Divergent synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines.

Indole-3-carbinol, bisindolylmethanes (BIMs) and indole-3-methanamines exhibit diverse therapeutic activities. Fluorinated molecules are widely used in pharmaceuticals. Herein we report a facile and straightforward method for the successful synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines by a Friedel-Crafts reaction. The reaction involves the in situ generation of difluoroacetaldehyde from difluoroacetaldehyde ethyl hemiacetal in the presence of a base or an acid. This protocol is distinguished by its good to excellent yields, broad substrate compatibility, good functional group tolerance and scalability.

Carboxymethyl Chitosan/Sodium Alginate/Chitosan Quaternary Ammonium Salt Composite Hydrogel Supported 3J for the Treatment of Oral Ulcer.

Oral ulcer is a common inflammatory disease of oral mucosa, causing severe burning pain and great inconvenience to daily life. In this study, compound 3J with anti-inflammatory activity was synthesized beforehand. Following that, an intelligent composite hydrogel supported 3J was designed with sodium alginate, carboxymethyl chitosan, and chitosan quaternary ammonium salt as the skeleton, and its therapeutic effect on the rat oral ulcer model was investigated. The results show that the composite hydrogel has a dense honeycomb structure, which is conducive to drug loading and wound ventilation, and has biodegradability. It has certain antibacterial effects and good anti-inflammatory activity. When loaded with 3J, it reduced levels of TNF-α and IL-6 in inflammatory cells by up to 50.0%. It has excellent swelling and water retention properties, with a swelling rate of up to 765.0% in a pH 8.5 environment. The existence of a large number of quaternary ammonium groups, carboxyl groups, and hydroxyl groups makes it show obvious differences in swelling in different pH environments, which proves that it has double pH sensitivity. It is beneficial to adapt to the highly dynamic changes of the oral environment. Compared with single hydrogel or drug treatment, the drug-loaded hydrogel has a better effect on the treatment of oral ulcers.

Facile access to 2-hydroxy-2-substituted indole-3-ones via a copper-catalyzed oxidative cyclization of 2-arylethynylanilines.

This paper reports a practical and versatile oxidative cyclization of 2-arylethynylanilines towards 2-hydroxy-2-substituted indol-3-ones via a copper-catalyzed radical approach in the presence of O2. The transformation of 2-hydroxy-2-arylindol-3-ones to 3-hydroxy-3-arylindol-2-ones proceeds well with good yields and highlights the practicability and utility of this catalytic system. Mechanistic investigations showed that the acetyl substituent on 2-arylaethynylanilines played an important role in the formation of the cyclic products and the reaction proceeded via an N-center radical-based 5-endo-dig aza-cyclization pathway.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRASG12D- and G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.

Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities.

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC50 values of 2.65 µM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC50 of 10.9 µM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T1/2 = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.

Radiomics-based analysis of CT imaging for the preoperative prediction of invasiveness in pure ground-glass nodule lung adenocarcinomas.

OBJECTIVE: The purpose of the study is to investigate the performance of radiomics-based analysis in prediction of pure ground-glass nodule (pGGN) lung adenocarcinomas invasiveness using thin-section computed tomography images. METHODS: A total of 382 patients surgically resected single pGGN and pathologically confirmed were enrolled in the retrospective study. The pGGN cases were divided into two groups: the noninvasive group and the invasive adenocarcinoma (IAC) group. 330 patients were randomly assigned to the training and testing cohorts with a ratio of 7:3 (245 noninvasive lesions, 85 IAC lesions), while 52 patients (30 noninvasive lesions, 22 IAC lesions) were assigned to the external validation cohort. A model, radiomics model, and combined clinical-radiographic-radiomic model were built using the LASSO and multivariate backward stepwise regression analysis on the basis of the selected and radiomics features. The area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate and compare the model performance for invasiveness discrimination among the three cohorts. RESULTS: Three clinical-radiographic features (including age, gender and the mean CT value) and three radiomics features were selected for model building. The combined model and radiomics model performed better than the clinical-radiographic model. The AUCs of the combined model in the training, testing, and validation cohorts were 0.856, 0.859, and 0.765, respectively. The DCA demonstrated the radiomics signatures incorporating clinical-radiographic feature was clinically useful in predicting pGGN invasiveness. CONCLUSIONS: The proposed radiomics-based analysis incorporating the clinical-radiographic feature could accurately predict pGGN invasiveness, providing a noninvasive biomarker for the individualized and precise medical treatment of patients.

Advances in the development of phosphodiesterase-4 inhibitors.

