Drug Development Research最新文献

Novel thienopyrimidinone hybrids 5–25 were developed and synthesized as potential inhibitors of human EGFR and FGFR. The in vitro antiproliferative action of all compounds, towards the human breast tumor cells MDA-MB-231 and MCF-7, was evaluated with doxorubicin serving as a reference (IC₅₀ = 6.72 µM). Compound 23 demonstrated the highest anti-breast cancer efficacy against both cellular lines having IC₅₀ ranging from 2.95 to 3.80 µM. The enzyme inhibition of human EGFR and FGFR by the most active candidates 18, 21and 23–25 was further evaluated. Compounds 21 and 25 were the best EGFR inhibitors having IC₅₀ values of 0.077 and 0.059 µM, respectively, in comparison to Erlotinib (IC₅₀ = 0.04 µM). In comparison with Staurosporine (IC₅₀ = 0.024 µM), compounds 24 and 25 were the most active FGFR inhibitors having IC₅₀ values of 0.055 and 0.029 µM, respectively. The study of molecular docking was carried out among the most active EGFR inhibitors 21 and 25 and the most active FGFR inhibitors 24 and 25 to examine the relation between the binding pattern of these compounds with EGFR and FGFR catalytic active sites and their biological activity, whereas the computational results were aligned with the biological results. Finally, compound 25, which was found to be the best dual inhibitor against EGFR and FGFR, was tested for inducing apoptosis and affecting cellular arrest within G2/M phase as well as it was screened to measure its safety towards normal breast cells MCF10a with IC₅₀ value of 47.16 µM in contrast to the reference Staurosporine (IC₅₀ = 18.86 µM). Accordingly, compound 25 could be considered as a potential breast cancer therapy.

The anticancer potential of certain newly synthesized pyrazole and pyrazolopyridine derivatives has been estimated. NCI 60 cancer cells cytotoxic screening pointed out compounds 3e and 3f as the highest cytotoxic agents with % mean growth inhibition of 67.69% and 87.34%, respectively. The five dose outcomes outlined 3f as the most potent cytotoxic agent with promising MG-MID GI₅₀ = 3.3 µM when compared to erlotinib (MG-MID GI₅₀ = 7.68 µM). In the in vitro assays, compounds 3d, 3e, 3f, and 4a demonstrated dual inhibitory potential on EGFR^WT and VEGFR-2 with IC₅₀ range of 0.066−0.184 µM and 0.102−0.418 µM, respectively. The best dual EGFR/VEGRF-2 inhibitory effect was shown by the compound 3f. Moreover, the latter compound stopped the cell cycle at the G1/S phase. Also, it greatly boosted total apoptosis, including early and late apoptosis, by 54.5- and 84.7-fold, respectively, which supposes HCT-116 cell death via inducing apoptosis. This was confirmed by the elevation of the BAX and caspase-3 levels, and the decreased BCL-2 level. Moreover, the safety of the most active compound 3f was assessed and the results showed promising selectivity of compound 3f toward HCT-116 over FHC (selectivity index [SI]: 20.84) when compared to erlotinib (SI: 3.42). Finally, compound 3f demonstrated efficient binding to both EGFR and VEGFR-2 enzymes, which could explain the sufficient inhibition level of each enzyme.

Multiple sclerosis (MS) is a demyelinating disease in which the insulating cover (myelin sheath) of the brain and spinal cord is damaged. Demyelination results in a decreased signal transmission in the nervous system. Symptoms include double vision, muscle weakness, and difficulty with coordination. Genetic and viral infections have been proposed as plausible factors responsible for MS. Although there is no cure for MS, treatment prevents future attacks. At present, chemotherapy and monoclonal antibodies are the available treatments for MS. Heterocyclic compounds are currently being tested clinically for their efficacy. Some heterocyclic scaffolds have been found to be promising for the treatment of MS. In view of this, research has been conducted towards the design and discovery of chemical agents for MS. Hence, the literature relevant to drug design for MS in the last decade has been collated and described comprehensively so that it would be helpful for efficient drug design for MS in the future. Additionally, through the structure–activity relationship, the importance of crucial structural features was emphasized. The classification was primarily based on the type of heterocycle.

Drug resistance and cancer recurrence are major cause of Cervical cancer (CC) patient mortality. Cisplatin (CDDP) is the major drug that has been extremely used in all stages in treating CC, although relapse and malignant instances have been observed as a result of cisplatin resistance in CC. In the present study, we established Cisplatin resistant CC HeLa cell line model and the cytotoxic effects of Andro as a single agent or in combination with CDDP were investigated to assess its potential as a chemotherapeutic agent in cisplatin-resistant HeLa (CisR-HeLa) cells. Andro enhanced the cytotoxicity of CDDP in CisR-HeLa cells and shown a synergistic effect by reducing cell viability, proliferation, migration, invasion, and inducing apoptosis in cisplatin resistant cells. Furthermore, we evaluated the expression levels of inflammatory and oncogenic proteins, SPP1, NF-kB, iNOS, COX-2, and the PI3K/AKT signaling pathway, which are associated with cisplatin resistance, as well as using Andro to regulate the targeted markers in CisR-HeLa cells to overcome resistance. The results show that suppressing SPP1 and NF-kB by Andro alone or in combination with CDDP regulates iNOS, COX-2, and increases PTEN expression. The addition of Andro to CDDP inhibited PI3K and AKT expression as well as triggered synergistic apoptosis, which could be associated with variations in Bax and Bcl-2 protein levels. The results suggest that Andro in combination with CDDP exhibits synergistic anti-tumor growth efficacy that targets multiple inflammatory markers, resulting in a promising treatment option for individuals with recurrent cancer due to drug resistance and advanced CC.

