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Mononuclear gold(I) acyclic diaminocarbenes (ADCs) were prepared by the reaction of 1,2-cyclohexanediamine with the corresponding isocyanide complexes [AuCl(CNR)] (R = Cy, ^t Bu). The three-component coupling of aldehydes, amines, and alkynes was investigated by using these gold(I) ADC complexes. The new gold(I) metal complexes are highly efficient catalysts for the synthesis of propargylamines and indolizines in the absence of solvent and in mild conditions. This method affords the corresponding final products with excellent yields in short reaction times. Additionally, chiral gold(I) complexes with ADCs have been prepared and tried in the enantioselective synthesis of propargylamines. Show less

Tetrazole cycle is a promising pharmacophore fragment frequently used in the development of novel drugs. This moiety is a stable, practically non-metabolized bioisosteric analog of carboxylic, cis-amide, and other functional groups. Over recent 10-15 years, various isomeric forms of tetrazole (NH-unsubstituted, 1H-1- substituted, and 2H-2-substituted tetrazoles) have been successfully used in the design of promising anticancer drugs. Coordination compounds of transition metals containing tetrazoles as ligands, semisynthetic tetrazolyl derivatives of natural compounds (biogenic acids, peptides, steroids, combretastatin, etc.), 5-oxo and 5- thiotetrazoles, and some other related compounds have been recognized as promising antineoplastic agents. This review presents a comprehensive analysis of modern approaches to synthesis of these tetrazole derivatives as well as their biological (anticancer) properties. The most promising structure types of tetrazoles to be used as anticancer agents have been picked out. Show less

Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin- and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies. Show less

Significance: Iron and oxygen are intimately linked: iron is an essential nutrient utilized as a cofactor in enzymes for oxygen transport, oxidative phosphorylation, and metabolite oxidation. However, excess labile iron facilitates the formation of oxygen-derived free radicals capable of damaging biomolecules. Therefore, biological utilization of iron is a tightly regulated process. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor, which can respond to oxidative and electrophilic stress, regulates several genes involved in iron metabolism. Recent Advances: The bulk of NRF2 transcription factor research has focused on its roles in detoxification and cancer prevention. Recent works have identified that several genes involved in heme synthesis, hemoglobin catabolism, iron storage, and iron export are under the control of NRF2. Constitutive NRF2 activation and subsequent deregulation of iron metabolism have been implicated in cancer development: NRF2-mediated upregulation of the iron storage protein ferritin or heme oxygenase 1 can lead to enhanced proliferation and therapy resistance. Of note, NRF2 activation and alterations to iron signaling in cancers may hinder efforts to induce the iron-dependent cell death process known as ferroptosis. Critical Issues: Despite growing recognition of NRF2 as a modulator of iron signaling, exactly how iron metabolism is altered due to NRF2 activation in normal physiology and in pathologic conditions remains imprecise; moreover, the roles of NRF2-mediated iron signaling changes in disease progression are only beginning to be uncovered. Future Directions: Further studies are necessary to connect NRF2 activation with physiological and pathological changes to iron signaling and oxidative stress. Antioxid. Redox Signal. 00, 000–000. Show less

A trans-DDP based monofunctional phenanthridine Pt(ii) complex was synthesized and characterized. Its anticancer activity was studied in vitro on a panel of human cancer cell lines and mouse intestinal cancer organoids. This complex displays significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. Show less

