Synthesis and BK channel-opening activity of 2-amino-1,3-thiazole derivatives.

A series of 2-amino-5-arylmethyl- or 5-heteroarylmethyl-1,3-thiazole derivatives were synthesized and evaluated for BK channel-opening activities in cell-based fluorescence assay and electrophysiological recording. The assay results indicated that the activities of the investigated compounds were influenced by the physicochemical properties of the substituent at benzene ring.

Design, synthesis of novel C-3'-N-sulfonyl modified taxane analogues from 1-deoxybaccatin VI and their impact on anti-HCC activity.

A new series of C-3'-N-sulfonyl paclitaxel analogs were designed and synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. The synthesized compounds were evaluated for their in vitro anti-Hepatocellular carcinoma (HCC) activity against human hepatoma (HepG2) cell line. Bioassay results showed that compounds 17c, 17d and 17f exhibited more potent inhibitory activity against HepG2 cell line in comparison with paclitaxel. It is suggested that paclitaxel analogs containing the C-3'-N-sulfonyl could be considered as a precursor structure for further synthesis of more potent analogues.

Efficient Synthesis of Spirooxindole Pyrrolones by a Rhodium(III)-Catalyzed C-H Activation/Carbene Insertion/Lossen Rearrangement Sequence.

A rhodium(III)-catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem C-H activation, carbene insertion, Lossen rearrangement, and a nucleophilic addition process. The potential utility of this reaction was further demonstrated by the late-stage diversification of drug molecules.

The synthesis and antistaphylococcal activity of N-sulfonaminoethyloxime derivatives of dehydroabietic acid.

A series of N-sulfonaminoethyloxime derivatives of dehydroabietic acid were synthesized and investigated for their antibacterial activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Most of the target compounds having chloro, bromo, trifluoromethyl phenyl moiety exhibited potent in vitro antistaphylococcal activity. The meta-CF3 phenyl derivative T23 showed the highest activity with MIC of 0.39-0.78 µg/mL against S. aureus Newman, while several analogues showed similar potent antibacterial activity with MIC values between 0.78 and 1.56 µg/mL against five multidrug-resistant S. aureus. The stability of T35 in plasma of SD rat and the cellular cytotoxicity were also evaluated.

Synthesis and anti-inflammatory evaluation of novel paclitaxel analogs.

A series of paclitaxel analogs modified at C-3'-N and C-7 positions were synthesized from baccatin III and their structures were confirmed by 1H-NMR, 13C-NMR, HR-MS. Compound 7e exhibited potent ability to decrease TNFα (tumor necrosis factor α) in the LPS-activated RAW264.7 murine macrophage-like cell line. The preliminary data indicated that the anti-inflammatory effects may be related to MD-2 and Toll-like receptor 4 (TLR4), rather than Toll-like receptor 2 (TLR2).

The synthesis and BK channel-opening activity of N-acylaminoalkyloxime derivatives of dehydroabietic acid.

A series of N-acylaminoalkyloxime derivatives of dehydroabietic acid were synthesized and evaluated for BK channel-opening activities in an assay system of CHO-K1 cells expressing hBKα channels. The structure-activity relationship study revealed that a non-covalent interaction between the S atom of the 2-thiophene and the carbonyl O atom may contribute to conformation restriction for interaction with the ion channel. This research could guide the design and synthesis of novel abietane-based BK channel opener.

The synthesis and antistaphylococcal activity of dehydroabietic acid derivatives: Modifications at C-12.

A series of 12-oxime and O-oxime ether derivatives of dehydroabietic acid were synthesized and investigated for the antibacterial activity against Staphylococcus aureus Newman strain and five multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The aromatic oximate derivative 11a showed the highest activity with MIC of 0.39-0.78µg/mL against S. aureus Newman. Of note, compounds 10b, 11 and 14 showed the most potent antibacterial activity against five multidrug-resistant S. aureus with MIC values of 1.25-3.13µg/mL. These results offered useful information for further strategic optimization in search of the antibacterial candidates against infection of multidrug-resistant Gram-positive bacteria.

Cu(II)-Mediated C(sp(2))-H Hydroxylation.

A Cu(II)-mediated ortho-C-H hydroxylation using a removable directing group has been developed. The reaction exhibits considerable functional group tolerance. The use of O2 as an oxidant is crucial for the reactivity. Water is also found to significantly improve this reaction.

