Current Medicinal Chemistry - Volume 31, Issue 38, 2024

During pregnancy, the woman’s body undergoes anatomical and physiological changes, making this period susceptible to maternal-fetal diseases and complications. The consequences of not treating pregnant women include premature birth, low birth weight fetuses, and postnatal behavior disorders. Developing new therapies can accelerate the discovery of safe and effective drugs, contributing to designing novel natural and synthetic products to treat complications the pregnancy.

This study aimed to carry out a patent review to identify and explore trends in innovation and therapeutic strategies for treating pregnant women.

The Espacenet and WIPO databases were used, with the inclusion criteria being the keywords “pregnancy and drug” and code A61k, from 2008 to 2023, and as exclusion were the access to the patent and focus on human pregnant women.

After the final screening, 32 patents were selected, with strategies for the treatment of diseases in pregnant women. Of these, 20 patents are on preclinical studies on animals and 12 on pregnant women. It was observed that universities lead the ranking of applications (17/32), and China has the highest number of patents (18/32). Most findings contain herbal medicines and/or the association of natural extracts with synthetic drugs.

From this perspective, new drug administration systems were also developed, which can be a promising source for obtaining new medicines for the treatment of pregnant women; however, research is still limited and shows a gap in stimulating the rapid development of safe drugs that improve the health of pregnant women.

A family of 4H-benzo[d][1,3]oxazines were obtained from a group of N-(2-alkynyl)aryl benzamides precursors via gold(I) catalysed chemoselective 6-exo-dig C-O cyclization.

The precursors and oxazines obtained were studied in breast cancer cell lines MCF-7, CAMA-1, HCC1954 and SKBR-3 with differential biological activity showing various degrees of inhibition with a notable effect for those that had an aryl substituted at C-2 of the molecules. 4H-benzo[d][1,3]oxazines showed an IC50 rating from 0.30 to 157.4 µM in MCF-7, 0.16 to 139 in CAMA-1, 0.09 to 93.08 in SKBR-3, and 0.51 to 157.2 in HCC1954 cells.

We observed that etoposide is similar to benzoxazines while taxol effect is more potent. Four cell lines responded to benzoxazines while SKBR-3 cell line responded to precursors and benzoxazines. Compounds 16, 24, 25 and 26 have the potent effect in cell proliferation inhibition in the 4 cell lines tested and correlated with oxidant activity suggesting a possible mechanism by ROS generation.

These compounds represent possible drug candidates for the treatment of breast cancer. However, further trials are needed to elucidate its full effect on cellular and molecular features of cancer.

The tumor microenvironment (TME) is created by the tumor and dominated by tumor-induced interactions. Long-term survival of lung adenocarcinoma (LUAD) patients is strongly influenced by immune cell infiltration in TME. The current article intends to construct a gene signature from LUAD ICI for predicting patient outcomes.

For the initial phase of the study, the TCGA-LUAD dataset was chosen as the training group for dataset selection. We found two datasets named GSE72094 and GSE68465 in the Gene Expression Omnibus (GEO) database for model validation. Unsupervised clustering was performed on the training cohort patients using the ICI profiles. We employed Kaplan-Meier estimators and univariate Cox proportional-hazard models to identify prognostic differentially expressed genes in immune cell infiltration (ICI) clusters. These prognostic genes are then used to develop a LASSO Cox model that generates a prognostic gene signature. Validation was performed using Kaplan-Meier estimation, Cox, and ROC analysis. Our signature and vital immune-relevant signatures were analyzed. Finally, we performed gene set enrichment analysis (GSEA) and immune infiltration analysis on our finding gene signature to further examine the functional mechanisms and immune cellular interactions.

Our study found a sixteen-gene signature (EREG, HPGDS, TSPAN32, ACSM5, SFTPD, SCN7A, CCR2, S100P, KLK12, MS4A1, INHA, HOXB9, CYP4B1, SPOCK1, STAP1, and ACAP1) to be prognostic based on data from the training cohort. This prognostic signature was certified by Kaplan-Meier, Cox proportional-hazards, and ROC curves. 11/15 immune-relevant signatures were related to our signature. The GSEA results indicated our gene signature strongly correlates with immune-related pathways. Based on the immune infiltration analysis findings, it can be deduced that a significant portion of the prognostic significance of the signature can be attributed to resting mast cells.

We used bioinformatics to determine a new, robust sixteen-gene signature. We also found that this signature's prognostic ability was closely related to the resting mast cell infiltration of LUAD patients.

Allosteric inhibition of EGFR tyrosine kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies.

A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, ¹HNMR, ¹³CNMR, and HR-mass spectroscopy.

Compound S4 had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC50 value comparable to Erlotinib. Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. All of the new derivatives, including S4, met the in silico requirements for EGFR allosteric inhibitory activity.

Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.

To facilitate drug discovery and development for the treatment of osteoporosis.

With global aging, osteoporosis has become a common problem threatening the health of the elderly. It is of important clinical value to explore new targets for drug intervention and develop promising drugs for the treatment of osteoporosis.

To understand the major molecules that mediate the communication between the cell populations of bone marrow-derived mesenchymal stem cells (BM-MSCs) in osteoporosis and osteoarthritis patients and identify potential reusable drugs for the treatment of osteoporosis.

Single-cell RNA sequencing (scRNA-seq) data of BM-MSCs in GSE147287 dataset were classified using the Seurat package. CellChat was devoted to analyzing the ligand-receptor pairs (LR pairs) contributing to the communication between BM-MSCs subsets. The LR pairs that were differentially expressed between osteoporosis samples and control samples and significantly correlated with immune score were screened in the GSE35959 dataset, and the differentially expressed gene in both GSE35959 and GSE13850 data sets were identified as targets from a single ligand or receptor. The therapeutic drugs for osteoporosis were screened by network proximity method, and the top-ranked drugs were selected for molecular docking and molecular dynamics simulation with the target targets.

Twelve subsets of BM-MSCs were identified, of which CD45-BM-MSCS_4, CD45-BM-MSCS_5, and CD45+ BM-MSCs_5 subsets showed significantly different distributions between osteoporosis samples and osteoarthritis samples. Six LR pairs were identified in the bidirectional communication between these three BM-MSCs subsets and other BM-MSCs subsets. Among them, MIF-CD74 and ITGB2-ICAM2 were significantly correlated with the immune score. CD74 was identified as the target, and a total of 48 drugs targeting CD47 protein were identified. Among them, DB01940 had the lowest free energy binding score with CD74 protein and the binding state was very stable.

This study provided a new network-based framework for drug reuse and identified initial insights into therapeutic agents targeting CD74 in osteoporosis, which may be meaningful for promoting the development of osteoporosis treatment.