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Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are susceptible to innate and acquired resistance. The bulk of platinum anticancer research has focused on Cisplatin and its derivatives. Here, we take inspiration from the design of platinum complexes and ligands used successfully with other metals to create six novel complexes. Herein, the synthesis, characterization, DNA binding affinities, and lipophilicity of a series of non-traditional organometallic Pt(II)-complexes are described. These complexes have a basic [Pt(PL)(AL)]Cl2 molecular formula which incorporates either 2-pyrrolidin-2-ylpyridine, 2-(1H-Imidazol-2-yl)pyridine, or 2-(2-pyridyl)benzimidazole as the PL; the AL is resolved diaminocyclohexane. Precursor [Pt(PL)(Cl)2] complexes were also characterized for comparison. While the cytotoxicity and DNA binding properties of the three precursors were unexceptional, the corresponding [Pt(PL)(AL)]2+ complexes were promising; they exhibited different DNA binding interactions compared with Cisplatin but with similar, if not slightly better, cytotoxicity results. Complexes with 2-pyrrolidin-2-ylpyridine or 2-(2-pyridyl)benzimidazole ligands had similar DNA binding properties to those with 2-(1H-Imidazol-2-yl)pyridine ligands but were not as cytotoxic to all cell lines. The variation in activity between cell lines was remarkable and resulted in significant selectivity indices in MCF10A and MCF-7 breast cancer cell lines, compared with previously described similar Pt(II) complexes such as 56MESS. [ABSTRACT FROM AUTHOR]

Cancer poses a significant threat to global health and new treatments are required to improve the prognosis for patients. Previously, unconventional platinum complexes designed to incorporate polypyridyl ligands paired with diaminocyclohexane have demonstrated anticancer activity in KRAS mutated cells, previously thought to be undruggable and have cytotoxicity values up to 100 times better than cisplatin. In this work, these complexes were used as inspiration to design six novel cyclometallated examples, whose fluorescence could be exploited to better understand the mechanism of action of these kinds of platinum drugs. The cytotoxicity results revealed that these cyclometallated complexes (CMCs) have significantly different activity compared to the complexes that inspired them; they are as cytotoxic as cisplatin and have much higher selectivity indices in breast cancer cell lines (MCF10A/MCF-7). Complexes 1b, 2a, and 3b all had very high selectivity indexes compared to previous Pt(II) complexes. This prompted further investigation into their DNA binding properties, which revealed that they had good affinity to ctDNA, especially CMCs 1a and 3b. Their inherent fluorescence was successfully utilised in the calculation of their DNA binding affinity and could be useful in future work. [ABSTRACT FROM AUTHOR]

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (2) exhibiting the lowest GI50 of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1–4; however, this was not always translated to the observed cytotoxicity. [ABSTRACT FROM AUTHOR]

Herein is described the development of a series of novel quadruplex DNA (QDNA)-stabilising cyclometallated square–planar metal complexes (CMCs). Melting experiments using quadruplex DNA (QDNA) demonstrated that interactions with the complexes increased the melting temperature by up to 19 °C. This QDNA stabilisation was determined in two of the major G-quadruplex structures formed in the human c-MYC promoter gene (c-MYC) and a human telomeric repeat sequence (H-Telo). The CMCs were found to stabilise H-telo more strongly than c-MYC, and the CMCs with the highest cytotoxic effect had a low–moderate correlation between H-telo binding capacity and cytotoxicity (R2 values up to 10 times those of c-MYC). The melting experiments further revealed that the stabilisation effect was altered depending on whether the CMC was introduced before or after the formation of QDNA. All CMCs' GI50 values were comparable or better than cisplatin in human cancer cell lines HT29, U87, MCF-7, H460, A431, Du145, BE2-C, SJ-G2, MIA, and ADDP. Complexes 6, 7, and 9 were significantly more cytotoxic than cisplatin in all cell lines tested and had good to moderate selectivity indices, 1.7–4.5 in MCF10A/MCF-7. The emission quantum yields were determined to be relatively high (up to 0.064), and emission occurred outside cellular autofluorescence, meaning CMC fluorescence is ideal for in vitro analyses. [ABSTRACT FROM AUTHOR]

Platinum(IV) prodrugs of the [Pt(PL)(AL)(COXi)(OH)]2+ type scaffold (where PL is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, 4, exhibited a GI50 of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that 1 and 2 inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs 1–4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity. [ABSTRACT FROM AUTHOR]

A series of complexes of the type rac -[Ru(N4-TL)(PL)]2+ (where N4-TL = 1,6-di(2′-pyridyl)-2,5-dimethyl-2,5-diazahexane (picenMe2, N4-TL- 2) and PL = 1,10-phenanthroline (phen, Ru- 2), dipyrido[3,2- d :2′,3′- f ]quinoxaline (dpq, Ru- 3), 7,8-dimethyl-dipyrido[3,2- a :2′,3′- c ]phenazine (dppzMe2, Ru- 4), 2-phenyl-1 H -imidazo[4,5- f ][1,10]phenanthroline (phenpyrBz, Ru- 5), 2-(p -tolyl)-1 H -imidazo[4,5- f ][1,10]phenanthroline (phenpyrBzMe, Ru- 6), and 2-(4-nitrophenyl)-1 H -imidazo[4,5- f ][1,10]phenanthroline (phenpyrBzNO2, Ru- 7), were synthesised. All structures were confirmed using NMR, electrospray ionisation mass spectrometry (ESI-MS), high-performance liquid chromatography (HPLC), and UV analysis and for four complexes X-ray crystallography. The in vitro cytotoxicity assays revealed that Ru- 6 was 5, 10, and 40-fold more potent than oxaliplatin, cisplatin, and carboplatin, respectively. Six complexes of the type [Ru(picenMe2)(PL)]2+ (where PL = phen, dpq, dppzMe2, phenpyrBz, phenpyrBzMe, or phenpyrBzNO2) were synthesised and characterised. The in vitro cytotoxicity assays revealed that Ru- 6 was 5, 10, and 40-fold more potent than oxaliplatin, cisplatin, and carboplatin, respectively. [ABSTRACT FROM AUTHOR]

Lipophilic platinum(IV) complexes were synthesised of the type [Pt(HL)(AL)(OH)(R)]2+ and [Pt(HL)(AL)(R)2]2+ (HL = 5,6-dimethyl-1,10-phenanthroline or 1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and R = increasingly lipophilic carboxylate axial ligands (C10–18)) from hydrophilic platinum(II) precursors that exhibit exceptional anticancer activity. The increased overall lipophilicity of the complexes suggested the formation of spontaneously self-assembled structures in an aqueous environment. The anti-proliferative properties were assessed against one non-cancerous and a panel of cancerous cell lines. Nanomolar levels of activity were observed against several cell lines, with the lowest GI50 of 3.4 nm against the Du145 prostate cancer cell line and over 1100-fold greater activity than cisplatin against HT29 colon carcinoma. RP-HPLC was utilised to establish the relative lipophilicities of each complex. While there seemed to be an increase in cellular accumulation for the lipophilic derivatives in some instances, ICP-MS studies showed no clear correlation between increasing lipophilicity, cellular accumulation and cytotoxicity. [ABSTRACT FROM AUTHOR]

