Design and synthesis of novel ß-carboline-bisindole hybrids as potential anticancer agents.

We are reporting a short and convenient pathway for the synthesis of novel ß-carboline-bisindole hybrid compounds from relatively cheap and commercially available chemicals such as tryptamine, dialdehydes and indoles. These newly designed compounds can also be prepared in high yields with the tolerance of many functional groups under mild conditions. Notably, these ß-carboline-bisindole hybrid compounds exhibited some promising applications as anticancer agents against the three common cancer cell lines MCF-7 (breast cancer), SK-LU-1 (lung cancer), and HepG2 (liver cancer). The two best compounds 5b and 5g inhibited the aforementioned cell lines with the same range of the reference Ellipticine at less than 2 µM. A molecular docking study to gain more information about the interactions between the synthesized molecules and the kinase domain of the EGFR was performed. Therefore, this finding can have significant impacts on the development of future research in medicinal chemistry and drug discovery.

Imidazole[1,5-a]pyridine derivatives as EGFR tyrosine kinase inhibitors unraveled by umbrella sampling and steered molecular dynamics simulations.

Although the use of the tyrosine kinase inhibitors (TKIs) has been proved that it can save live in a cancer treatment, the currently used drugs bring in many undesirable side-effects. Therefore, the search for new drugs and an evaluation of their efficiency are intensively carried out. Recently, a series of eighteen imidazole[1,5-a]pyridine derivatives were synthetized by us, and preliminary analyses pointed out their potential to be an important platform for pharmaceutical development owing to their promising actions as anticancer agents and enzyme (kinase, HIV-protease,…) inhibitors. In the present theoretical study, we further analyzed their efficiency in using a realistic scenario of computational drug design. Our protocol has been developed to not only observe the atomistic interaction between the EGFR protein and our 18 novel compounds using both umbrella sampling and steered molecular dynamics simulations, but also determine their absolute binding free energies. Calculated properties of the 18 novel compounds were in detail compared with those of two known drugs, erlotinib and osimertinib, currently used in cancer treatment. Inspiringly the simulation results promote three imidazole[1,5-a]pyridine derivatives as promising inhibitors into a further step of clinical trials.

Facile iodine-promoted synthesis of bis(1-imidazo[1,5-a]pyridyl)arylmethanes and exploration of applications.

A practical strategy for the iodine-promoted synthesis of bis(1-imidazo[1,5-a]pyridyl)arylmethane and its derivatives has been developed. These compounds exhibit high cytotoxicity toward various cancer cell lines and moreover they are promising ligands for the Cu-catalysed synthesis of quinolines.

Reaction of 1-acetonaphthones with anilines and elemental sulfur: rapid construction of 1-anilinonaphtho[2,1-b]thiophenes.

1-Anilinonaphtho[2,1-b]thiophenes could be conveniently synthesized from a three-component reaction of 1-acetonaphthones with anilines and elemental sulfur under catalyst-free simple heating conditions.

Cu-catalyzed Synthesis of Quinolines by Dehydrogenative Reaction of 2-Aminobenzyl Alcohol and Ketones: A Combined Experimental and Computational Study.

Quinoline derivatives are important moieties in bioactive molecules and advanced materials. However, an efficient strategy to synthesize quinoline derivatives remains challenging. Herein, we describe an efficient and practical method for the synthesis of quinolines by Cu-catalyzed cyclization of 2-amino benzyl alcohol with ketones (or secondary alcohols) via an acceptorless dehydrogenation pathway. Interestingly, a range of highly functionalized quinolines is prepared in good yields using low catalyst loading under relatively mild conditions. Furthermore, density functional theory (DFT) calculations are carried out to investigate mechanistic insights for the acceptorless dehydrogenation pathway.

Hetero- and homoleptic binuclear gold(I)-thiolate and -halide complexes - ligand exchange kinetics and supramolecular structures.

