Synthesis,characterization, and miRNA-mediated PI3K suppressing activity of novel cisplatin-derived complexes of selenones

New therapeutic options are crucially for most cancers, particularly those with poor clinical outcomes. Five new derivatives of cisplatin-containing selenone ligands with the general formula, cis-[Pt(NH₃)₂(Selenone)₂](NO₃)₂ (1–5) were synthesized and characterized using elemental analysis, Infrared, and nuclear magnetic resonance (¹H, ¹³C & ⁷⁷Se) spectroscopy. Spectroscopic and computational data supported the coordination of selenones to platinum(II). The structures of the complexes were predicted using density functional theory calculations. Molecular docking studies were carried out using the AutoDock Tools docking program. The in vitro cytotoxicity of these complexes and cisplatin against three human cancer cell lines, HeLa, A549, and HCT116 was investigated using the MTT assay. The best candidate complex, complex 3, was subjected to mechanistic assessments, including miRNA profiling, PI3K deactivation, and induction of apoptosis. Docking studies showed that all the newly synthesized platinum(II) complexes interacted with the minor DNA groove. The synthesized complexes showed promising cytotoxic effects against the tested cell lines. Complex 3 modulated the miRNA expression signature in A549 cells. Pathway enrichment analyses of differentially expressed miRNA gene targets identified the PI3K/AKT signaling pathway as a promising target. Complex 3 inhibited PI3K activity and induced apoptosis. Collectively, our study identified promising new platinum(II) derivatives such as complex 3, paving the way for future in vitro and in vivo validations and safety studies.     

A rearranged seco-steroid with new skeleton and five new abnormal progesteroids from Nodulisporium sp.

Abeo-nodulisporisteroid A (1), an abnormal steroid with a rearranged C3 chain at C-9 possibly derived from seco-ring A via Wagner-Meerwein rearrangement and oxidations, was obtained from Nodulisporium sp. together with five related new seco-progesteroids (nodulisporisteroids M-Q, 2–6), which were elucidated by the extensive spectroscopic analysis and X-ray crystallography. A plausible biosynthetic pathway of 1–6 was also proposed. Furthermore, these isolated compounds were also evaluated for cytotoxicities against five human tumour cell lines, antimicrobial activities, and inhibitions against PI3K gamma, Aβ₄₂ aggregation, and α-glucosidase.     

Donor-acceptor-donor triads incorporating tetrathiafulvalene and perylene diimide units: synthesis, electrochemical and spectroscopic studies

Three donor-acceptor-donor triads 1-3 consisting of tetrathiafulvalene units attached to perylene diimides by flexible and rigid spacers were synthesized and characterized. UV/vis spectroscopic and cyclic voltammetric results indicate that they all show negligible intramolecular charge transfer interaction in their ground states. As compared to the reference compound 21, triads 1-3 display reduced fluorescence and their fluorescence lifetimes are shortened, which is probably owing to the photoinduced electron transfer interactions between the PI units and TTF units. The different photophysical behaviors between 1 and 2 (and 3) might be due to their difference in the spatial separation of TTF and PI units. It is preliminarily found that the steric hindrance of the groups attached to TTF units can affect their photostability.     

Convergent synthesis of a common pentasaccharide-repeating unit corresponding to the O-specific polysaccharide of Escherichia coli O4:K3, O4:K6, and O4:K12

A convergent chemical synthesis of a pentasaccharide found in the O-specific polysaccharide of Escherichia coli O4:K3, O4:K6, and O4:K12 has been achieved in excellent yield. A [3+2] block synthetic strategy has been adopted to couple a disaccharide donor 11 with a trisaccharide acceptor 10 for the construction of the pentasaccharide derivative 12 which on deprotection furnished target pentasaccharide 1 as its 4-methoxyphenyl glycoside. Disaccharide thioglycoside donor 11 and trisaccharide acceptor 10 were prepared from suitably protected monosaccharide intermediates. Yields were excellent in all steps.     