Novel platinum(IV) complexes were synthesised to examine the facile modulation of the lipophilicity of the complex by incorporating axial ligands of increasing length, ranging from 2–6 carbons. RP-HPLC was used to establish the lipophilicity of each complex. The in vitro cytotoxicities of all complexes were determined against a panel of malignant cell lines and a non-cancerous cell line. While there was no clear correlation between lipophilicity and cytotoxicity, all complexes demonstrated nanomolar activity against all cell lines. The most potent complexes exhibited 850-fold greater activity than cisplatin against HT29 colon carcinoma with GI50 values of 13 nM. [ABSTRACT FROM AUTHOR]

Platinum complexes of the type [Pt(PL)(AL)]2+ where PL is a derivative of 1,10-phenanthroline and AL is cis-1,4-diaminocyclohexane (1,4-dach), have been synthesised and characterised by ultraviolet spectroscopy, elemental microanalysis, nuclear magnetic resonance and X-ray crystallography. The calf-thymus DNA binding affinity of these complexes was determined by isothermal titration calorimetry, revealing higher DNA affinity than their 1S,2S-diaminocyclohexane analogues. In vitro cytotoxicity was assessed in eleven human cell lines, revealing unexpectedly low activity for the 1,4-dach complexes. [ABSTRACT FROM AUTHOR]

Six platinum(II) complexes of the type [Pt(P L )(A L )] 2 + , where P L is a bidentate pyridyl-1,2,3-triazole “click” ligand and A L is the R , R or S , S isomer of 1.2-diaminocyclohexane, have been synthesised and characterised by several methods including elemental microanalysis, proton NMR spectroscopy and X-ray crystallography. The in vitro cytotoxicity of each complex was assessed in eleven cell lines, revealing moderate to good activity for complexes incorporating 2-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine. [ABSTRACT FROM AUTHOR]

This study reports a detailed biophysical analysis of the DNA binding and cytotoxicity of six platinum complexes (PCs). They are of the type [Pt(PL)( SS-dach)]Cl2, where PL is a polyaromatic ligand and SS-dach is 1 S,2 S-diaminocyclohexane. The DNA binding of these complexes was investigated using six techniques including ultraviolet and fluorescence spectroscopy, linear dichroism, synchrotron radiation circular dichroism, isothermal titration calorimetry and mass spectrometry. This portfolio of techniques has not been extensively used to study the interactions of such complexes previously; each assay provided unique insight. The in vitro cytotoxicity of these compounds was studied in ten cell lines and compared to the effects of their R,R enantiomers; activity was very high in Du145 and SJ-G2 cells, with some submicromolar IC50 values. In terms of both DNA affinity and cytotoxicity, complexes of 5,6-dimethyl-1,10-phenanthroline and 2,2′-bipyridine exhibited the greatest and least activity, respectively, suggesting that there is some correlation between DNA binding and cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Mitotane (o,p′-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites, o,p′-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p′-DDA (1,1-[o,p′-dichlorodiphenyl] acetic acid, DDA) provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites, DDE and DDA. The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p′-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77–88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6ml/min followed by UV detection at λ 226nm. Inter and intra-day validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2μg/ml for mitotane and DDE, and 0.5μg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1–18 times higher than the parent compound. [Copyright &y& Elsevier]

A series of complexes of the type rac - cis - β -[Ru(N 4 -T L)(N 2 -bidentates)]2+ (where N 4 -T L = 1,6-di(2′-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz 2 , N 4 -T L - 2) and N 2 -bidentates = 1,10-phenanthroline (phen, Ru-2), dipyrido[3,2-d:2′,3′- f ]quinoxaline (dpq, Ru-3), 7,8-dimethyl-dipyrido[3,2-a:2′,3′-c] phenazine (dppzMe 2, Ru-4), 2-phenyl-1H-imidazo[4,5- f ][1,10]phenanthroline (phenpyrBz, Ru-5), 2-(p-tolyl)-1H-imidazo[4,5- f ][1,10]phenanthroline (phenpyrBzMe, Ru-6), 2-(4-nitrophenyl)-1H-imidazo[4,5- f ][1,10]phenanthroline (phenpyrBzNO 2, Ru-7), were synthesised and characterised and X-ray crystallography of Ru-5 obtained. The in vitro cytotoxicity assays revealed that Ru- 6 was 5, 2 and 19-fold more potent than oxaliplatin, cisplatin, and carboplatin, respectively displaying an average GI 50 value of ≈ 0.76 μM against a panel of 11 cancer cell lines. [Display omitted] • Reports the synthesis and characterisation of rac - cis - β -[Ru(N 4 -T L)(N 2 -bidentates)]2+. • Potential metal complex architectures photosensitizers/photodynamic therapy. • In vitro cytotoxicity assays revealed potency in cancer cell lines. [ABSTRACT FROM AUTHOR]

Purpose. The serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) are key enzymes in regulating entry into the cell cycle, mitosis and apoptosis. Inhibition of PP1 and PP2A is associated with enhanced S-phase entry culminating in G2/M arrest and apoptotic cell death. Thymidylate synthase (TS) is a key regulatory enzyme in DNA synthesis, inhibition of which is often a first-line treatment for colorectal carcinoma. In this study the effect of combining PP inhibition with TS inhibition in two colorectal cell lines was examined. Methods. Cantharidin and nolatrexed were used to inhibit PP and TS activity, respectively. The MTT cytotoxicity assay and cell cycle analysis were performed following single-drug treatment of HT29 and HCT116 colorectal cell lines. The median effect method was used to determine a combination index (CI), where drug antagonism was indicated by a CI>1.1, additivity by a CI between 0.9 and 1.1, and synergism by a CI<0.9. Results. Both cell lines were equally sensitive to cantharidin alone (GI50 values 5.4 and 7.3 μM), which induced a significant increase in the S-phase population of both cell lines within 6 h with a concomitant increase in DNA synthesis. This response culminated in G2/M cell cycle arrest within 24 h and subsequent cell death. In response to nolatrexed alone, HT29 cells were more sensitive than HCT116 cells (GI50 1.9 μM vs 9.8 μM), with G1/S-phase cell cycle arrest occurring within 24 h in both cell lines. In HT29 cells, this was followed by cell death, whereas in HCT116 cells, a proportion of cells died following arrest but the predominant event was re-entry into the cell cycle. The simultaneous exposure of HT29 cells to the combination of nolatrexed and cantharidin in drug molar ratios of 1:1 and 1:2.5 for 72 h was synergistic producing composite CIs of 0.88 and 0.87, respectively. The sequence of nolatrexed followed by cantharidin 24 h later resulted in greater synergism (CI values of 0.75, 0.52, 0.55, 0.68 for molar ratios of 10:1, 1:1, 1:2.5, 1:10), whereas the reverse sequence was antagonistic, suggesting that the point of interaction is downstream of TS inhibition. In HCT116 cells only additive and antagonistic interactions were observed for any of the treatment combinations. The lack of synergism in these cells may be caused by the reduced sensitivity of these cells to nolatrexed as a single agent. Conclusion. The effect of TS inhibition can be enhanced by the inhibition of serine/threonine protein phosphatases. [ABSTRACT FROM AUTHOR]