Heteroleptic and homoleptic binuclear Au(I) complexes [Au2(µ-PAnP)(SPh)(X)] (X = Cl- or Br-), [Au2(µ-PAnP)(SPh)2] and [Au2(µ-PAnP)(SPhCO2H)2] (SPh = benzenethiolate and SPhCO2H = 4-thiolatobenzoic acid) containing the bridging diphosphine, 9,10-bis(diphenylphosphino)anthracene (PAnP), were synthesized and characterized by single crystal X-ray diffraction. [Au2(µ-PAnP)(SPh)2] exists as a monomer in its crystals but [Au2(µ-PAnP)(SPhCO2H)2] polymerizes into zig-zag chains via intermolecular hydrogen bonding. [Au2(µ-PAnP)(SPh)(Cl)] forms cyclophane-like dimers of Ci symmetry in crystals via intermolecular aurophilic interactions (Au-Au distance = 3.3081(5) Å). Recrystallization of [Au2(µ-PAnP)(SPh)(Br)] invariably led to crystals composed of [Au2(µ-PAnP)(SPh)(Br)] and [Au2(µ-PAnP)(Br)2]. Despite the chemically different P atoms in the heteroleptic [Au2(µ-PAnP)(SPh)(Cl)] and [Au2(µ-PAnP)(SPh)(Br)], solutions of the complexes show only a single signal in their 31P{1H} NMR spectra at room temperature which resolved into two singlets of equal intensity at 183 K. Identical signals which show the same thermal behavior were observed in solutions of [Au2(µ-PAnP)(SPh)2] and [Au2(µ-PAnP)(X)2] in 1 : 1 molar ratios, indicating that there are three exchanging species, [Au2(µ-PAnP)(SPh)(X)], [Au2(µ-PAnP)(SPh)2] and [Au2(µ-PAnP)(X)2], in solution. A solution of [Au2(µ-PAnP)(Cl)2] and [Au2(µ-PAnP)(Br)2] in 1 : 1 molar ratio shows two singlets, implying that the exchange is not due to the dissociation of either PAnP or halide ligands, but rather it involves the exchange of the thiolate and the halide ligands (SPh- ↔ X-). A mixture of [(PPh3)Au(SPh)] and [(PPh3)Au(Cl)] (1 : 1 molar ratio) showed only one signal in its room temperature 31P{1H} NMR spectrum, indicating that the ligand exchange can happen intermolecularly. Self-exchange of SPh- ligands is possible as the room temperature 31P NMR spectrum of a mixture of [Au2(µ-PAnP)(SPh)2] and [Au2(µ-PAnP)(SPhCO2H)2] displayed only one signal. The rate constants of the exchange were determined by fitting the line shapes of the 31P NMR signals at different temperatures. The activation energies (Eas), obtained from Arrhenius plots, for the SPh- ↔ Cl- and SPh- ↔ Br- exchange are 36.9 ± 0.7 and 33.7 ± 1.0 kJ mol-1, respectively. The activation enthalpy and activation entropy, obtained from Eyring plots, for the SPh- ↔ Cl- and SPh- ↔ Br- exchange are 35.0 ± 0.7 kJ mol-1 and -25.7 ± 3.2 J K-1, and 32.0 ± 1.0 kJ mol-1 and -21.8 ± 4.7 J K-1, respectively. Based on the kinetic results, two possible mechanisms were proposed for the reactions.

A dynamic tetranuclear gold(i)-cyclophane - gold(i)-centred chirality and fluxionality arising from an intramolecular shift of Au-S bonds.

A tetranuclear gold(i) complex [Au4(µ-PAnP)2(µ-L)2] (PAnP = 9,10-bis(diphenylphosphino)anthracene and L = benzene-1,2-dithiolate) has been synthesized and characterised by multinuclear NMR and X-ray crystallography. The molecule has a cyclophane-like structure which can be considered to be composed of two [Au2(µ-PAnP)(µ-L)] units held together by Au-S bonds and aurophilic interactions (Au-Au = 3.0712(2) Å). L acts as a chelating and bridging ligand with one of its S atoms bonded to two Au ions as sulfonium ions and there are two Au2S2 cores on each side of the cyclophane. A sulfur atom in each Au2S2 core is a chiral sulfonium ion, being bonded to two chemically distinct Au ions. Two Au ions are bonded to four atoms (2S, P and Au) in an asymmetric environment, making them a rare example of gold(i)-centred chirality. The two Au2S2 cores have RAu, RS and SAu, SS configurations, and the chiralities of the sulfonium ion and the gold ion are correlated. Variable-temperature NMR spectroscopy showed that the metallacyclophane undergoes rapid exchange in solution. A bond shift mechanism involving simultaneous cleavage and formation of Au-S bonds is proposed for the exchange.

