyrins as Potent Phototoxic Anti‐Cancer Agents after Irradiation with Red Light

Novel photoactive (metallo)porphyrins were synthesised and characterised. When irradiated with light at a wavelength greater than 600 nm, these porphyrins act as photosensitisers and show high cytotoxicity towards two different human cancer cell lines with IC₅₀ values down to 0.4 μM . A paramagnetic copper(II) porphyrin is the first photosensitiser to display excellent phototoxicity, explained by the electron paramagnetic resonance (EPR) spin trapping of hydroxy radicals and experimentally confirmed by the discovery of elevated levels of reactive oxygen species (ROS) inside A2780 cells after irradiation with red light. This finding indicates that paramagnetic compounds should be considered for photodynamic therapy (PDT). Furthermore, an additive effect of cisplatin and a zinc porphyrin, both at subtherapeutic concentrations of 0.22 μm, was observed.     

Photodynamic Therapy of Oligoethylene Glycol‐Dendronized Reduction‐Sensitive Porphyrins

Graphene oxide (GO ) and its functionalized derivatives have attracted increasing attention in medical treatment. Herein, a reduction sensitive PEI‐GO ‐SS ‐TPP was synthesized for photodynamic therapy. More than 80% porphyrin release was observed in the presence of 10 mmol•L⁻¹ DTT in one day. The confocal laser scanning microscopy confirmed that the cell uptake efficiency of PEI‐GO‐SS‐TPP was remarkably enhanced as compared to free porphyrin which was significantly dependent on incubation time. For photodynamic therapy, GSH‐OEt could effectively increase the photodynamic therapy efficiency of PEI‐GO ‐SS ‐TPP . Compared with free porphyrin, the toxicity from PEI‐GO ‐SS ‐TPP is much higher with a low IC₅₀ (2.1 µg/mL ) value. All results indicate that the PEI‐GO ‐SS ‐TPP PSs are promising for photodynamic therapy.     

Cyclometalated Ruthenium(II) Anthraquinone Complexes Exhibit Strong Anticancer Activity in Hypoxic Tumor Cells

Hypoxia is the critical feature of the tumor microenvironment that is known to lead to resistance to many chemotherapeutic drugs. Six novel ruthenium(II) anthraquinone complexes were designed and synthesized; they exhibit similar or superior cytotoxicity compared to cisplatin in hypoxic HeLa, A549, and multidrug‐resistant (A549R) tumor cell lines. Their anticancer activities are related to their lipophilicity and cellular uptake; therefore, these physicochemical properties of the complexes can be changed by modifying the ligands to obtain better anticancer candidates. Complex 1 , the most potent member of the series, is highly active against hypoxic HeLa cancer cells (IC₅₀=0.53 μM ). This complex likely has 46‐fold better activity than cisplatin (IC₅₀=24.62 μM ) in HeLa cells. This complex tends to accumulate in the mitochondria and the nucleus of hypoxic HeLa cells. Further mechanistic studies show that complex 1 induced cell apoptosis during hypoxia through multiple pathways, including those of DNA damage, mitochondrial dysfunction, and the inhibition of DNA replication and HIF‐1α expression, making it an outstanding candidate for further in vivo studies.     

Imine‐N‐Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p‐Cymene Anticancer Complexes: A Structure–Activity Relationship Study

A family of novel imine‐N‐heterocyclic carbene ruthenium(II) complexes of the general formula [(η⁶‐p‐cymene)Ru(C^N)Cl]PF₆⁻ (where C^N is an imine‐N‐heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine‐N‐heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD⁺ is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC₅₀=14.36 μm ), with an approximately 1.5‐fold better activity than the clinical platinum drug cisplatin (IC₅₀=21.30 μm ) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy.     

Inhibitors of the Bifunctional 2‐C‐Methyl‐d‐erythritol 4‐Phosphate Cytidylyl Transferase/2‐C‐Methyl‐d‐erythritol‐2,4‐cyclopyrophosphate Synthase (IspDF) of Helicobacter pylori

A library of over 103 thousand compounds was screened for inhibitors of the IspD domain (2‐C‐methyl‐d ‐erythritol 4‐phosphate cytidylyl transferase domain) of the bifunctional IspDF protein from Helicobacter pylori using a photometric assay. Around 300 compounds showed IC₅₀ values below 100 μm , and three compounds had IC₅₀ values below 1 μm . A few IspD inhibitors could also inhibit the IspF domain (2‐C‐Methyl‐d ‐erythritol‐2,4‐cyclopyrophosphate synthase) of the IspDF protein. The most potent IspD inhibitors were tested as growth inhibitors of H. pylori. Several compounds showed inhibition of bacterial growth with IC₅₀ in the single‐digit μm range. The most potent growth inhibitor had an IC₅₀ value of 3.4 μm . The most potent growth inhibitor without measurable effect on eukaryotic cell viability had an IC₅₀ value of 7.2 μm .