This study aimed to determine the phytochemical, antioxidant, and anticancer activities of the crude extract and its fractions of Cupaniopsis anacardioides. The results showed that total phenolic content (TPC), their secondary metabolites (flavonoids—TFC; proanthocyanidins—TPro), and antioxidant activity were significantly different between the crude extract and its fractions. The butanol fraction (F3) had the highest levels of TPC, TFC, and TPro, followed by the crude extract, aqueous fraction (F4), dichloromethyl fraction (F2), and hexane fraction (F1). High-Pressure Liquid Chromatography (HPLC) analysis revealed 14 major bioactive compounds were identified in the C. anacardioides extract. Further analysis showed F3 fraction contained the highest levels of the major bioactive compounds, while F1 fraction had the lowest. A similar pattern was observed for antioxidant activities. The crude extract, F3 and F4 fractions were further tested for cytotoxicity against 10 cancer cell lines, including HT29 (colon); U87, SJG2 (glioblastoma); MCF-7 (Breast); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); MIA PaCa-2 (pancreas); and one non-tumour-derived normal breast cell line (MCF10A). Except for Du145 (prostate), the crude extract, F3 and F4 fractions inhibited the cancer cell lines at 100 µg/mL, with F3 possessing greater activity against these cancer cell lines. Future studies are recommended to isolate and identify the major bioactive compounds of the F3 fraction, and further tested their impact against cancer cell lines. This could identify the potential of anticancer agents from C. anacardioides. [ABSTRACT FROM AUTHOR]

We previously reported on the interaction of 10-chloro-7H-benzo[de]benzo[4,5] imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI50 values of 0.001-2.1 ^iM in select breast cancer cell lines MCF-7, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, BT474 cells, while having modest effects of 2.1-7 ^iM in other cell lines including HT29, U87, SJ-G2, A2780, DU145, BE2-C, MIA, MDA-MB-231 or normal breast cells, MCF10A (3.2 ^iM). The most potent growth inhibitory effect of BBQ was observed in the triple negative cell line, MDA-MB-468 with a GI50 value of 0.001 ^M, presenting a 3,200-fold greater response than in the normal MCF10A breast cells. Additions of Cl, CH3, CN to the phenyl ring and ring expansion from benzoimidazole to dihydroquinazoline hindered the growth inhibitory potency of the BBQ analogues by blocking potential sites of CYP1 oxidative metabolism, while addition of Cl or NO2 to the naphthyl rings restored potency. In a cell-based reporter assay all analogues induced 1.2 to 10-fold AhR transcription activation. Gene expression analysis confirmed the induction of CYP1 oxygenases by BBQ. The CYP1 inhibitor a-naphthoflavone, and the SULT1A1 inhibitor quercetin significantly reduced the growth inhibitory effect of BBQ, confirming the importance of both phase I and II metabolic activation for growth inhibition. Conventional molecular modelling/docking revealed no significant differences between the binding poses of the most and least active analogues. More detailed DFT analysis at the DSD-PBEP86/Def-TZVPP level of theory could not identify significant geometric or electronic changes which would account for this varied AhR activation. Generation of Fukui functions at the same level of theory showed that CYP1 metabolism will primarily occur at the phenyl head group of the analogues, and substituents within this ring lead to lower cytotoxicity. [ABSTRACT FROM AUTHOR]

Pt(IV)56MESSX 2 , Pt(IV)5MESSX 2 and Pt(IV)PHENSSX 2 (where X = Cl, Br or I) was synthesised in a one pot reaction using N -halogensuccinimide (NXS). In vitro cytotoxicity assays revealed that they were more active than analogous complexes with hydroxido axial ligands, and demonstrate comparable activity with the corresponding Pt(II) complex. • First reported synthesis for Pt(IV)56MESSX 2 , Pt(IV)5MESSX 2 and Pt(IV)PHENSSX 2 where X = Cl, Br or I. • New synthetic approach to afford Pt(IV)56MESSX 2 , Pt(IV)5MESSX 2 and Pt(IV)PHENSSX 2. • Cytotoxicity of Pt(IV)56MESSX 2 , Pt(IV)5MESSX 2 and Pt(IV)PHENSSX 2. A series of complexes of the type [Pt(P L)(A L)(X) 2 ]2+ (where P L = 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline; A L = 1 S ,2 S -diaminocyclohexane and, X = Cl, Br or I) with anticancer potency, were synthesised in a one pot reaction using N -halogensuccinimide (NXS) as both the source of the ligand and the oxidizing reagent. It was determined that 2.4 equivalents of NXS resulted in 100% oxidation of Pt(II) in a solution of equal parts H 2 O, ethanol and 1 M HCl. This method of oxidation was 24 times faster than the established peroxide method resulting in the acceleration of the complete synthesis of [Pt(P L)(A L)(X) 2 ]2+. All structures were confirmed using NMR, ESI-MS, CD and UV, while the purity was confirmed by microanalysis. The in vitro cytotoxicity assays revealed that they were more active than analogous complexes with hydroxido axial ligands, and share comparable activity with the corresponding Pt(II) complex. [ABSTRACT FROM AUTHOR]

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Traditional intravenous platinum(II) chemotherapy drugs such as cisplatin, oxaliplatin and carboplatin are highly effective in treating multiple cancer types. Unfortunately, this treatment is most often beset with detrimental side effects that inevitably impact the patient's willingness to comply with treatment programs. Platinum(II) drugs are scarcely selective, have poor bioavailability, and exhibit inherent and acquired resistance. A promising approach to address these impediments is the development of kinetically stable octahedral platinum(IV) complexes. This design strategy has been exploited for cisplatin and its derivatives and has been reported widely in the literature. This is a highly attractive approach for synthetic chemists due to the versatility it offers. Here, we contribute to this paradigm shift by using structurally distinct platinum(IV) scaffolds as effective prodrugs. The findings reported are expected to advance our understanding of cancer treatment. Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (1–6) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1–6. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (5 and 6) were determined to be the most biologically potent, demonstrating GI50 values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI50 value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1–6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy. [ABSTRACT FROM AUTHOR]