Die Zersetzungsreaktion des Dialan-Radikalanions [R2Al-AlR2]·− in DME: I. Kristallstrukturen von R2Al(Me)OC2H4OMeK(DME) und R2Al(OC2H4OMe)2K (R  CH(SiMe3) 2)

Tetrakis[bis(trimethylsilyl)methyl]dialane(4) (1) reacts as recently reported with potassium in 1,2-dimethoxyethane (DME) to yield after purification the surprisingly stable radical monoanion [R₂AlAlR₂]·⁻ [K(DME)₃]⁺ (2) (R  CH(SiMe₃)₂). With a longer reaction time of some days at room temperature and an excess of potassium, however, complete decomposition occurs under cleavage of ether molecules and formation of several new products. One of these compounds was identified as R₂AlMe(OC₂H₄OMe)K(DME) (3) and characterized by a crystal structure determination. Two further derivatives were synthesized and their spectroscopic data compared to the decomposition products: R₂Al(OC₂H₄OMe)₂K (6), also characterized by crystal structure determination, and [R₂AlMe₂]⁻ [K(DME)₆]⁺ (9), but due to the NMR characterization only 9 could be a component of the above-mentioned reaction mixture. In both aluminium alcoholates (3 and 6) the potassium ion is bound in a chelating manner by oxygen atoms of the aluminate unit, probably for this reason they are very soluble in non-polar solvents. In the solid state 3 polymerizes by intermolecular K…H₃CAl bridges forming one-dimensional chains along a crystallographic glide plane, and 6 forms dimers via KOK bridges and fourfold coordinated oxygen atoms.     

Identification of new dual spleen tyrosine kinase (Syk) and phosphoionositide-3-kinase δ (PI3Kδ) inhibitors using ligand and structure-based integrated ideal pharmacophore models

Owing to the complex pathophysiology of autoimmune disorders, it is very challenging to develop successful treatment strategies. Single-target agents are not desired therapeutics for such multi-factorial disorders. Considering the current need for the treatment of complex autoimmune disorders, dual inhibitors of Syk and PI3Kδ have been designed using ligand and structure-based molecular modelling strategies. In the present work, structure and ligand-based pharmacophore modelling was implemented for a varied set of Syk and PI3Kδ inhibitors. Ligand-based pharmacophore models (LBPMs) were developed for two kinases: ADPR.14 (r²_train = 0.809) for Syk, comprising one hydrogen bond acceptor, one hydrogen bond donor, one positive ionisable and one ring aromatic feature, and for PI3Kδ: AAARR.45 (r²_train = 0.942) consisting of three hydrogen bond acceptor and two ring aromatic features. The generated e-pharmacophore models revealed an additional ring aromatic and hydrophobic feature important for Syk and PI3Kδ inhibition, respectively. Subsequently, LBPMs were modified resulting in APDRR.14 hypothesis for Syk inhibitors and AAAHRR.45 hypothesis for PI3Kδ inhibitors employed for virtual screening. Thus, the combination of ligand and structure-based pharmacophore modelling helped in developing ideal pharmacophore models that may be an efficient tool for the designing of novel dual inhibitors of Syk and PI3Kδ.     

Phomactins K–M,three novel phomactin-type diterpenes from a marine-derived fungus

Three novel diterpenes, phomactins K–M (1–3), were isolated from the cultures of an unidentified marine-derived fungus. The structures of 1–3 were elucidated from spectroscopic data (NMR, MS, IR), and the absolute configurations of 1, 2, and the relative configuration of 3 were determined by X-ray diffraction analysis.     

Novel asymmetric total syntheses of (R)-(−)-pyridindolol, (R)-(−)-pyridindolol K1, and (R)-(−)-pyridindolol K2 via a mild one-pot aromatization of N-tosyl-tetrahydro-β-carboline with (S)-2,3-O-isopropylidene-l-glyceraldehyde as the source of chirality

Novel total syntheses of (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 are described. By using l-tryptophan methyl ester and (S)-2,3-O-isopropylidene-l-glyceraldehyde as the starting materials, (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 were synthesized in 5–7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-β-carboline (N-Ts-THBC), which was obtained via Pictet–Spengler reaction of l-tryptophan methyl ester with (S)-2,3-O-isopropylidene-l-glyceraldehyde, and subsequent N-tosylation.     