Cancer treatment with platinum compounds is an important achievement of modern chemotherapy. However, despite the beneficial effects, the clinical impact of these agents is hampered by the development of drug resistance as well as dose-limiting side effects. The efficacy but also side effects of platinum complexes can be mediated by uptake through plasma membrane transporters. In the kidneys, plasma membrane transporters are involved in their secretion into the urine. Renal secretion is accomplished by uptake from the blood into the proximal tubules cells, followed by excretion into the urine. The uptake process is mediated mainly by organic cation transporters (OCT), which are expressed in the basolateral domain of the plasma membrane facing the blood. The excretion of platinum into the urine is mediated by exchange with protons via multidrug and toxin extrusion proteins (MATE) expressed in the apical domain of plasma membrane. Recently, the monofunctional, cationic platinum agent phenanthriplatin, which is able to escape common cellular resistance mechanisms, has been synthesized and investigated. In the present study, the interaction of phenanthriplatin with transporters for organic cations has been evaluated. Phenanthriplatin is a high affinity substrate for OCT2, but has a lower apparent affinity for MATEs. The presence of these transporters increased cytotoxicity of phenanthriplatin. Therefore, phenanthriplatin may be especially effective in the treatment of cancers that express OCTs, such as colon cancer cells. However, the interaction of phenanthriplatin with OCTs suggests that its use as chemotherapeutic agent may be complicated by OCT-mediated toxicity. Unlike cisplatin, phenanthriplatin interacts with high specificity with hMATE1 and hMATE2K in addition to hOCT2. This interaction may facilitate its efflux from the cells and thereby decrease overall efficacy and/or toxicity. Show less

A novel high-nitrogen compound, 1,2-bis(3-nitro-1-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-yl)diazene, was designed and synthesized. The corresponding hydrazine energetic salts were prepared through spontaneous reductive conversion by structurally varied amino salts. All energetic salts showed good thermal stabilities with decomposition temperatures ranging from 212 to 259 °C, and high positive heats of formation in the range of 411.1 to 1554.7 kJ mol−1. Furthermore, hydroxyammonium salt featured a promising integrated energetic performance (vD = 9038 m s−1, IS = 8 J, and FS = 360 N), which is superior to that of RDX (vD = 8890 m s−1, IS = 7.4 J, FS = 120 N), showing promising properties for new high-nitrogen high-energy-density materials. Show less

Iron-sulfur clusters are ancient cofactors that play a fundamental role in metabolism and may have impacted the prebiotic chemistry that led to life. However, it is unclear whether iron-sulfur clusters could have been synthesized on prebiotic Earth. Dissolved iron on early Earth was predominantly in the reduced ferrous state, but ferrous ions alone cannot form polynuclear iron-sulfur clusters. Similarly, free sulfide may not have been readily available. Here we show that UV light drives the synthesis of [2Fe-2S] and [4Fe-4S] clusters through the photooxidation of ferrous ions and the photolysis of organic thiols. Iron-sulfur clusters coordinate to and are stabilized by a wide range of cysteine-containing peptides and the assembly of iron-sulfur cluster-peptide complexes can take place within model protocells in a process that parallels extant pathways. Our experiments suggest that iron-sulfur clusters may have formed easily on early Earth, facilitating the emergence of an iron-sulfur-cluster-dependent metabolism. Show less

As anticipated in the title, this contribution is basically divided into two, strictly connected, parts. The first is a personal overview of the ruthenium drug candidate NAMI‐A, almost 30 years after its synthesis and the discovery of its unprecedented antimetastatic properties in animal models at nontoxic dosages. The sections relating to the chemical and biological behavior of the complex, and the hypotheses on its mechanism(s) of action, are kept to a minimum, whereas more space is devoted to discussion of the results of the clinical investigations. The second part deals in detail with a number of undemonstrated misconceptions (or myths) that, over the years, have thrived around NAMI‐A and other ruthenium drug candidates, thus negatively affecting the whole field of Ru anticancer drugs. Show less