A new series of cytotoxic platinum(IV) complexes (1–8) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes 1–8 were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely 4 and 6, eliciting an average GI50 value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, 4 exhibited the highest degree of potency amongst the derivatives, displaying a GI50 value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, 56MESS (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, 4 (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes' solubility, stability, lipophilicity, and reactive oxygen species production. [ABSTRACT FROM AUTHOR]

The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors. [ABSTRACT FROM AUTHOR]

Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7–870 μM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver β-glucosidase and β-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported the discovery of a simple conjugated cyano pharmacophore which had led to the development of (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (1), as a selective inhibitor of oestrogen receptor positive (ER+ve) human breast cancer cell line, MCF-7. Further exploration though modification of the acrylonitrile and aromatic substituents has highlighted key structural components necessary for broad spectrum cytotoxicity. The acrylic acid derivates (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylic acid (8) and (Z)-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid (9) were inactive; confirming the importance of the cyanide moiety. The most potent 2-phenylacrylonitriles synthesized were (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-3-yl)acrylonitrile (3) and (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-5-yl)acrylonitrile (20) with an average GI50 values of 1.4 and 0.53 μM respectively. Five additional (Z)-2-(3,4-dichlorophenyl)-3-(indolyl)acrylonitriles also displayed average GI50 values of ≤8.4 μM. In the case of indole 20, this represents a 32-fold increase in broad spectrum cytotoxicity relative to the lead (1). [Copyright &y& Elsevier]

Abstract: Cantharidin (1) and norcantharidin (2) display high levels of anticancer activity against a broad range of tumour cell lines. Synthetic manipulation of norcantharidin yields (3S,3aR,4S,7R,7aS)-3-hydroxyhexahydro-4,7-epoxyisobenzofuran-1(3H)-one (3), which also displays a high level of anticancer activity against tumour cells but interestingly, shows selectivity towards HT29 (colon; GI50 = 14 μM) and SJ-G2 (glioblastoma; GI50 = 15 μM) cell lines. Substitution at the hydroxyl group of the cyclic lactone within (3) produces a diasteromeric pair of products that have no difference in cytotoxicity over the cell lines tested. Incorporation of an isopropyl tail at this position (16) produced the most promising compound of this series to date, with strong selectivity towards HT29 (colon; GI50 = 19 μM) and SJ-G2 (glioblastoma; GI50 = 21 μM) cell lines but completely void of any activity against the remaining tumour cell lines (GI50 > 100 μM), as per the parent molecule. We also discovered that the introduction of a terminal phosphate moiety (28) at the same position produced a different trend in cytotoxicity with strong activity in BE2-C (neuroblastoma; GI50 = 9 μM) cells; suggestive of an alternate mode of action. [Copyright &y& Elsevier]

5-Fluorouracil (5-FU) is a commonly used anti-cancer drug with notable activity in clinical practice, yet it causes significant unpredictable and often serious toxicity. Both 5-FU and uracil (U) are catabolised by dihydropyrimidine dehydrogenase (DPD) to form dihydrofluorouracil (FUH2) and dihydrouracil (UH2), respectively. A means of predicting toxicity before treatment would be more valuable. Variations in dihydropyrimidine dehydrogenase (DPD) activity between patients are at least partly responsible for variable toxicity. Measurement of the UH2 to U ratio may be a measure of pyrimidine catabolism and thus be utilised to predict subsequent toxicity. We have developed an efficient extraction and detection method using HPLC for the simultaneous measurement of UH2 and U in plasma. A single C18 Spherisorb ODS2 (25 cm) column using isocratic elution was utilised. U, UH2 and the internal standard 4-chlorouracil were detected at wavelengths of 257, 220, and 268 nm, respectively. The chromatographic run time was 45 min which is half that of other methods. The detection limit was 0.02 μM for U and 0.1 μM for UH2 using only 0.5 ml of plasma for both compounds. The basal plasma concentrations of U and UH2 in 23 individuals ranged from 0.025 to 0.27 μM and 0.4–1.7 μM, respectively. This simple method may permit the assessment of pyrimidine catabolism, and therefore allow prediction of the toxicities associated with the use of fluorinated pyrimidines. [Copyright &y& Elsevier]

As part of our ongoing study of the specialised metabolites present in brown algae belonging to the Cystophora genus, eight new steroids including three pairs of diastereoisomers were isolated from Cystophora xiphocarpa (Harvey) (Sargassacea, Fucales). The metabolites identified by standard spectrometric methods are (16 S ,22 S)-16,22-dihydroxyergosta-4,24(28)-dien-3-one and (16 S ,22 R)-16,22-dihydroxyergosta-4,24(28)-dien-3-one, (16 S ,22 S ,24 R)-16,22,24-trihydroxyporifera-4,28-dien-3-one and (16 S ,22 S ,24 S)-16,22,24-trihydroxystigma-4,28-dien-3-one along with (16 S ,22 S ,24 E)-16,22-dihydroxystigma-4,24(28)-dien-3-one and (16 S ,20 S)-16,20-dihydroxyergosta-4,24(28)-dien-3-one. (16 S ,22 S ,24 E)-16,22-Dihydroxystigma-4,24(28)-dien-3-one possessed the most potent cytotoxicity of the steroids in this series with cell growth inhibitions of GI 50 8.7 ± 0.7 μM against colon cancer HT29, GI 50 5.6 ± 0.8 μM against the breast cancer line MCF-7 and GI 50 4.5 ± 0.2 μM against the ovarian cancer cell line A2780. (16 S ,22 R)-16,22-dihydroxyergosta-4,24(28)-dien-3-one was found to be active against the ovarian cancer cell line A2780 with a GI 50 of 6.2 ± 0.1 μM. [Display omitted] • The structure elucidation of new steroids from brown alga Cystophora xiphocarpa is reported. • The configuration of hydroxy substituents at carbon-22 was determined. • Significant activity against colon, breast and ovarian cancer was found. [ABSTRACT FROM AUTHOR]