Leishmaniasis and trypanosomiasis are parasitic diseases that are closely linked to poverty, pose significant local burdens, and are common in tropical and subtropical regions. Various synthetic tetralone derivatives were studied as potential scaffolds for antileishmanial and antitrypanosomal activities. The compounds were studied for their effectiveness against multiple kinetoplastid protozoan pathogens: Leishmania major, Leishmania mexicana, and bloodstream trypomastigotes of Trypanosoma brucei brucei. Two different strains of T. b. brucei were used. The first strain was the wild-type Trypanosoma brucei (s427-WT), and the second strain was the multidrug resistant (MDR) strain B48, which was produced by deleting the TbAT1 gene from s427WT and subsequent adaptation to high levels of resistance to diamidines and organo-arsenical drugs. Compounds 4c, 7c, 9b, and 11b showed activity against two strains of Trypanosoma and two different Leishmania species, establishing them as versatile leads with broad anti-kinetoplastid activity. Compound 4c, a tetralone derivative with a bromo-containing trimethoxybenzylidene moiety and methyl-substituted cyclohexanone ring, was identified as the most potent inhibitor for both T. b. brucei strains, with EC₅₀ values of 0.19 and 0.22 µM for WT and B48, respectively, showing the absence of cross-resistance with the diamidine and arsenical trypanocide classes. In addition, compound 4c exhibited more potency than both controls, eflornithine and pentamidine, against the MDR strain. We conclude that tetralone derivates could be a valuable starting point for the discovery of new antiparasitic drugs.

Diabetes nephropathy (DN) is a severe diabetic chronic microvascular complication and the major cause of end-stage renal disease (ESRD). Our study aimed to investigate the effects of isoliquiritigenin (ISL) a natural flavonoid compound on DN and to explore the underlying mechanisms. The db/db mice were received intragastric treatments of ISL (5, 10, or 20 mg/kg), vehicle or positive drug metformin (300 mg/kg) once a day for 12 weeks, and the db/m mice treated with vehicle were used as controls. ISL significantly ameliorated pathological changes and functional injury in the kidneys of db/db mice in a dose-dependent manner. The administration of 20 mg/kg ISL reduced the levels of serum creatinine (Scr; 49.0 ± 1.7 vs. 56.9 ± 2.9 μmol/L; p < 0.01), blood urine nitrogen (BUN; 9.6 ± 1.3 vs. 12.0 ± 1.1 mmol/L; p < 0.05), albumin to creatinine ratio (ACR; 1925.8 ± 798.1 vs. 4269.4 ± 925.6 μg/mg; p < 0.01) and urinary albumin (276.2 ± 39.9 vs. 576.9 ± 108.9 μg; p < 0.05). Further study identified advanced glycation end product (AGE)–receptor for AGE (RAGE) axis as a target of ISL. ISL (20 mg/kg) lowered renal AGE level (2.5 ± 0.5 vs. 3.8 ± 0.6 μg/mg; p < 0.01) and RAGE expression, leading to improvements in renal fibrosis, oxidative stress, and inflammation. To sum up, our study demonstrated that ISL displayed preventive effects on the experimental model of DN through suppressing AGE–RAGE pathway, and provided some insights into the application of ISL in DN treatment.

Ovarian cancer is the seventh most common lethal tumor among women in the world. FOXM1 is a transcription factor implicated in the initiation and progression of ovarian cancer by regulating key oncogenic genes. The role of regulatory regions in regulating the expression of FOXM1 in ovarian cancer is not completely clarified. Treatment with bromodomain and extraterminal (BET) inhibitors JQ-1 and I-BET were explored in ovarian cancer cell lines (OVCAR3, A2780, or SKOV3) to evaluate FOXM1 expression and biological behavior by qPCR, CCK8 assay, colony formation assay, wound-healing, and transwell assays. The regulatory regions (enhancer sequence spanning promoter or exon 1) of FOXM1 were deleted using CRISPR-Cas9 in the OVCAR3 cell line. FOXM1 expression and tumor biological behavior were further assessed in FOXM1 regulatory regions deleted OVCAR3 cell line. The mouse xenograft model was assessed at the indicated time points following subcutaneous injection of enhancer-deleted cells. Treatment with the JQ-1 and I-BET reduced the expression of FOXM1, decreasing cell proliferation, migration, and invasion in a panel of ovarian cancer cell lines including OVCAR3, A2780, and SKOV3 cells. By mining the published ChIP-sequencing data (H3K27Ac) from 12 ovarian cancer cell lines, we identified a potential enhancer and promoter region. Deletion of the spanning enhancer and promoter region of FOXM1 reduced mRNA and protein expression. Similarly, cell proliferation, migration, invasion, and tumorigenesis in both cells and mouse xenograft models were significantly attenuated. Our study demonstrates that JQ-1 and I-BET can regulate the expression of the FOXM1 gene-relating network. These data also indicate that disruption of the span enhancer and promoter region activity of FOXM1 has a vital role in the anti-ovarian cancer effect, hiding a potential opportunity for the evaluation of this non-coding DNA deletion disrupts the FOXM1 transcriptional network in ovarian cancer development.