The KEAP1-NRF2 system regulates the cellular defence against oxidative and xenobiotic stresses. NRF2 is a transcription factor that activates the expression of cytoprotective genes encoding antioxidative, detoxifying and metabolic enzymes as well as transporters. Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein. When cells are exposed to stresses, KEAP1 stops promoting NRF2 degradation, and NRF2 rapidly accumulates and activates the transcription of target genes. Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1-mediated NRF2 degradation has been observed in various cancer types. Constitutive NRF2 accumulation confers cancer cells with a proliferative advantage as well as resistance to anti-cancer drugs and radiotherapies. To suppress the chemo- and radio-resistance of cancer cells caused by NRF2 accumulation, we conducted high-throughput chemical library screening for NRF2 inhibitors and identified febrifugine derivatives. We found that application of the less-toxic derivative halofuginone in a low dose range rapidly reduced NRF2 protein levels. Halofuginone induced a cellular amino acid starvation response that repressed global protein synthesis and rapidly depleted NRF2. Halofuginone treatment ameliorated the resistance of NRF2-addicted cancer cells to anti-cancer drugs both in vitro and in vivo. These results provide preclinical proof-of-concept evidence for halofuginone as an NRF2 inhibitor applicable to treatment of chemo- and radio-resistant forms of cancer. Show less

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts. Show less

Iron-sulfur (Fe-S) clusters are fundamental to numerous biological processes in most organisms, but these protein cofactors can be prone to damage by various oxidants (e.g., O2, reactive oxygen species, and reactive nitrogen species) and toxic levels of certain metals (e.g., cobalt and copper). Furthermore, their synthesis can also be directly influenced by the level of available iron in the environment. Consequently, the cellular need for Fe-S cluster biogenesis varies with fluctuating growth conditions. To accommodate changes in Fe-S demand, microorganisms employ diverse regulatory strategies to tailor Fe-S cluster biogenesis according to their surroundings. Here, we review the mechanisms that regulate Fe-S cluster formation in bacteria, primarily focusing on control of the Isc and Suf Fe-S cluster biogenesis systems in the model bacterium Escherichia coli. Show less

Pyridyl–tetrazole ligands 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetamide (L1), 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)acetamide (L2), 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetohydrazide (L3) and 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)acetohydrazide (L4) have been prepared and coordinated with CuCl2·2H2O to furnish the corresponding complexes [Cu(L1) 2 ]–[Cu(L4) 2 ]. EPR spectra of the complexes are characteristic of square planar geometries, with nuclear hyperfine spin 3/2. DNA-binding studies using UV–Vis absorption spectroscopy, viscosity and thermal denature studies revealed that all of these complexes are avid binders of calf thymus DNA. The antioxidant properties of the free ligands and the Cu(II) complexes were investigated using the p-nitrosodimethyl aniline hydroxyl radical scavenging method, and [Cu(L4) 2 ] was found to show the highest activity. Show less

Abstract The coordination compound of the antihypertensive ligand irbesartan (irb) with copper(II) (CuIrb) was synthesized and characterized by FTIR, FT-Raman, UV–visible, reflectance and EPR spectroscopies. Experimental evidence allowed the implementation of structural and vibrational studies by theoretical calculations made in the light of the density functional theory (DFT). This compound was designed to induce structural modifications on the ligand. No antioxidant effects were displayed by both compounds, though CuIrb behaved as a weak 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·) scavenger (IC50 = 425 μM). The measurements of the contractile capacity on human mesangial cell lines showed that CuIrb improved the antihypertensive effects of the parent medication. In vitro cell growth inhibition against prostate cancer cell lines (LNCaP and DU 145) was measured for CuIrb, irbesartan and copper(II). These cell lines have been selected since the angiotensin II type 1 (AT1) receptor (that was blocked by the angiotensin receptor blockers, ARB) has been identified in them. The complex exerted anticancer behavior (at 100 μM) improving the activity of the ligand. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. Graphical Abstract Experimental and DFT characterization of an irbesartan copper(II) complex has been performed. The complex exhibits low scavenging activity against DPPH· and significant growth inhibition of LNCaP and DU 145 prostate cancer cell lines. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. This compound improved the antihypertensive effect of irbesartan. This effect was observed earlier for the mononuclear Cu–candesartan complex, but not in structurally modified sartans forming dinuclear or octanuclear Cu–sartan compounds. Show less

Modulatory profiling of lethal small-molecule compounds identified FIN56 as an inducer of ferroptosis. FIN56 promotes the degradation of glutathione peroxidase 4 and directly activates squalene synthase, an enzyme involved in cholesterol synthesis. Show less