Thiosemicarbazone Schiff bases 1 and 4 are useful lead candidates for future organic drug design development to treat cancers. Diphenyltin(IV) compounds 5, 8, 11 and 14 exhibited excellent cytotoxic activity against all the cancer cell lines tested. • Thiosemicarbazone Schiff bases 1 & 4 are useful lead candidates for anticancer drug development. • Diphenyltin(IV) compounds with trigonal bipyramidal geometry had excellent cytotoxicity. • Compounds 5, 8, 11 & 14 had the highest cytotoxicity against ten cancer cell lines tested. • Compounds 5, 8, 11 & 14 had low cytotoxicity against normal breast cancer cells MCF-10A. Twelve tin(IV) compounds (5 – 16) derived from four tridentate thiosemicarbazone Schiff bases of 4-methyl-3-thiosemicarbazide with 2-hydroxy-3-methoxybenzaldehyde (1, 2) and 4-phenyl-3-thiosemicarbazide with 2,3-dihydroxybenzaldehyde (3, 4) of the general formulae [R 2 Sn(L n)] and [Sn(L n) 2 ] (where R = Ph or Me; L n = 1 , 2 , 3 and 4) were synthesized and characterized by elemental analysis, IR, UV–vis, mass spectrometry and multinuclear NMR (1H, 13C and 119Sn) spectroscopy. X-ray crystallographic data was obtained for 11′ , a 2:1 co-crystal between Ph 2 Sn(L2) (11) and 3-methoxysalicylaldehyde azine, and Me 2 Sn(L2) (12) where L2H 2 is 2-(2-hydroxy-3-methoxybenzylidene)- N -phenylhydrazinecarbothioamide. The analysis revealed distinct coordination geometries for 11 and 12 approaching trigonal–bipyramidal. In the crystal of 11′ , supramolecular dimers arising from amine N H...S(thiolate) hydrogen bonding and {...HNCS} 2 synthons are evident; π(chelate ring)...π(oxidobenzylidene) stacking is also apparent. In the crystal of 12 , supramolecular, helical chains are generated by a combination of amine N H...O(phenoxide) hydrogen bonding and Sn...S secondary bonding. The cytotoxic activity of the compounds against a panel of ten cancer cell lines, [HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas), and one normal cell line, MCF-10A (normal breast)] were investigated. The thiosemicarbazone Schiff bases 1 and 4 as well as the diphenyltin(IV) compounds showed a strong ability to inhibit the growth of cancer cells, with particular selectivity against HT29, MCF-7, A2780, A431, BE2-C, SJ-G2 and MIA cell lines. The structure–activity relationship of all these compounds were studied by evaluating the effect of alkyl and aryl groups attached on the thiosemicarbazone backbone, the methoxy/hydroxyl groups present at the meta -position of the phenyl ring and alkyl or aryl groups bound to the tin center. [ABSTRACT FROM AUTHOR]

A series of tridentate ONS Schiff bases were synthesised via condensation by reacting 2,3-dihydroxybenzaldehyde with S-2-methylbenzyldithiocarbazate (S2MBDTC) (1), S-4-methylbenzyldithiocarbazate (S4MBDTC) (2) and S-benzyldithiocarbazate (SBDTC) (3) in an equimolar ratio (10 mmol). The Schiff bases were then reacted with diphenyltin(IV) and dimethyltin(IV) dichloride in an equimolar ratio (1 mmol) yielding six new organotin(IV) compounds (4–9). All the compounds were successfully characterised by elemental analysis, FT-IR, multinuclear NMR, UV–Vis, mass spectroscopy and molar conductivity. The molecular geometries for five compounds, 3, 5, 6, 8 and 9, have been established by X-ray crystallography. The five-coordinate geometry for each of the diorganotin molecules was defined by two carbon atoms from the tin-bound substituents as well as three donor atoms derived from the dinegative, tridentate dithiocarbazate ligands, namely thiolate-S, phenoxide-O and imine-N atoms. The resultant five-coordinate C2NOS geometries were intermediate between ideal square pyramidal and trigonal bipyramidal geometries. The diphenyltin(IV) compounds (4–6) exhibited particularly promising and selective cytotoxicity against the A2780 (ovarian), BE2-C (neuroblastoma), SJ-G2 (glioblastoma) and MIA (pancreas) cancer cell lines. The interactions of the compounds (4–9) with calf thymus (CT-DNA) were evaluated using an electronic absorption method, and 7, 8, 9 were found to have good DNA binding affinity. The molecular docking studies of compounds (4–9) with DNA revealed that the compounds interacted with duplex DNA via hydrogen bonding, hydrophobic and electrostatic interactions. [ABSTRACT FROM AUTHOR]

The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 ± 1.3 to 1.6 ± 0.3 μM) and CME (IC50(CME) = 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors. [ABSTRACT FROM AUTHOR]

Plants from the family Myoporaceae, which includes the genus Myoporum, are extremely prized by the Australian Aboriginal people for their medicinal properties. Leaves from a plant, which was subsequently identified as Myoporum montanum, were provided for chemical investigation by representatives of an Aboriginal community from the Northern Tablelands district of northern New South Wales, Australia. Acetone extraction of the leaves provided a complex mixture of compounds including sesquiterpene hydrocarbons and more polar furanosesquiterpenes, which were identified by gas-liquid chromatography and retention indices (sesquiterpene hydrocarbons) and spectrometric techniques (furanosesquiterpenes). The major compounds found in a water extract were studied for their antibacterial activity using a disc diffusion assay and for their cell growth inhibition activity. The acetone extract contained sesquiterpene hydrocarbons (~30% of the total extract) in which the major compounds were germacrene-D and bicyclogermacrene. In addition, the extract contained five known toxic furanosesquiterpenes: myoporum ketol, (-)-10,11-dehydroisomyodesmone, (+)-10,11-dehydromyodesmone, 10,11-dehydromyoporum ketol, (-)-10,11-dehydromyoporone, and (±)-myoporone. An aqueous extract of the leaves, emulating the medicinal tea used by the Australian Aboriginal community, was found not to contain significant quantities of the sesquiterpene hydrocarbons and the most toxic furanosesquiterpenes. (±)-Myoporone and (-)-10,11-dehydromyoporone remained in the extract as well as a new furanosesquiterpene, 11-hydroxymyoporone. These three compounds were found to have significant antibacterial activity against Staphylococcus epidermidis, Enterococcus faecalis, and Moraxella catarrhalis but low cytotoxicity against a range of cancer cell lines and normal breast cells at 25 μM. [ABSTRACT FROM AUTHOR]