Efficacy and safety of tralokinumab in the treatment of atopic dermatitis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To assess the efficacy and safety of Tralokinumab in the treatment of moderate-to-severe atopic dermatitis (AD). METHODS: PubMed, Embase, Clinical Trials Website, and Cochrane Library were systematically searched for eligible randomized controlled trials which assessed the effects of Tralokinumab on AD. Primary outcomes included Scoring Atopic Dermatitis score, EASI-75%, and Investigator's Global Assessment score of 0 or 1 in 12 to 16 weeks. Secondary outcomes included the Eczema area and severity index score, the Numeric Rating Scales score, the dermatology life quality index score, and the overall incidence of adverse events. The quality of included studies was evaluated using the Cochrane System and the modified Jadad scale. Analysis was performed using Stata 16 software. RESULTS: Eight randomized controlled trials involving 2878 patients were included in this meta-analysis. Compared to placebo, Tralokinumab treatment exhibited a significantly higher Scoring Atopic Dermatitis score [SMD = -0.53, 95% confidence intervals [CI]: -0.62 to -0.44, P < .00001], an increased number of patients with EASI-75% [odds ratio (OR) = 2.44, 95% CI: 2.00-2.97, P < .00001] and Investigator's Global Assessment score of 0 or 1 in 12 to 16 weeks [OR = 2.12, 95% CI: 1.71-2.63, P < .00001]. No significant difference was observed in the incidence of overall adverse events [OR = 1.00, 95% CI: 0.85-1.18, P = 1.00] between the 2 groups. CONCLUSION: Tralokinumab is effective and safe in treatment of moderate-to-severe AD.

Theoretical study on the reaction mechanisms of CH3O- with O2(X3Σ(g)-) and O2(a1Δ(g)).

The detailed potential energy surfaces (PESs) of poorly understood ion-molecule reactions of CH(3)O(-) with O(2)(X(3)Σ(g)(-)) and O(2)(a(1)Δ(g)) are accounted for by the density functional theory and ab initio of QCISD and CCSD(T) (single-point) theoretical levels with 6-311++G(d,p) and 6-311++G(3df,2pd) basis sets for the first time. For the reaction of CH(3)O(-) with O(2)(X(3)Σ(g)(-)) ((3)R), it is shown that a hydrogen-bonded complex (3)1 is initially formed on the triplet PES, which is 1.8 kcal/mol above reactants (3)R at the CCSD(T)//QCISD level, from which all the products P(1)-P(8) can be generated. As to the reaction of CH(3)O(-) with O(2)(a(1)Δ(g)) ((1)R), it is found that the two energetically low-lying complexes of (1)1(-31.5 kcal/mol) and (1)2(-24.1 kcal/mol) are initiated on the singlet PES. Starting from them, a total of seven products may be possible, that is, besides P(1), P(2), P(3), P(4), and P(8), which are the same as on the triplet PES, there exist also another two products, P(9) and P(10). For both reactions, taking the thermodynamics and kinetics into consideration, the hydride-transfer species P(1)(CH(2)O + HO(2)(-)) should be the most favorable product followed by P(8)(e + CH(2)O + HO(2)), which is a secondary product of electron-detachment from P(1), and the generation of endothermic P(7)(17.7 kcal/mol) for the reaction of CH(3)O(-) with O(2)(X(3)Σ(g)(-)) is also possible at high temperature, whereas the remaining products are negligible. The measured branching ratio of products for CH(3)O(-) with O(2)(X(3)Σ(g)(-)) by Midey et al. is 0.85:0.15 for P(1) and P(8), and that of CH(3)O(-) with O(2)(a(1)Δ(g)) is 0.52:0.48 with more P(8), which can be rationalized by our theoretical results that P(8) on the triplet PES is 4.9 kcal/mol above (3)R, whereas both P(1) and P(8) on the singlet PES are very low-lying at 45.6 and 25.2 kcal/mol below (1)R energetically. The measured total reaction rate constant of CH(3)O(-) with O(2)(a(1)Δ(g)) is k = 6.9 × 10(-10) cm(3) s(-1) at 300 K, which is larger than that of k = 1.1 × 10(-12) cm(3) s(-1) for the reaction of CH(3)O(-) with O(2)(X(3)Σ(g)(-)). This is understandable because both P(1) and P(8) on the singlet PES can be generated barrierlessly, whereas to give all the products on the triplet PES has to pass the barrier of (3)1(1.8 kcal/mol) at the CCSD(T)//QCISD level. It is expected that the present theoretical study may be helpful for understanding the reaction mechanisms related to CH(3)O(-) and even CH(3)S(-).

Public Data Set of Protein-Ligand Dissociation Kinetic Constants for Quantitative Structure-Kinetics Relationship Studies.