Health risk assessment related to cyanotoxins exposure of a community living near Tri An Reservoir, Vietnam.

Cyanotoxins released by cyanobacteria are currently a concern due to potential impacts on plants, animals, and human health. Many instances of cyanotoxin poisoning have been reported around the world, including acute, chronic, and fatal cases. In recent years, the Tri An Reservoir (TAR) in Vietnam has experienced influxes of cyanotoxins from toxic blue-green algae at levels which exceed the World Health Organization's (WHO) permitted level of 1 µg/L. Previous studies have focused on assessing cyanobacterial diversity, the presence of cyanotoxins in water, or the effect on aquatic plants and animals. Therefore, this study aims to assess the health risks associated with cyanobacteria exposure for people living near the TAR in Dong Nai Province, Vietnam, using the Monte Carlo simulation technique. In total, 120 water samples were collected at five points of the reservoir from 2017 to 2019. Seventy-five local people who have been exposed to the water from the reservoir were interviewed. Microcystin (MC) concentration was measured with a high-pressure liquid chromatography (HPLC) system and was used to assess the health risk to local people. The results showed that the MC concentration in raw water ranged from below detection limit (BDL) to 18.67 µg/L in 2017 and from BDL to 8.6 µg/L in 2019, with the predominant variant being MC-RR. The concentration of MCs in the TAR in 2017 and 2019 exceeded the WHO's permitted level of 1 µg/L by 76% and 19%, respectively. The results showed that the rate of MC exposure likely to cause cancer was approximately 1-5%. The oral exposure rate while bathing was less than 2.5%. Direct oral exposure of cyanobacteria with no carcinogenicity was relatively high (40-50%) and the most affected group was adults.

Robotic Radical Hysterectomy for Cervical Adenocarcinoma after Preoperative Brachytherapy in 10 Steps.

STUDY OBJECTIVE: Minimally invasive surgery decreases postoperative morbidity after radical hysterectomy (RH) for early-stage cervical cancer. However, a randomized trial and large retrospective data question its safety after observing lower rates of survival than open surgery [1,2]. The causes of this higher recurrence rate are not definitely established but may result from cancer exposure to the peritoneum during vaginal section and cancerous cells' spillage enhanced by pneumoperitoneum or a uterine manipulator. The aim of this surgical video was to present a standardized step-by-step approach for robotic RH according to the recent recommendations from the ARCAGY -Group of National Investigators for the Study of Ovarian and Breast Cancers surgeon's group [3]. DESIGN: Step-by-step video demonstration of the technique. SETTING: Tertiary center specialized in gynecologic oncology and minimally invasive surgery. INTERVENTIONS: A 48-year-old woman was diagnosed with a stage IB2 endocervical adenocarcinoma (International Federation of Gynecology and Obstetrics 2018) with a tumor size of 27 mm. Surgery was planned after preoperative pulsed dose rate uterovaginal brachytherapy. Surgery was performed following 10 reproducible steps: • Pelvic sentinel node identification according to the SENTICOL-III trial • Right infundibulopelvic and round ligaments transection • Right uterine vessels transection • Parametrectomy • Right uterosacral ligament transection • Bladder mobilization • Identical left dissection • Rectovaginal space development • Colpectomy by vaginal route after complete pneumoperitoneum exsufflation • Robotic vaginal cuff closure and pelvic inspection Thorough robotically assisted vaginal cuff closure was carried out as a comparative study suggesting that abdominal closure may decrease vaginal complications and dehiscence [3]. CONCLUSION: No international recommendations for the RH approach have yet been endorsed. Patients must be clearly informed about the benefit-risk ratio of the surgical route. If a minimally invasive RH is still decided, the patient should be referred to experienced centers, and precautionary measures must be implemented [4]. Colpotomy by vaginal route without pneumoperitoneum is recommended. Uterine manipulators have to be strictly avoided. Preoperative brachytherapy has been reported in experienced centers in France with favorable histologic response with high rates of pathologic complete response (near 70%) and seems particularly worthwhile for tumor sizes ranging from 2 to 4 cm or presenting with lymphovascular invasion [5].