We have developed six dihydroxidoplatinum(IV) compounds with cytotoxic potential. Each derived from active platinum(II) species, these complexes consist of a heterocyclic ligand (HL) and ancillary ligand (AL) in the form [Pt(HL)(AL)(OH)2]2+, where HL is a methyl-functionalised variant of 1,10-phenanthroline and AL is the S,S or R,R isomer of 1,2-diaminocyclohexane. NMR characterisation and X-ray diffraction studies clearly confirmed the coordination geometry of the octahedral platinum(IV) complexes. The self-stacking of these complexes was determined using pulsed gradient stimulated echo nuclear magnetic resonance. The self-association behaviour of square planar platinum(II) complexes is largely dependent on concentration, whereas platinum(IV) complexes do not aggregate under the same conditions, possibly due to the presence of axial ligands. The cytotoxicity of the most active complex, exhibited in several cell lines, has been retained in the platinum(IV) form. [ABSTRACT FROM AUTHOR]

Platinum anticancer complexes incorporating 2,2′-bipyridine (bpy), 4,4′-dimethyl-2,2′-bipyridine (44Me2bpy) or 2-(2′-pyridyl)quinoxaline (2pq) as polyaromatic ligands and the S, S or R, R isomer of 1,2-diaminocyclohexane as ancillary ligands in the form [Pt(PL)(AL)]2+ have been synthesised and characterised. X-ray diffraction was used to elucidate the structure and stacking behaviour of the complexes, revealing interesting properties that may impact their biological activity. Pulsed gradient spin-echo NMR experiments elucidated the aggregation behaviour of these complexes in solution. The cytotoxicity of each complex was assessed against the L1210 murine leukaemia, HT29 human colon carcinoma and U87 human glioblastoma cell lines and compared to other complexes within this class. The complexes incorporating 44Me2bpy were found to be the most potent at inhibiting cell growth with IC50 values for the S, S isomer (0.13-0.5 μ M) less than that for cisplatin (0.36-11 μ M), oxaliplatin (0.9-1.8 μ M) or carboplatin (>50 μ M). Most complexes were found to be very effective against HT29 colon carcinoma cells. [ABSTRACT FROM AUTHOR]

An efficient and divergent methodology for the synthesis of new anthracenone-pyranones and anthracenone-furans is described. Key reactions discussed in these syntheses include an aldehyde promoted annulation with a β-keto-sulfoxide, a domino alkyne insertion/carbonylation/Nu-acylation and a DMEDA promoted Castro–Stephens reaction. We also report the in vitro growth inhibition of these compounds in a range of human cancer cells. The natural product BE-26554A displayed good cell growth activity on BE2-C neuroblastoma and SMA glioblastoma cell lines at 0.17 and 0.16 μM (GI 50 ), respectively. Of note, were a CF 3 functionalised anthracenone 4-pyranone (chromone) derivative 22 , and an anthracenone-furan derivative 54 which displayed 0.20 μM and 0.38 μM growth inhibition, respectively, in the BE2-C neuroblastoma cell line. [ABSTRACT FROM AUTHOR]

Eucalyptus robusta (Sm.) (ER) is a widely distributed tree native to the east coast of Australia, which has also been established in numerous other countries. ER leaves contain high levels of essential oils and are rich in total phenolic compounds (TPC), which have been linked with health benefits; however, there is limited information on the bioactivity of ER leaf extracts. This study aimed to optimise water extraction conditions for TPC, prepare a spray-dried powdered extract and test its physicochemical, antioxidant and anti-proliferative properties. The results showed that optimal water extraction conditions for TPC were 85 °C, 15 min and a water-to-leaf ratio of 20:1 mL/g. Under these conditions, spray-dried powdered extract was prepared with a recovery yield of 85%. The extract was water-soluble and had a TPC level of 407 mg GAE/g. It also possessed potent antioxidant capacity, comparable to pure ascorbic acid, but higher than pure α-tocopherol. In addition, the powdered extract demonstrated significant activity against a panel of cancer cell lines, which included cancers of the pancreas, breast, lung, brain, skin, colon and ovary. Of note, the ER extract exerted a more significant toxic effect on pancreatic cancer (PC) cells compared to gemcitabine, the first line chemotherapeutic agent for PC. We suggest that future studies should purify individual bioactive compounds from ER for further investigation of its potential health promoting and anti-cancer activity. [ABSTRACT FROM AUTHOR]

Abstract: Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42μM in MCF-7 (breast) cells and 24μM in A2780 (ovarian) cells and >50μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of <5μM were observed with 4l against HT29 (colon) and SW480 (colon); 5a against HT29; and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active. [Copyright &y& Elsevier]

[Display omitted] Virtual screening identified N -(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI 50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total. Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF 3 and -C(CH 3) 3 substituents well tolerated (MiaPaCa-2 GI 50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI 50 values ranged from 1.4 to 30 μM against cohort-1 and 1.4–30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[ b ][1,4]dioxine (51) returned cohort-2 GI 50 values of 1.2–3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition. [ABSTRACT FROM AUTHOR]

Dynamin GTPase activity increases when it oligomerizes either into helices in the presence of lipid templates or into rings in the presence of SH3 domain proteins. Dynasore is a dynamin inhibitor of moderate potency ( IC50 ˜ 15 μM in vitro). We show that dynasore binds stoichiometrically to detergents used for in vitro drug screening, drastically reducing its potency ( IC50 = 479 μM) and research tool utility. We synthesized a focused set of dihydroxyl and trihydroxyl dynasore analogs called the Dyngo™ compounds, five of which had improved potency, reduced detergent binding and reduced cytotoxicity, conferred by changes in the position and/or number of hydroxyl substituents. The Dyngo compound 4a was the most potent compound, exhibiting a 37-fold improvement in potency over dynasore for liposome-stimulated helical dynamin activity. In contrast, while dynasore about equally inhibited dynamin assembled in its helical or ring states, 4a and 6a exhibited >36-fold reduced activity against rings, suggesting that they can discriminate between helical or ring oligomerization states. 4a and 6a inhibited dynamin-dependent endocytosis of transferrin in multiple cell types ( IC50 of 5.7 and 5.8 μM, respectively), at least sixfold more potently than dynasore, but had no effect on dynamin-independent endocytosis of cholera toxin. 4a also reduced synaptic vesicle endocytosis and activity-dependent bulk endocytosis in cultured neurons and synaptosomes. Overall, 4a and 6a are improved and versatile helical dynamin and endocytosis inhibitors in terms of potency, non-specific binding and cytotoxicity. The data further suggest that the ring oligomerization state of dynamin is not required for clathrin-mediated endocytosis. [ABSTRACT FROM AUTHOR]

