A mass balance study of [14C]SHR6390 (dalpiciclib), a selective and potent CDK4/6 inhibitor in humans.

SHR6390 (dalpiciclib) is a selective and effective cyclin-dependent kinase (CDK) 4/6 inhibitor and an effective cancer therapeutic agent. On 31 December 2021, the new drug application was approved by National Medical Product Administration (NMPA). The metabolism, mass balance, and pharmacokinetics of SHR6390 in 6 healthy Chinese male subjects after a single oral dose of 150 mg [14C]SHR6390 (150 µCi) in this research. The Tmax of SHR6390 was 3.00 h. In plasma, the t 1/2 of SHR6390 and its relative components was approximately 17.50 h. The radioactivity B/P (blood-to-plasma) AUC0-t ratio was 1.81, indicating the preferential distribution of drug-related substances in blood cells. At 312 h after administration, the average cumulative excretion of radioactivity was 94.63% of the dose, including 22.69% in urine and 71.93% in stool. Thirteen metabolites were identified. In plasma, because of the low level of radioactivity, only SHR6390 was detected in pooled AUC0-24 h plasma. Stool SHR6390 was the main component in urine and stool. Five metabolites were identified in urine, and 12 metabolites were identified in stool. Overall, faecal clearance is the main method of excretion.

High expression of KMT2D is a promising biomarker for poor gastric cancer prognosis.

OBJECTIVE: To investigate the expression of histone lysine N-methyltransferase 2D (KMT2D) in gastric cancer patients and its relationship with the prognosis. METHODS: A total of 126 gastric cancer patients admitted to Hubei Provincial Hospital of TCM from January 2014 to June 2017 were selected as the research subjects, and patients' clinical data were analyzed retrospectively. First, the KMT2D mRNA or protein expression in the patient's tissue was detected using quantitative real-time PCR or immunohistochemistry. Afterwards, the relationship between the KMT2D protein expression and the prognosis of patients was analyzed using a Kaplan-Meier curve. Also, the predictive value of the KMT2D mRNA and protein expression for the prognosis and death rate of gastric cancer patients was evaluated using a receiver operating characteristic curve. Finally, the risk factors for poor prognosis and death of the gastric cancer patients were analyzed using a Cox regression analysis. RESULTS: Overall, the KMT2D mRNA expression level and positive rate of protein expression in the gastric cancer tissues were significantly higher than that in paracancerous tissues (P<0.05). A positive expression of the KMT2D protein in gastric cancer tissues was correlated with the following factors in patients: age ≥60 years, tumor differentiation degree, TNM stage III-IV, lymph node metastasis, depth of invasion T3-T4, distant metastasis and high serum carbohydrate antigen 19-9 (CA19-9) levels (P<0.05). Also, the 5-year overall survival and progression-free survival of gastric cancer patients with a positive KMT2D expression were lower than those with negative KMT2D expressions (P<0.05). The resulting areas under the curve for predicting the prognosis and death of gastric cancer patients with the KMT2D mRNA and protein expression were 0.823 and 0.645, respectively. In addition, tumor maximum diameter >5 cm, poor differentiation, TNM stage III-IV, lymph node metastasis, high serum CA19-9 level, KMT2D mRNA expression ≥1.48 and KMT2D protein positive expression were risk factors affecting the prognosis and death of gastric cancer patients (P<0.05). CONCLUSION: KMT2D is highly expressed in gastric cancer tissue and it is expected to be a potential biomarker for predicting the poor prognosis of gastric cancer patients.

Absorption, distribution, metabolism, and excretion of [14C]NBP (3-n-butylphthalide) in rats.

3-n-Butylphthalide (NBP) has a considerable neuroprotective effect and is currently used for the treatment of ischemic stroke. NBP was launched on the market in 2004. However, information on its metabolism in humans and preclinical animal models is insufficient. Although the metabolism of unradiolabeled NBP in humans has been reported, the quantitative metabolite profile, blood-to-plasma radioactivity concentration ratio (B/P), and tissue distribution of this drug remain unclear. We evaluated the pharmacokinetics, tissue distribution, mass balance, and metabolism of NBP in rats after a single oral dose of 60 mg/kg (100 µCi/kg) [14C]NBP to understand the biotransformation of NBP comprehensively and to provide preclinical drug metabolism data prior to human mass balance studies with [14C]NBP in the near future. NBP absorption was rapid (Tmax = 0.75 h) and declined with a terminal half-life of 9.73 h. In rats, the B/P was 0.63 during the 48 h postdose period, indicating that drug-related substances did not tend to be distributed into blood cells. Tissue distribution was determined by using the oxidative combustion method. NBP-related components were widely distributed throughout the body, and high concentrations were detected in the stomach, small intestine, fat, bladder, kidney, liver and ovary. At 168 h after oral administration, the mean cumulative recovered radioactivity was 99.85% of the original dose, and was 85.12% in urine and 14.73% in feces. Metabolite profiles were detected via radiochromatography. A total of 49 metabolites were identified in rat plasma, urine, and feces. The main metabolic pathways were oxidation, glucuronidation, and sulfation. Overall, NBP was absorbed rapidly, distributed throughout the body, and excreted in the form of metabolites. Urine was the main excretion route, and the absorption, distribution, metabolism and excretion of NBP showed no significant gender difference between male and female rats.