Coupling d6 Ir(III) and d8 Pt(II) Chromophores.

Two classes of widely studied luminescent metal complexes are octahedral d6 (i.e., Ir3+) and square planar d8 (i.e., Pt2+) polypyridyl complexes, which have distinctly different photophysics and photoreactivity. In this study we report a series of d6-d8 IrIII-PtII hybrid complexes arising from coordination of metalloligands IrL2(benzene-1-thioether-2-thiolate) or Ir(L)2(benzene-1,2-dithiolate) anion [L = 2-phenylpyridine (ppy), 2-(2,4-difluorophenyl)pyridine (dfppy), or 1-phenylisoquinoline (piq)] to Pt(terpy)2+ (terpy = 2,2':6',2″-terpyridine). X-ray crystal structures of the Ir-Pt complexes show the IrL2 and Pt(terpy) chromophores are cofacially oriented with interplanar distances of 3.268-3.442 Å. Density functional theory (DFT) calculations show that the highest occupied molecular orbital and the lowest unoccupied molecular orbital are localized in the IrL2 and the Pt(terpy), respectively. All the complexes display a low-energy absorption band (λmax = 460-534 nm, εmax = (0.75-2.13) × 103 M-1 cm-1), which is attributed to interchromophore-charge-transfer (ICCT) transition, according to time-dependent DFT calculations. The 3ICCT excited state is emissive, giving long-lived phosphorescence that reaches as low as near-infrared (λmax = 668-710 nm, τ = 0.17-0.79 µs).

Heteroleptic nickel(ii)-diNHC complexes and an unusual 'reverse' carbene-transfer reaction to silver(i).

A series of rare [NiX2(MeCCprop)] complexes bearing the cis-chelating benzimidazole-derived dicarbene ligand MeCCprop and varying anionic coligands (2, X = N3; 3, X = NCS; 4, X = I; 5, X = O2CCF3) have been prepared and coligand dependent structural and spectroscopic features have been evaluated. This study also revealed an unusual 'reverse' carbene transfer reaction from nickel to silver giving the disilver species [Ag2X2(µ-κ2-MeCCprop)] (6, X = OAc; 7, X = O2CCF3). A preliminary catalytic study of two representative NiII diNHC complexes in the aqueous and phosphine-free Suzuki-Miyaura coupling reaction of aryl halides is reported as well. These reactions provide good yields of coupling products, but do not require inert conditions.

Comparative Risk of Liver and Intestinal Fluke Infection from Either Wild-Caught or Cultured Fish in Vietnam.

A survey for fish-borne zoonotic trematode (FZT) metacercariae in fish from the Northern Mountain Region of Vietnam was conducted from May to August 2014. The major objective was to evaluate the impact of water body types on the prevalence of FZT. A total of 846 fish (31 species) were collected from three water body types, including aquaculture ponds, rivers, and reservoirs. A pepsin digestion method was used for the recovery of metacercariae from fish. Overall, 29 of the 31 fish species were infected with FZTs. Prevalence was 56.8% in river fish, 46.7% in pond fish, and 29.3% in reservoir fish. The prevalence of Clonorchis sinensis metacercariae was 10.6% in reservoir fish, and 2.6% in river fish; fish from ponds were uninfected. The infection intensity of C. sinensis was 29.7 metacercariae/reservoir fish and 2.1 metacercariae/river fish. The prevalence of C. sinensis was highest (25.9%) in Toxabramis houdemeri. The intestinal flukes Haplorchis pumilio, Haplorchis taichui, Haplorchis yokogawai, Centrocestus formosanus and Procerovum varium were recovered from 29 fish species, with an overall prevalence of 46.8% and a mean infection intensity of 23.6 metacercariae. The results indicate that a C. sinensis sylvatic cycle involving wild fish species is important in the epidemiology of liver fluke and that consumption of raw or inadequately prepared wild-caught fish is a the major risk factor for human Clonorchiasis in this region. Both wild-caught and cultured fish present a high risk for infection with intestinal flukes. The habitat requirements of the snail host may be the important determining factor in favoring a sylvatic cycle of C. sinensis. This information is relevant to the development of effective prevention and control strategies, and emphasizes the priority that must be given to education of the local communities on the risks of consuming raw or improperly prepared fish dishes.