The role of copper in the proliferation of cancer cells is under investigation and has been explored in the context of cancer chemotherapy. The evidence that proliferation of cancer cells requires a higher abundance of Cu(II) than their normal counterparts has prompted the development of new copper chelators that can avidly bind copper ions, forming redox active metal complexes that ultimately lead to harmful reactive oxygen species (ROS) in neoplasms. In this context, the mandatory properties of the chelators for medical applications are safety (neglectable cytotoxicity), high binding affinity and selectivity towards Cu(II). We report the synthesis, structure (calculations and single crystal X-ray diffraction), spectroscopic (IR; UV-Vis) and magnetic properties of two novel copper(II) complexes based on 5-(3-aminosaccharyl)-tetrazoles (TS and 2MTS), as well as their in vitro cytotoxicity against the human hepatic carcinoma cell line HepG2. Quite interestingly, we found that the saccharinate-tetrazoles tested exhibit strong binding selectivity to Cu(II), over Fe(II) and Ca(II). Additionally, the corresponding copper complexes have shown a huge increase in the in vitro cytotoxicity against tumoral cells, compared to the corresponding nontoxic ligands. Thus, the new ligands may be viewed as potential precursors of selective cytotoxic agents, acting as non-cytotoxic pro-drugs that can be activated inside neoplastic cells, known to be richer in Cu(II) than the corresponding normal cells. Show less

Five mixed thiolatobismuth(III) complexes [BiPh(5‐MMTD)2{4‐MMT(H)}] (1), [Bi(1‐MMTZ)2{(PYM)(PYM(H))2}] (2), [Bi(MBT)2(5‐MMTD)] (3), [Bi(4‐BrMTD)3{2‐MMI(H)}] (4) and [Bi(1‐MMTZ)2{1‐MMTZ(H)}(2‐MMI){2‐MMI(H)2}] (5) were synthesised from imidazole‐, thiazole‐, thiadiazole‐, triazole‐, tetrazole‐ and pyrimidine‐based heterocyclic thiones. Four of these complexes 1–4 were synthesized from BiPh3, while complex 5 was obtained from Bi[4‐(MeO)Ph]3. Complexes 1–5 were structurally characterised by XRD. Evaluation of the antibacterial properties against Mycobacterium smegmatis, Staphylococcus aureus, Methicillin‐resistant S. aureus (MRSA), Vancomycin‐resistant Enterococcus (VRE), Enterococcus faecalis and Escherichia coli showed that mixed thiolato complexes containing the anionic thiazole‐based ligands MBT and 4‐BrMTD are most effective. The mixed thiolato complexes [Bi(MBT)2(5‐MMTD)] (3) having thiazole‐ and thiadiazole‐ and [Bi(4‐BrMBT)3{2‐MMI(H)}] (4) containing thiazole‐ and imidazole‐based ligands proved to be more efficient, with low minimum inhibitory concentrations of 1.73 and 3.45 µm for 3 against VRE and E. faecalis, respectively, and 2.20 µm for 4 against M. smegmatis and E. faecalis. All complexes showed little or no toxicity towards mammalian COS‐7 cell lines at 20 µg mL–1. Show less