Phosphodiesterase 4 (PDE4) hydrolyzes cyclic adenosine monophosphate (cAMP) and plays a vital roles in many biological processes. PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases, including asthma, chronic obstructive pulmonary disease (COPD) and psoriasis. Many PDE4 inhibitors have progressed to clinical trials and some have been approved as therapeutic drugs. Although many PDE4 inhibitors have been approved to enter clinical trials, however, the development of PDE4 inhibitors for the treatment of COPD or psoriasis has been hampered by their side effects of emesis. Herein, this review summarizes advances in the development of PDE4 inhibitors over the last ten years, focusing on PDE4 sub-family selectivity, dual target drugs, and therapeutic potential. Hopefully, this review will contribute to the development of novel PDE4 inhibitors as potential drugs.

Radiosynthesis, optimization and pharmacokinetic study of the 99m Tc-labeled human epidermal growth factor receptor 2 affibody molecule probe 99m Tc-(HE) 3 Z HER2:V2.

OBJECTIVE: To prepare a single-photon molecular probe easily labeled with 99m Tc for evaluating the expression status of the human epidermal growth factor receptor 2 (HER2) receptor in ovarian cancer. MATERIALS AND METHODS: The HEHEHE tag was added to the amino terminus of the affibody Z HER2:V2 by the method of gene recombinant expression, and a new affibody was synthesized which was easy to be labeled with 99m Tc. The newly prepared affibody was labeled with 99m Tc, and pharmacokinetic studies were carried out. RESULTS: A new affibody (HE) 3 Z HER2:V2 was prepared by the method of gene recombination and expression, which is easy to be labeled with 99m Tc. The 99m Tc labeling of the affibody can reach about 95% at 90°C. The pharmacokinetic study has shown that the 99m Tc-labeled molecular probe has a fast clearance time in the blood and little side effect, which may be a promising single-photon emission computed tomography (SPECT) imaging agent. CONCLUSION: The affibody (HE) 3 Z HER2:V2 is easy to be labeled with 99m Tc, has a high yield and has a suitable half-life in vivo, which is suitable for the next step in ovarian cancer model imaging research.

Cp*Ir(III) and Cp*Rh(III)-catalyzed annulation of salicylaldehydes with fluorinated vinyl tosylates.

A mild, selective and redox-neutral Cp*Ir(III)- and Cp*Rh(III)-catalyzed C-H activation/annulation of salicylaldehydes with fluorovinyl tosylates is reported. The use of monofluorovinyl tosylate favors the synthesis of C2- and C3-substitution-free chromones via C-H activation/ß-F elimination/annulation, whereas difluorovinyl tosylate leads to the construction of C2-fluoroalkoxy chromones. Mild reaction conditions and good functional-group tolerance were observed. Further functionalization of the resulting chromones via halogenation, alkynylation, alkylation and hydrocyanation was successfully realized.

A preliminary evaluation study of applying a deep learning image reconstruction algorithm in low-kilovolt scanning of upper abdomen.

OBJECTIVE: To investigate feasibility of applying deep learning image reconstruction (DLIR) algorithm in a low-kilovolt enhanced scan of the upper abdomen. METHODS: A total of 64 patients (BMI<28) are selected for the enhanced upper abdomen scan and divided evenly into two groups. The tube voltages in Group A are 100kV in arterial phase and 80kV in venous phase, while tube voltages are 120kV during two phases in Group B. Image reconstruction algorithms used in Group A include the filtered back projection (FBP) algorithm, the adaptive statistical iterative reconstruction-Veo (ASIR-V 40% and 80%) algorithm, and the DLIR algorithm (DL-L, DL-M, DL-H). Image reconstruction algorithm used in Group B is ASIR-V40%. The different reconstruction algorithm images are used to measure the common hepatic artery, liver, renal cortex, erector spinae, and subcutaneous adipose in the arterial phase and the average CT value and standard deviation of the portal vein, liver, spleen, erector spinae, and subcutaneous adipose in the portal phase. The signal-to-noise ratio (SNR) is calculated, and the images are also scored subjectively. RESULTS: In Group A, noise in the aorta, liver, portal vein (the portal phase), spleen (the portal phase), renal cortex, retroperitoneal adipose, and muscle is significantly lower in both the DL-H and ASIR-V80% images, and the SNR is significantly higher than those in the remaining groups (P<0.05). The SNR of each tissue and organ in Group B is not significantly different from that in DL-M, DL-L, and ASIR-V40% in Group A (P>0.05). The subjective image quality scores in the DL-H and B groups are higher than those in the other groups, and the FBP group has significantly lower image quality than the remaining groups (P<0.05). CONCLUSION: For upper abdominal low-kilovolt enhanced scan data, the DLIR-H gear yields a more satisfactory image quality than the FBP and ASIR-V.

A Moving Meckel Diverticulum on 99mTc-Pertechnetate Imaging in a Patient With Inguinal Hernia.

A boy aged 1 year 8 months underwent Tc-pertechnetate scintigraphy to evaluate the cause of bloody stool. On the initial images, there was an abnormal activity in the right abdomen, which changed location to the right groin in later images. A Meckel diverticulum was identified by histopathology examination. We concluded this case of moving Meckel diverticulum was caused by the synergy between an inguinal hernia and high abdominal pressure.