A Scaffold-Hopping Strategy toward the Identification of Inhibitors of Cyclin†G Associated Kinase.

We recently reported the discovery of isothiazolo[4,3-b]pyridine-based inhibitors of cyclin G associated kinase (GAK) displaying low nanomolar binding affinity for GAK and demonstrating broad-spectrum antiviral activity. To come up with novel core structures that act as GAK inhibitors, a scaffold-hopping approach was applied starting from two different isothiazolo[4,3-b]pyridines. In total, 13 novel 5,6- and 6,6-fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with Kd values in the low micromolar range that can serve as chemical starting points for the discovery of GAK inhibitors based on a different scaffold.

A simple and versatile strategy for taming FOX-7.

A novel derivatization strategy was developed for the exciting reactive chemistry of FOX-7. The as-synthesized FOX-7-derived polynitro compounds exhibited high crystal densities, excellent detonation performances, and good impact and friction sensitivities. This study opens a new path for the ever-expanding chemistry of FOX-7.

Designing Explosive Poly(Ionic Liquid)s as Novel Energetic Polymers.

The development of ionic-liquid-derived functional materials would be vital for stimulation of the interdisciplinary research in the fields of ionic liquid chemistry and material science. Here, a series of novel poly(ionic liquid)s with explosive capability were designed and prepared by introducing the energetic nitrato group and nitro-rich anions, such as nitrate, dinitramide, and nitroform into the polymeric chains. The as-synthesized explosive poly(ionic liquid)s (E-PILs) were fully characterized, and their physicochemical and detonation properties were investigated. All E-PILs show higher detonation performances than state-of-the-art energetic polymers including glycidyl azide polymer (GAP) and poly(glycidyl nitrate) [poly(GLYN)]. Some E-PILs exhibit higher calculated detonation velocities and pressures than 2,4,6-trinitrotoluene (TNT). These E-PILs are promising candidates for applications as new high-performance energetic polymers.

Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds.

Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.

Synthesis of gem-Dinitromethylated and Fluorodinitromethylated Derivatives of 5,5'-Dinitro-bis-1,2,4-triazole as Promising High-Energy-Density Materials.

gem-Dinitromethylated and fluorodinitromethylated 5,5'-dinitro-3,3'-bis-1,2,4-triazole (DNBT) (2 and 3) along with seven ionic derivatives 4-9, were synthesized and characterized by NMR and IR spectroscopies, elemental analysis, single-crystal X-ray diffraction (XRD), and differential scanning calorimetry (DSC). XRD revealed that compounds 2 and 3 crystallized in the monoclinic P21 /n space group and compound 5 crystallized in the monoclinic P21 /c space group. The physicochemical properties of the as-synthesized compounds 2-9 were investigated and the results indicated that compounds 3, 6, and 7 exhibited a good balance between high energy and low sensitivity, demonstrating their potential as new high-energy-density materials (HEDMs). The proposed synthetic strategy for introducing gem-dinitromethyl and fluorodinitromethyl groups into the DNBT framework to prepare materials with high energy and low sensitivity suitable for HEDMs looks promising.

Phosphine-catalyzed [3+2] annulation of α-substituted allenoates with ester-activated α,ß-unsaturated imines: a novel variation of the Lu [3+2] cycloaddition reaction.

A phosphine-catalyzed [3+2] annulation reaction of α-substituted allenoates with ester-activated α,ß-unsaturated imines is reported, which provides new and efficient access to highly functionalized cyclopentenes bearing one all-carbon quaternary center. This reaction also expands the scope of the famous Lu [3+2] cycloaddition reaction.

Phosphine-catalyzed [4 + 2] annulation and vinylogous addition reactions between 1,4-dien-3-ones and 1,1-dicyanoalkenes.

Phosphine-catalyzed [4 + 2] annulation and vinylogous Michael addition reactions between 1,4-dien-3-ones and 1,1-dicyanoalkenes are presented. Under the catalysis of PBu(3) (20 mol %), 1,4-dien-3-ones like styryl ketones with 2-aryl 1,1-dicyanoalkenes as doubly activated alkenes readily undergo a formal [4 + 2] cycloaddition reaction, affording polysubstituted cyclohexanones in satisfactory yield and good diastereoselectivity; with the doubly activated alkenes bearing an acidic methyl or methylene at the 2-position, a vinylogous Michael addition of 1,4-dien-3-ones occurs under the same reaction conditions, giving a non-cyclized multifunctional adduct in good yield. These two phosphine-catalyzed transformations represent atom economical carbon-carbon bond forming reactions capable of rapid construction of molecular complexity. Based on experimental results, formation of the products has been mechanistically rationalized, and a phosphonium activation is proposed.

Phosphine-catalyzed [4 + 1] annulation between α,ß-unsaturated imines and allylic carbonates: synthesis of 2-pyrrolines.

In this report, a phosphine-catalyzed [4 + 1] annulation between α,ß-unsaturated imines and allylic carbonates is described. This reaction represents the first realization of catalytic [4 + 1] cyclization of 1,3-azadienes with in situ formed phosphorus ylides, which provides highly efficient and diastereoselective synthesis of 2-pyrrolines.