2‐R‐2H‐Tetrazol‐5‐ylacetic acids (abbreviated as 2‐R‐taa; R = Me, iPr, tBu) react with K2[PtCl4] in 1 m HCl in H2O at r.t. furnishing trans‐platinum(II) complexes trans‐[PtCl2(2‐R‐taa)2] (1–3), whereas cis‐isomeric species cis‐[PtCl2(2‐R‐taa)2] (R = iPr, 4; tBu, 5) are isolated at lower temperature (4–6 °C). In the presence of EtOH in the reaction mixture, esterification of the tetrazol‐5‐ylacetoxy group of 2‐tBu‐taa leads to trans‐[PtCl2(ethyl 2‐tert‐butyl‐2H‐tetrazol‐5‐ylacetate)2] (6). Complexes 1–6 were characterized by elemental analyses (CHN), HRESI+‐MS, 1H, 13C{1H}, 195Pt{1H} NMR and IR spectroscopy, differential scanning calorimetry/thermogravimetry (DSC/TG), and X‐ray diffraction (for 1·H2O, 2, 3·2H2O, 4, 5·2H2O, and 6). The generation of the tetrazole‐based complexes in solution (1 m DCl in D2O, 25 °C) was studied by 1H NMR spectroscopy and HPLC‐MS. The obtained data indicate the initial formation of anionic [PtCl3(2‐R‐taa)]– complexes that are subsequently converted into disubstituted isomeric platinum(II) species cis‐ and trans‐[PtCl2(2‐R‐taa)2]. By contrast to cis‐ and trans‐[PtCl2(2‐R‐taa)2] that were inactive in two human cancer models in vitro (IC50 > 100 µm), complex 6 demonstrated noticeable antiproliferative effects in HT‐29 colon and MCF‐7 breast carcinoma cell lines with IC50 values of 14.2 ± 1.1 and 5.8 ± 1.2 µm, respectively. Show less

Two new mononuclear water soluble copper(II) complexes, [Cu{(5-pyrazinyl)tetrazolate}2(1,10-phenanthroline)] 1 and [Cu{(5-pyrazinyl)tetrazolate}(1,10-phenanthroline)2](NO3)0.5(N3)0.52, have been synthesized using the metal mediated [2 + 3] cycloaddition reaction between copper bound azide and pyrazinecarbonitrile. The interactions of these copper tetrazolate complexes 1 and 2 with biomolecules like DNA and bovine serum albumin (BSA) are studied and the catecholase like catalytic activity of compound 2 is also explored. Structural determination reveals that both compounds 1 and 2 are octahedral in nature. Screening tests were conducted to quantify the binding ability of complexes (1 and 2) towards DNA and it was revealed that complex 2 has a stronger affinity to bind to CT-DNA. DFT studies indicated that a lower HOMO–LUMO energy gap between the DNA fragment and metal complexes might be the reason for this type of stronger interaction. DNA cleavage activity was explored by gel-electrophoresis and moderate to strong DNA cleavage properties were observed in the presence and absence of co-reagents. Inhibition of cleavage in the presence of sodium azide indicates the propagation of the activity through the production of singlet molecular oxygen. Furthermore enzyme kinetic studies reflect that complex 2 is also effective in mimicking catecholase like activities. An ESI-MS spectral study indicates the probable involvement of dimeric species [(phen)2Cu-(OH)2-Cu(phen)2]2+ in the catalytic cycle. Show less

Abstract2‐(1H‐Tetrazol‐5‐yl)pyridine (L) has been reacted separately with Me2NCH2CH2Cl⋅HCl and ClCH2CH2OH to yield two regioisomers in each case,N,N‐dimethyl‐2‐[5‐(pyridin‐2‐yl)‐1H‐tetrazol‐1‐yl]ethanamine (L1)/N,N‐dimethyl‐2‐[5‐(pyridin‐2‐yl)‐2H‐tetrazol‐2‐yl]ethanamine (L2) and 2‐[5‐(pyridin‐2‐yl)‐1H‐tetrazol‐1‐yl]ethanol (L3)/2‐[5‐(pyridin‐2‐yl)‐2H‐tetrazol‐2‐yl]ethanol (L4), respectively. These ligands,L1–L4, have been coordinated with CuCl2⋅H2O in 1 : 1 composition to furnish the corresponding complexes1–4. EPR Spectra of Cu complexes1and3were characteristic of square planar geometry, with nuclear hyperfine spin 3/2. Single X‐ray crystallographic studies of3revealed that the Cu center has a square planar structure. DNA binding studies were carried out by UV/VIS absorption; viscosity and thermal denaturation studies revealed that each of these complexes are avid binders of calf thymus DNA. Investigation of nucleolytic cleavage activities of the complexes was carried out on double‐stranded pBR322 circular plasmid DNA by using a gel electrophoresis experiment under various conditions, where cleavage of DNA takes place by oxidative free‐radical mechanism (OH⋅).In vitroanticancer activities of the complexes against MCF‐7 (human breast adenocarcinoma) cells revealed that the complexes inhibit the growth of cancer cells. TheIC50values of the complexes showed that Cu complexes exhibit comparable cytotoxic activities compared to the standard drug cisplatin. Show less