Protein-ligand binding affinity reflects the equilibrium thermodynamics of the protein-ligand binding process. Binding/unbinding kinetics is the other side of the coin. Computational models for interpreting the quantitative structure-kinetics relationship (QSKR) aim at predicting protein-ligand binding/unbinding kinetics based on protein structure, ligand structure, or their complex structure, which in principle can provide a more rational basis for structure-based drug design. Thus far, most of the public data sets used for deriving such QSKR models are rather limited in sample size and structural diversity. To tackle this problem, we have compiled a set of 680 protein-ligand complexes with experimental dissociation rate constants (k off), which were mainly curated from the references accumulated for updating our PDBbind database. Three-dimensional structure of each protein-ligand complex in this data set was either retrieved from the Protein Data Bank or carefully modeled based on a proper template. The entire data set covers 155 types of protein, with their dissociation kinetic constants (k off) spanning nearly 10 orders of magnitude. To the best of our knowledge, this data set is the largest of its kind reported publicly. Utilizing this data set, we derived a random forest (RF) model based on protein-ligand atom pair descriptors for predicting k off values. We also demonstrated that utilizing modeled structures as additional training samples will benefit the model performance. The RF model with mixed structures can serve as a baseline for testifying other more sophisticated QSKR models. The whole data set, namely, PDBbind-koff-2020, is available for free download at our PDBbind-CN web site (http://www.pdbbind.org.cn/download.php).

Theoretical study on the reaction mechanism of NH2(-) with O2 (a1Δg).

A detailed theoretical study of the potential energy surface of poorly understood ion-molecule reaction of NH(2)(-) and O(2) (a(1)Δ(g)) is explored at the density functional theory B3LYP/6-311++G(d,p), ab initio of QCISD/6-311++G(d,p) and CCSD(T)/6-311++G(3df, 2pd) (single-point) theoretical levels for the first time. It is shown that there are six total possible products from P(1) to P(6) on the singlet potential energy surface. Among these, the charge-transfer product P(1) (NH(2) + O(2)(-)) is the most favorable product with predominant abundances, whereas P(4) (NO(-) + H(2)O) and P(2) (HNO + OH(-)) may be the second and third feasible products followed by the almost neglectable P(3) (NO(2)(-) + H(2)), while P(5) (c-NO(2)(-) + H(2)) and P(6) (ONO(-) + H(2)) will not be observed due to their either high barriers or being secondary products. The present theoretical study points out that besides P(1) (NH(2) + O(2)(-)) and P(2) (HNO + OH(-)), P(4) (NO(-) + H(2)O) should be also observed, which is different from the previous experiment study by Anthony Midey et al. in 2008. In addition, almost all of the reaction pathways to products are exothermic and the reaction rate should be very fast since the reaction barriers are very low except for P(5) (c-NO(2)(-) + H(2)) which is in agreement with the measured total reaction rate constant k = 9.0 × 10(-10) cm(3)s(-1) at 300 K in the experiment study. It is expected that the present theoretical study may be helpful for the understanding of the reaction mechanism related to NHX(-), NX(2)(-), PHX(-), and PX(2)(-) (X = H, F, and Cl).

[The sedative and hypnotic effects and safety of oral emulsified isoflurane in rats].

OBJECTIVE: To investigate the sedative and hypnotic effects and safety of oral emulsified isoflurane in rats. METHODS: Thirty healthy Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the emulsified isoflurane group were orally administered with emulsified isoflurane with the sequential method, while the rats in the normal sodium group and the intralipid group were orally administered with sodium and intralipid respectively. The rats in the emulsified isoflurane group received 2.15 mL/100 g of 8% emulsified isoflurane, a dosage calculated with an increase of a common ratio (r = 0.8) on the basis of median effective dose (ED50). Similarly, 2.15 mL/100 g of normal sodium and 2.15 mL/100 g of 30% intralipid were given to the rats in the normal sodium group and the intralipid group, respectively. The neurobehaviors of the rats were assessed, and the interval of disappearance and recovery of the righting reflex were recorded. RESULTS: Oral emulsified isoflurane reduced the autonomic activity time and induced the loss of righting reflex. The ED50 of the loss of righting reflex was 1.72 mL/100 g. The rats orally administered with 2.15 mL/100 g of 8% emulsified isoflurane had 90% of loss of righting reflex, with a sleeping latency of 15-20 min and up to 60 min of sleeping duration. CONCLUSION: Oral emulsified isoflurane has obvious sedative and hypnotic effects.

Copper-Catalyzed Oxalamide-Directed ortho-C-H Amination of Anilines with Alkylamines.