Abstract: With our lead compound (E)-3-(4-chlorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (1) inducing 50% growth inhibition of 11 cancer cell lines at 27–61μM, potency enhancements were rapidly established through the synthesis of a series of focused compound libraries. Six highly focused libraries (46 compounds in total) were synthesised. Each library allowed the identification of a new lead compound, viz Library A identified (E)-3-(pentafluorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (11) and (E)-3-(1H-indol-3-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (13) as inhibitors with improved cytotoxicity. Synthesis of discrete libraries of amidoacrylamide analogues (Ar–C013;Ar✠Ar–C013;C(013;Ar) resulted in a series of analogues significantly more potent that the lead, 1. Three furan three analogues: (E)-3-(5-chlorofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (33), (E)-3-(5-bromofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (34) and (E)-2-cyano-3-(furan-3-yl)-N-(4-methoxybenzyl)acrylamide (37) returned broad spectrum growth inhibition (GI50 values of 5–16μM). Replacement of the furan moiety with simple aromatics gave an additional three analogues: (E)-2-cyano-N-(4-methoxybenzyl)-3-phenylacrylamide (39), (E)-3-(4-chlorophenyl)-2-cyano-N-(4-methoxybenzyl)acrylamide (41) and (E)-2-cyano-N-(4-methoxyphenyl)-3-(naphthalen-1-yl)acrylamide (45) with GI50 values of 7–24μM. The final library retained the aromatic substituents but introduced a 3,4-dichlorbenzylamine moiety to afford the 1-naphthyl substituted 52, which was the most potent broad spectrum cytotoxic analogue produced here in with an average GI50 =8.6μM. This represents a fivefold potency enhancement relative to 1 and a new cytotoxic scaffold suitable for further development. [Copyright &y& Elsevier]

Several norcantharidin derivatives (IV) are synthesized by substitution of the hydroxy group as well as further modifications in the side chain. [ABSTRACT FROM AUTHOR]

Abstract: A family of norcantharidin analogues possessing a terminal alcohol (ethanol, propanol, butanol, pentanol, hexanol and cyclohexanol) moiety were treated with either chlorodiethyl, chlorodiphenyl or chloro-bis-trichloroethyl-phosphate to afford highly focused libraries of the corresponding phosphate esters. Subsequent biological screening against a panel of nine human cancer cell lines identified a trend between the ease of phosphate unmasking (phosphate ester hydrolysis) and cell death. The most potent analogues possessed either a diphenyl or a bis-trichloroethyl moiety. The effect of alkyl spacer was also examined with the hexyl analogues typically more potent. 4-Aza-4-(3-{bis(2,2,2-trichloroethyl)phosphate}propyl)-10-oxatricyclo[5.2.1.0]decane-3,5-dione (10b) was the most potent analogue synthesised with an average GI50 of 11μM across a panel of nine human carcinoma cell lines: colon carcinoma (HT29 and SW480); breast carcinoma (MCF-7); ovarian carcinoma (A2780); lung carcinoma (H460); skin carcinoma (A431); prostate carcinoma (DU145); neuronal carcinoma (BE2-C) and brain carcinoma (SJ-G2). This represents a fivefold improvement in anti-proliferative activity relative to the lead, norcantharidin. [Copyright &y& Elsevier]

Summary: Clathrin-mediated endocytosis (CME) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling. [ABSTRACT FROM AUTHOR]

Abstract: With the major problems with resistance in parasitic nematodes of livestock to anthelmintic drugs, there is an urgent need to develop new nematocides. In the present study, we employed a targeted approach for the design of a series of norcantharidin analogues (n =54) for activity testing against the barber’s pole worm (Haemonchus contortus) of small ruminants in a larval development assay (LDA) and also for toxicity testing on nine distinct human cell lines. Although none of the 54 analogues synthesized were toxic to any of these cell lines, three of them (N-octyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B2), N-decyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B3) and 4-[(4-methyl)-3-ethyl-2-methyl-5-phenylfuran-10-oxa-4-azatricyclo[5.2.1]decane-3,5-dione (B21) reproducibly displayed 99–100% lethality to H. contortus in LDA, with LD50s of 25–40μM. The high ‘hit rate’ (5.6%) indicates that the approach taken here has advantages over conventional drug screening methods. A major advantage of norcantharidin analogues over some other currently available anthelmintics is that they can be produced in one to two steps in large amounts at low cost and high purity, and do not require any additional steps for the isolation of the active isomer. This positions them well for commercial development. [Copyright &y& Elsevier]

Abstract: Cantharidin (1) and norcantharidin (2) are potent protein phosphatase 1 and 2A inhibitors that also display high levels of anticancer activity against a broad range of tumor cells lines. Surprisingly, Δ-5,6-ethyl norcantharidin (3, cis-tetrahydrofurano[3,4-c]furan-1,3-dione) displays neither phosphatase inhibition nor anticancer activity. This suggests that the 5,6-ethyl bridge is pivotal to both anti-cancer and protein phosphatase activity. Additionally bioisosteric replacement of the ethereal oxygen has no effect on biological activity nor does modification of the anhydride moiety. Unlike the parent norcantharidin, anhydride ring opening has no effect on either protein phosphatase inhibition or anti-cancer activity. Additionally, this work highlights the discovery of the octyl substituted, cis-5-benzyl-2-hexyltetrahydro-2H,3aH-pyrrolo[3,4-c]pyrrole-1,3-dione, 9p, and the octyl substituted, cis-octyltetrahydro-5H-furo[3,4-c]pyrrole-4,6-dione, 8p, as two new cytotoxic agents which are equipotent (9p) with, and more potent (8p) than norcantharidin. [Copyright &y& Elsevier]

Telomerase activity is primarily determined by transcriptional regulation of the catalytic subunit, human telomerase reverse transcriptase (hTERT). Several mRNA splice variants for hTERT have been identified, but it is not clear if telomerase activity is determined by the absolute or relative levels of full-length (functional) and variant hTERT transcripts. We have developed an SYBR green-based reverse transcription-quantitative polymerase chain reaction assay for the enumeration of the four common hTERT mRNA variants and correlated these with telomerase activity and telomere length in 24 human melanoma cell lines. All except five of the lines expressed four hTERT transcripts, with an overall significant level of co-occurrence between absolute mRNA levels of full-length α+/β+ hTERT and the three splice variants α-/β+, α+/β-, and α-/β-. On average, α+/β+ made up the majority (48.1%) of transcripts, followed by α+/β- (44.6%), α-/β- (4.4%), and α-/β+ (2.9%). Telomerase activity ranged from 1 to 247 relative telomerase activity and correlated most strongly with the absolute amount of α+/β+ (R = 0.791, P = .000004) and the relative amount of α+/β- (R = -0.465, P = .022). This study shows that telomerase activity in melanoma cells is best determined by the absolute expression of full-length hTERT mRNA and indicates a role for the hTERT β deletion variant in the negative regulation of enzyme activity. [ABSTRACT FROM AUTHOR]