Methylation of Lys and Arg residues on non-histone proteins has emerged as a prevalent post-translational modification and as an important regulator of cellular signal transduction mediated by the MAPK, WNT, BMP, Hippo and JAK-STAT signalling pathways. Crosstalk between methylation and other types of post-translational modifications, and between histone and non-histone protein methylation frequently occurs and affects cellular functions such as chromatin remodelling, gene transcription, protein synthesis, signal transduction and DNA repair. With recent advances in proteomic techniques, in particular mass spectrometry, the stage is now set to decode the methylproteome and define its functions in health and disease. Show less

In our search towards copper(II) based anticancer compounds, copper(II) complexes [Cu(bitpy)2](ClO4)21, [Cu(bitpy)(phen)](NO3)22 and [Cu(bitpy)(NO3)](NO3) 3 were synthesized and characterized. All the three complexes contain the tridentate ligand bitpy, which bears biologically relevant benzimidazolyl head group, as one of the ligands. Because of the presence of the planar benzimidazolyl group in the bitpy ligand, the complexes exhibited intercalative mode of binding with DNA. The DNA binding constant, K(b), for complexes 1, 2 and 3 were determined to be (1.84 ± 0.32) × 10(4), (1.83 ± 0.57) × 10(4) and (1.87 ± 0.21) × 10(4) M(-1) respectively. All the three complexes possessed DNA condensing ability. The DNA condensing ability of the complexes was in the order 2 > 1 > 3. The DNA condensation induced by these three complexes was found to be reversed in the presence of 1 M NaCl. In vitro cytotoxicity of three complexes was tested against osteosarcoma MG63 cell line as well as normal fibroblast NIH3T3 cell line by MTT reduction assay. Complexes 1 and 2 were found to be highly toxic towards MG63 than NIH3T3 cell line and both these complexes brought about cell death in the MG-63 cell line due to apoptosis. Whereas, complex 3 exhibited almost equal toxic effect towards both MG63 and NIH3T3 cell lines. Based on the fact that both complexes 1 and 2 brought about reversible condensation of DNA and induced apoptosis in osteosarcoma MG-63 cell line, it is hypothesized that they might possess potential pharmaceutical applications. Show less

AbstractHomo‐ and heteroleptic bismuth thiolato complexes have been synthesised and characterised from biologically relevant tetrazole‐, imidazole‐, thiadiazole‐ and thiazole‐based heterocyclic thiones (thiols): 1‐methyl‐1H‐tetrazole‐5‐thiol (1‐MMTZ(H)); 4‐methyl‐4H‐1,2,4‐triazole‐3‐thiol (4‐MTT(H)); 1‐methyl‐1H‐imidazole‐2‐thiol (2‐MMI(H)); 5‐methyl‐1,3,4‐thiadiazole‐2‐thiol (5‐MMTD(H)); 1,3,4‐thiadiazole‐2‐dithiol (2,5‐DMTD(H)2); and 4‐(4‐bromophenyl)thiazole‐2‐thiol (4‐BrMTD(H)). Reaction of BiPh3 with 1‐MMTZ(H) produced the rare BiV thiolato complex [BiPh(1‐MMTZ)4], which undergoes reduction in DMSO to give [BiPh(1‐MMTZ)2{(1‐MMTZ(H)}2]. Reactions with PhBiCl2 or BiPh3 generally produced monophenylbismuth thiolates, [BiPh(SR)2]. The crystal structures of [BiPh(1‐MMTZ)2{1‐MMTZ(H)}2], [BiPh(5‐MMTD)2], [BiPh{2,5‐DMTD(H)}2(Me2CO)] and [Bi(4‐BrMTD)3] were obtained. Evaluation of the bactericidal properties against M. smegmatis, S. aureus, MRSA, VRE, E. faecalis and E. coli showed complexes containing the anionic ligands 1‐ MMTZ, 4‐MTT and 4‐BrMTD to be most effective. The dithiolato dithione complexes [BiPh(4‐MTT)2{4‐MTT(H)}2] and [BiPh(1‐MMTZ)2{1‐MMTZ(H)}2] were most effective against all the bacteria: MICs 0.34 μM for [BiPh(4‐MTT)2{4‐MTT(H)}2] against VRE, and 1.33 μM for [BiPh(1‐MMTZ)2{1‐MMTZ(H)}2] against M. smegmatis and S. aureus. Tris‐thiolato BiIII complexes were least effective overall. All complexes showed little or no toxicity towards mammalian COS‐7 cells at 20 μg mL−1. Show less