Coordination enhancement of single-molecule magnet behavior of Tb(III)–Cu(II) dinuclear systems

Tb(III)–Cu(II) based single-molecule magnets (SMMs) were synthesized to investigate the relationship between magnetic anisotropy and the symmetry of the ligand field, by the reaction of [TbCu(o-vanilate)₂(NO₃)₃] with 2,2-dimethyl-1,3-propanediamine (3), followed by the reaction of one another equivalent of o-vaniline (4). Both complexes behave as SMM in the temperature range of 2.8–4.0 K (3) and 2.8–5.2 K (4), showing semi-circle shapes of Cole–Cole plots with α parameters in the ranges of 0.27–0.41 and 0.11–0.32. The energy barriers Δ/k_B for the spin flippings were estimated from the Arrhenius plots to be 29(2) K for 3 and 32.2(6) K for 4, respectively.     

Euphorane C,an unusual C17-norabietane diterpenoid from Euphorbia dracunculoides induces cell cycle arrest and apoptosis in human leukemia K562 cells

Four new polycyclic diterpenoids euphoranes A ? D (1–4), together with 12 known terpenoids (5–16) were isolated from the whole plants of Euphorbia dracunculoides. Compound 2 represents the first example of aromatic 15,16,17-trinorabietane diterpenoid in Euphorbia species, and euphorane C (3) is an unusual 17-norabietane diterpenoid. The absolute configurations of 1, 2, and 4 were determined by single crystal X-ray diffraction, while that of 3 was established with the aid of ECD and 1D NMR quantum chemical calculation. Moreover, the absolute stereochemistry of 11 was demonstrated for the first time by crystallographic data. Compounds 1–16 were screened for antiproliferative activities against five human cancer cell lines, and 3 showed significant cytotoxicity against the human leukemia K562 cells with IC₅₀ value of 3.59 μM. Preliminary mechanistic investigation revealed that 3 could induce cell cycle arrest at G0/G1 phase and apoptosis in K562 cells.     

Consensus model for identification of novel PI3K inhibitors in large chemical library

Phosphoinositide 3-kinases (PI3Ks) inhibitors have treatment potential for cancer, diabetes, cardiovascular disease, chronic inflammation and asthma. A consensus model consisting of three base classifiers (AODE, kNN, and SVM) trained with 1,283 positive compounds (PI3K inhibitors), 16 negative compounds (PI3K non-inhibitors) and 64,078 generated putative negatives was developed for predicting compounds with PI3K inhibitory activity of IC₅₀ ≤ 10 μM. The consensus model has an estimated false positive rate of 0.75%. Nine novel potential inhibitors were identified using the consensus model and several of these contain structural features that are consistent with those found to be important for PI3K inhibitory activities. An advantage of the current model is that it does not require knowledge of 3D structural information of the various PI3K isoforms, which is not readily available for all isoforms.     

Synthesis and anti-tumor activity evaluation of novel podophyllotoxin derivatives

In order to investigate the effects on the cytotoxicity of indole-3-oxalylamino podophyllotoxin analogs, seven novel podophyllotoxin derivatives were synthesized.The compounds were tested against Hela, K562 or K562/A02 cancer cells in vitro,four of which showed significant cytotoxicity.Among them 9a,9b and 9c were superior to the positive control VP-16.     

Identification of novel PI3Kδ inhibitors by docking,ADMET prediction and molecular dynamics simulations

BackgroundPhosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects.MethodComputer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor.ResultsBased on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: −12.175 kcal/mol, cdocker binding energy: −42.975 kcal/mol and ΔG_bind value: −90.457 kcal/mol) and BAS 00227397 (Glide score: −10.988 kcal/mol, cdocker binding energy: −39.3376 kcal/mol and ΔG_bind value: −81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand’s behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket.ConclusionCompound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.     

Hyrtimomines,indole alkaloids from Okinawan marine sponges Hyrtios spp.

Six new indole alkaloids, hyrtimomines F–K (1–6), were isolated from Okinawan marine sponges Hyrtios spp. The structures of 1–6 were elucidated on the basis of spectroscopic analysis. Hyrtimomine F (1) is a structurally unique bisindole alkaloid possessing an α-keto-?-caprolactam ring, while hyrtimomine G (2) is a symmetrical bisindole alkaloid. Hyrtimomines H–K (3–6) are indole alkaloids possessing β-carboline skeleton with an imidazolium unit. Antimicrobial activities of hyrtimomines F–K (1–6) were evaluated.     