Abstract: Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low μM IC50s) comparable to that of norcantharidin (PP1 IC50 =10.3±1.37μM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC50 =2.69±1.37μM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC50 =6.5±2.3μM; and PP2A IC50 =7.9±0.82μM (PP1/PP2A=0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC50 =48±9; and PP2A IC5 85±3μM (PP1/PP2A=0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC50s of 89±6 and 42±3μM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date. [Copyright &y& Elsevier]

Abstract: A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9–43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H+; 23) or alternatively, osmylation (OsO4/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C10, C12 or C14 alkyl chain or a C12 linked bis-norcantharimide displayed the highest levels of cytotoxicity. [Copyright &y& Elsevier]

Abstract: Norcantharidin (3) is a potent PP1 (IC50 =9.0±1.4μM) and PP2A (IC50 =3.0±0.4μM) inhibitor with 3-fold PP2A selectivity and induces growth inhibition (GI50 ∼45μM) across a range of human cancer cell lines including those of colorectal (HT29, SW480), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (DU145), neuroblastoma (BE2-C), and glioblastoma (SJ-G2) origin. Until now limited modifications to the parent compound have been tolerated. Surprisingly, simple heterocyclic half-acid norcantharidin analogues are more active than the original lead compound, with the morphilino-substituted (9) being a more potent (IC50 =2.8±0.10μM) and selective (4.6-fold) PP2A inhibitor with greater in vitro cytotoxicity (GI50 ∼9.6μM) relative to norcantharidin. The analogous thiomorpholine-substituted (10) displays increased PP1 inhibition (IC50 =3.2±0μM) and reduced PP2A inhibition (IC50 =5.1±0.41μM), to norcantharidin. Synthesis of the analogous cantharidin analogue (19) with incorporation of the amine nitrogen into the heterocycle further increases PP1 (IC50 =5.9±2.2μM) and PP2A (IC50 =0.79±0.1μM) inhibition and cell cytotoxicity (GI50 ∼3.3μM). These analogues represent the most potent cantharidin analogues thus reported. [Copyright &y& Elsevier]

Fourteen modified norcantharidin analogues have been synthesised and screened for their ability to inhibit the serine/threonine protein phosphatases 1 and 2A. The most potent compounds found were 10 (PP1 IC50=13±5 μM; PP2A IC50=7±3 μM) and 16 (PP1 IC50=18±8 μM; PP2A IC50=3.2±0.4 μM). Overall, only analogues possessing at least one acidic residue at the former anhydride warhead displayed any PP1 or PP2A inhibitory action. The ability of these analogues to inhibit PP1 and PP2A correlates well with their observed anti-cancer activity against a panel of five cancer cell lines: A2780 (human ovarian carcinoma), G401 (human kidney carcinoma), HT29 (human colorectal carcinoma), H460 (human lung carcinoma) and L1210 (murine leukemia). [Copyright &y& Elsevier]

Diels–Alder addition of furans (furan, furfuryl alcohol, and 3-bromofuran) to maelic anhydride yields three distinct 5,6-dehydronorcantharidins. Hydrogenation of (4,10-dioxatricyclo[5.2.1.0]decane-3,5-dione) (4a), in dry ethanol affords the monoester (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic aid monoethyl ester) (6). Subsequent transesterification affords a series of monoesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monomethyl ester (7)), 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monopropyl ester (8), (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monohexyl ester (9)) and differentially substituted diesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-isopropyl ester) (10), and (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-phenyl ester) (11). Analogues were firstly screened for their ability to inhibit protein phosphatases 1 (PP1) and 2A (PP2A) as the lead compounds cantharidin (1) and norcantharidin (2) are known PP1 and PP2A inhibitors. Only analogues 4a, 6–8 displayed good PP1 and PP2A inhibition (PP1 IC50’s=2.0, 2.96, 4.71, and 4.82 μM, respectively; PP2A IC50’s=0.2, 0.45, 0.41, and 0.47 μM, respectively). All analogues were also screened for their anti-cancer potential against a panel of tumour cell lines, HL60, L1210, SW480, WiDr, HT29, HCT116, A2780, ADDP, and 143B, producing GI50 values ranging from 6 μM to >1000 μM. Analogues possessing good PP1 and/or PP2A inhibition also returned moderate to good anti-cancer activity. Analogues with substituents directly attached to the intact bicyclo[2.2.1]heptane skeleton were poor to moderate anti-cancer agents. This correlates well with their lack of PP1 or PP2A activity. Analogues capable of undergoing a facile ring opening of the anhydride or with a single carboxylate were good PP1 and PP2A inhibitors, largely correlating to the observed anti-cancer activity in all cases, except 11. Analogue 11, whist neither a PP1 nor a PP2A inhibitor shows anti-cancer activity comparable to 1 and 2. We believe that intracellular esterases generate the corresponding dicarboxylate, which is a potent PP1 and PP2A inhibitor, and that it is this species which is responsible for the observed anti-cancer activity. [Copyright &y& Elsevier]

Six new tin(IV) compounds derived from tridentate dinegatively charged ONS dithiocarbazate Schiff bases derived from 2-hydroxy-3-methoxybenzaldehyde (H 2 L1, H 2 L2 and H 2 L3) and 2,3-dihydroxybenzaldehyde (H 2 L4, H 2 L5 and H 2 L6) (where H 2 Ln = di-acids of Schiff base) are reported. The compounds were characterised by elemental analysis, FT-IR and multinuclear NMR (1H, 13C and 119Sn) spectroscopy. The crystal structures of tin(IV) S -4-methybenzyl- β - N -(2-hydroxy-3-methoxybenzylmethylene)dithiocarbazate] (2) and tin(IV) S -benzyl- β - N -(2-hydroxy-3-methoxy benzylmethylene)dithiocarbazate] (3) were determined by X-ray single crystal diffraction analysis. X-ray crystallography showed the molecular geometries in homoleptic 2 and 3 to be quite similar in which the dinegative tridentate ligand coordinated the tin atoms via thiolate-S, phenoxide-O and imine-N atoms. The coordination geometries are based on an octahedron with like-atoms mutually trans. The experimental findings were validated by density functional theory (DFT) calculations at the B3LYP/LanL2DZ/6-311G(d,p) level of theory. All the tin(IV) compounds, except the insoluble compound 2 were screened for their in vitro cytotoxicity against a panel ten of cancer cell lines and one normal breast cell line (MCF-10 A) by MTT assay. Interestingly, the cytotoxicity of five tin(IV) compounds against HT29, MCF7 and MIA was higher than the reference drug, cisplatin. Image 1 • Octahedral homoleptic tin(IV) compounds were synthesised and evaluated for in vitro cytotoxicity against ten cancer cells. [ABSTRACT FROM AUTHOR]