Transcription inhibition by platinum anticancer drugs is an important component of their mechanism of action. Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms highly potent monofunctional adducts on DNA having a structure and spectrum of anticancer activity distinct from those of the parent drug. Understanding the functional consequences of DNA damage by phenanthriplatin for the normal functions of RNA polymerase II (Pol II), the major cellular transcription machinery component, is an important step toward elucidating its mechanism of action. In this study, we present the first systematic mechanistic investigation that addresses how a site-specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Pol II processing of the phenanthriplatin lesion differs significantly from that of the canonical cisplatin-DNA 1,2-d(GpG) intrastrand cross-link. A majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner, with specificity for CTP incorporation being essentially the same as for undamaged dG on the template. A small portion of Pol II undergoes slow, error-prone bypass of the phenanthriplatin-dG lesion, which resembles DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error-prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis. Because of the current interest in monofunctional, DNA-damaging metallodrugs, these results are of likely relevance to a broad spectrum of next-generation anticancer agents being developed by the medicinal inorganic chemistry community. Show less

The deep dichotomy of archaea and bacteria is evident in many basic traits including ribosomal protein composition, membrane lipid synthesis, cell wall constituents, and flagellar composition. Here we explore that deep dichotomy further by examining the distribution of genes for the synthesis of the central carriers of one carbon units, tetrahydrofolate (H4F) and tetrahydromethanopterin (H4MPT), in bacteria and archaea. The enzymes underlying those distinct biosynthetic routes are broadly unrelated across the bacterial-archaeal divide, indicating that the corresponding pathways arose independently. That deep divergence in one carbon metabolism is mirrored in the structurally unrelated enzymes and different organic cofactors that methanogens (archaea) and acetogens (bacteria) use to perform methyl synthesis in their H4F- and H4MPT-dependent versions, respectively, of the acetyl-CoA pathway. By contrast, acetyl synthesis in the acetyl-CoA pathway - from a methyl group, CO2 and reduced ferredoxin - is simpler, uniform and conserved across acetogens and methanogens, and involves only transition metals as catalysts. The data suggest that the acetyl-CoA pathway, while being the most ancient of known CO2 assimilation pathways, reflects two phases in early evolution: an ancient phase in a geochemically confined and non-free-living universal common ancestor, in which acetyl thioester synthesis proceeded spontaneously with the help of geochemically supplied methyl groups, and a later phase that reflects the primordial divergence of the bacterial and archaeal stem groups, which independently invented genetically-encoded means to synthesize methyl groups via enzymatic reactions. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. Show less

Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η- cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin. Show less

Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood-Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent-ocean interface via the ATP synthase, (iii) harnessing of Na(+) gradients generated by H(+)/Na(+) antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type 'reduced iron → reduced carbon' at the beginning of bioenergetic evolution. Show less