Ir(2-phenylpyridine)2(benzene-1,2-dithiolate) anion as a diastereoselective metalloligand and nucleophile: stereoelectronic effect, spectroscopy, and computational study of the methylated and aurated complexes and their oxygenation products.

The anionic complex [Ir(2-phenylpyridine)2(benzene-1,2-dithiolate)](-) ([IrSS](-)) is a nucleophile and metalloligand that reacts with methyl iodide and AuPR3(+) (R = Ph or Et) to form S-methylated complexes (thiother-thiolate and dithiother complexes) and S-aurated complexes, respectively. The reactions are completely diastereselective, producing only the enantiomers ΛS and ΔR or ΛSS and ΔRR. The diastereoselectivity is stereoelectronically controlled by the orientation of the highest occupied molecular orbital (HOMO) of [IrSS](-) arising from filled dπ-pπ antibonding interactions, and the chirality of the iridium ion. Methylation or auration removes the high-energy lone pair of the thiolate S atom, leading to low-lying HOMOs composed mainly of the Ir d-orbital and the 2-phenylpyridine π (ppyπ) orbital. The methylated and aurated complexes can be oxidized by H2O2 or peracid to give sulfinate-thiother, disulfoxide, and sulfinate-sulfoxide complexes, and the oxygenation further stabilizes the HOMO. All the complexes are luminescent, and their electronic spectra are interpreted with the aid of time-dependent density functional theory calculations. The thiother-thiolate complex exhibits ligand(S)-to-ligand(π* of ppy)-charge-transfer/metal-to-ligand-charge-transfer absorption (LLCT/MLCT) and a relatively low-energy (3)LLCT/MLCT emission, while the other complexes display (3)ππ*/MLCT emissions.

Synthesis and spectroscopy of anionic cyclometalated iridium(III)-dithiolate and -sulfinates--effect of sulfur dioxygenation on electronic structure and luminescence.

A new anionic heteroleptic Ir(III)-dithiolate complex Ir(ppy)2(benzene-1,2-dithiolate) (ppy = 2-phenylpyridine, [IrSS](-)) undergoes very fast air oxidation to form a monosulfinate complex [IrSSO2](-), which can be further dioxygenated by O2 or H2O2 to give a disulfinate complex [IrSO2SO2](-), which has been characterized by X-ray crystallography. The dioxygenation is accompanied by changes in the electronic structures of the complexes, leading to blue shift of emission from [IrSS](-) (λ(max) = 665 nm) to [IrSSO2](-) (λ(max) = 556 nm) and to [IrSO2SO2](-) (λ(max) = 460 nm). The molecular and electronic structures of the complexes are probed by DFT calculations. Time-dependent DFT (TD-DFT) calculations show the lowest energy spin-allowed electronic transitions for [IrSS](-) and [IrSSO2](-) are mainly ligand (3p orbital of S)-to-ligand (π* orbitals of ppy)-charge-transfer transition, whereas the lowest energy electronic transition in [IrSO2SO2](-) is predominantly metal-to-ligand-charge transfer in nature.

Formation of Tetrahydrofuran Derivatives and Acetonylation of Alkenes Using Carbon Radicals Derived from Manganese(III) Oxidation of Diketene.

Oxidation of a mixture of diketene and a 1,1-diarylethene 1 with manganese(III) acetate dihydrate gave an equilibrium mixture of 5-hydroxy-2-pentanone 2 and a tetrahydrofuran-2-ol, which was subsequently dehydrated in glacial acetic acid to yield 4-penten-2-one 4 in good yield. A similar reaction in the presence of alcohols or amines afforded 2-alkoxy-2-methyltetrahydrofurans 5 or 3-acetyl-2-aminodihydrofurans 9 in moderate yields. Diketene reacted with manganese(III) acetate in the presence of nucleophiles, such as water and alcohols, to give a mixture of unconjugated manganese(III) enolate A and conjugated manganese(III) enolate B. Major products 4 and 5 were formed by the oxidation of the conjugated manganese(III) enolate B. Tetrahydrofurylideneacetates 3 and 7 derived from the unstable unconjugated enolate A were also obtained as minor products. The reaction pathways are discussed.