A copper-catalyzed oxalamide-directed ortho-C-H amination of anilines has been developed by using 1 atm of air as the sole oxidant. The protocol shows excellent functional group tolerance, and some heterocyclic amines including indole, benzothiophene, benzothiazole, quinoline, isoquinoline, and quinoxaline could be compatible in the reaction. The late-stage diversification of medicinal drugs demonstrates the synthetic utility of this protocol.

Synthesis, biological activity and tubulin binding poses of 1-deoxy-9-(R)-dihydrotaxane analogs.

1-Deoxy-9alpha-dihydrotaxane analogs 9 and 10 were semi-synthesized from 1-deoxybaccatin VI, isolated from Taxus mairei, and tested for cytotoxic activity. Taxane 9 is 10-fold less cytotoxic than paclitaxel, while 10 is equally active. In the tubulin polymerization assay (ED(50) values), 10 is 4-fold less effective than paclitaxel, but 3-fold superior to 9. These observations can be explained by analysis of the corresponding taxane/beta-tubulin complexes.

Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media.

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.

Synthesis and biological evaluation of C-13, C-14 modified taxane analogues from 1-deoxybaccatin VI.

Four C-13, C-14 side chain modified 9(R)-hydroxy-1-deoxy-taxane analogues 15, 16, 19 and 22 were semi-synthesized from 1-deoxybaccatin VI. The in vitro antitumor activity of these compounds was evaluated against A549 and A2780 cell lines. The preliminary SAR analysis showed that introduction of oxygen-containing group on C-14 could improve the cytotoxic activities.

Copper mediated C-H amination with oximes: en route to primary anilines.

Here we report an efficient Cu(i)-mediated C-H amination reaction with oximes as amino donors to introduce NH2 groups directly. Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were tolerated well. The potential utility was further demonstrated in a late-stage modification of telmisartan (an antagonist for the angiotensin II receptor).

Design of diversified self-assembly systems based on a natural rosin-based tertiary amine for doxorubicin delivery and excellent emulsification.

A novel rosin-based ester tertiary amine (RETA) with three hydrophilic groups and a rigid hydrophobic group was synthesized from rosin by Diels-Alder addition, acylation and esterification reactions. RETA was characterized by infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance spectroscopy (13C NMR). Results from testing surface tension, zeta potential, and transmission electron spectroscopy showed that RETA had unique pH responsiveness. RETA self-assembled into worm-like micelles, spherical micelles 130 nm in diameter and big spherical worm-like aggregates with diameter of 2 µm at pH = 5.76, 8.04 and 9.38, respectively. The critical micelle concentration (CMC) of RETA was 0.42 mmol/L, and the surface tension at CMC (γcmc) was 38.73 mN/m when pH was 8.04. The RETA had a potential application in delivering doxorubicin hydrochloride (DOX) due to the pH responsiveness. Self-assembly mixed systems of RETA and rosin-based phosphoric acid (DDPD) were designed to improve emulsification. The mixed systems had obvious synergistic effects and unexpected emulsification. The γcmc and CMC of mixtures were 41.74 mN/m and 0.20 mmol/L, the size of mixture micelles increased up to 300 nm in the optimum molar ratio of RETA/DDPD (7:3) by TEM and cryo-TEM. It was worth noting that the mixture system formed vesicles in the RETA/DDPD molar ratio of 5:5. The stability time of emulsion with RETA and DDPD as emulsifier were only 63 s and 52 s respectively, but the stability time increased to 234 s in the optimum molar ratio. In addition, the formation mechanisms of micelles at different pH and in various mixtures were discussed in detail. What's more, cytotoxicity results showed that the toxicity of RETA was lower significantly than that of lecithin, a food ingredient in egg yolk and soybean. The cell viability was more than 83% in the high concentration of RETA (4000 µg/ml).

Synthesis and biological evaluation of novel A-seco-taxoids derived from 1-deoxybaccatin VI.

Three novel nor-seco-taxoids 13, 15, 23 in which the A rings are cleaved but the B, C, and D rings are retained were prepared from 1-deoxybaccatin VI via its nor-dioxo derivative and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. Oxidative introduction of C-1 hydroxyl to 1-deoxybaccatin VI with oxidising agent KBrO3 and catalyst RuCl3 led to the dioxo derivative 6 and its structure is determined by X-ray crystallographic analysis. A-seco taxoids 13, 15, 23 with a C-13 ester linkage were tested for cytotoxic activity and all compounds showed no measurable cytotoxic activity against HCT-116 cell line. However, 1-deoxy-9a-dihydrotaxane analogue 4 semi-synthesised from 1-deoxybaccatin VI is 10-fold less cytotoxic than paclitaxel, indicating the indispensible nature of the A ring double bond for the bioactivity of paclitaxel.