The structure and dielectric properties of ionic compounds with flexible ammonium moiety

The 3-morpholin-4-yl-propyl-ammine tetrafluoroborate(MPA+)(BF4)(1) and the 3-morpholin-4-ylpropyl-ammine perchlorate(MPA+)(Cl O4)(2) were synthesized and separated as colorless block crystal.The(MPA+)(BF4) undergoes a reversible phase transition at ca.347.3 K with a hysteresis of16.1 K.Dielectric measurement also can confirm the transition.The crystal structure determined at300 K(monoclinic,P21/c,a = 9.978(2) ,b = 7.5206(15) ′,c = 15.058(3) ,b = 96.99(3)8,v = 1121.6(4)  3,z = 4) and 373 K(triclinic,P-1,a = 10.021(7) ,b = 7.662(3) ,c = 7.920(4) ,a = 95.012(14)8,b = 101.67(4)8,g = 91.48(3)8,v = 592.7(6) 3,z = 2) reveal that this compound has two phase.The most distinct is the BF4 anion is disorder at 373 K,which is probably the driving force of the phase transition.DSC measurement,dielectric measurement and the crystal structure of the compound 2 did not change at 300 K and 100 K.     

Solubilities of hydrofluorocarbons in ionic liquids: Experimental and modelling study

In this work, experimental data on the gas solubility of hydrofluorocarbons (CHF₃, CH₂F₂ and CH₃F) in four room-temperature ionic liquids (RTILs) were determined within the temperature range 288 K to 308 K and at atmospheric pressure. The RTILs used were 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide([C₂mim][NTf₂]), (trihexyl)tetradecyl-phosphoniumbis(trifluoro-methylsulfonyl)imide ([P_6,6,6,14][NTf₂]), and N-methyl-2-hydroxyethylammoniumpropionate ([m-2-HEA][Pr]) and pentanoate ([m-2-HEA][P]). Two modelling approaches, which we denote as predictive and correlative, were compared. In the former, the cubic plus association equation of state (CPA EoS) is used as a predictive model to estimate the solubilities using only pure components physical properties. In the latter, the regular-solution theory is the basis to build an empirical model whose parameters are obtained through least-squares fitting of experimental values.     

Design,Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC₅₀ values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.     

Kinetics and mechanism of thermal gas-phase elimination of β-substituted carboxylic acids

3-Phenoxypropanoic acid (1), 3-(phenylthio)propanoic acid (2), and 4-phenylbutanoic acid (3) were pyrolysed between 520 and 682 K. Analysis of the pyrolysates showed the elimination products to be acrylic acid and the corresponding arene. Pyrolysis of ethyl 3-phenoxypropanoate (4) and its methyl analogue (5), ethyl 3-(phenylthio)propanoate (6) and its methyl counterpart (7), and 3-phenoxypropane nitrile (8) were also investigated between 617 and 737 K. The thermal gas-phase elimination kinetics and product analysis are compatible with a thermal retro-Michael reaction pathway involving a four-membered cyclic transition state.     

New triterpenoid saponins from the leaves of Cyclocarya paliurus

Two new secodammarane triterpenoid saponins, cyclocariosides I and J (1 and 2), and a new epoxydammarane triterpenoid saponin, cyclocarioside K (3) were isolated from the ethanol extracts of the leaves of Cyclocarya paliurus. The structures of these compounds were elucidated by spectroscopic techniques.     

Three new sorbicillin trimers,trisorbicillinones B,C, and D,from a deep ocean sediment derived fungus,Phialocephala sp. FL30r

Eighteen sorbicillonoids, including three new sorbicillin trimers, trisorbicillinones B (2), C (3), and D (4), were isolated from a deep ocean sediment derived fungus, Phialocephala sp. FL30r. Their structures were determined by IR, MS, CD, and NMR spectral data. The cytotoxic activities of the new trisorbicillinones B (2), C (3), and D (4) were tested against both P388 and K562 cell lines.