Anti-cancer agents in medicinal chemistry最新文献

Background: This study explored whether the cell cycle regulator cadherin 1 (CDH1) impacts colorectal cancer cell cycle and stemness via mediating ubiquitination of sirtuin 5 (SIRT5).

Methods: We first constructed CDH1 overexpression plasmid and small interfering RNA against SIRT5 (siSIRT5) and transfected them into HCT116/HT29 cells, followed by transfection efficiency verification. The effect of CDH1 on Cyclin F/SIRT5/CDH1 protein levels in HCT116/HT29 cells was verified by Western blot. After up-regulation of CDH1, changes in SIRT5 ubiquitination (immunoprecipitation), cell cycle (cell cycle kit), proliferation (5-Bromodeoxyuridine assay), and stemness marker expressions (qRT-PCR) in HCT116/HT29 cells were detected. Rescue assays were performed to examine cell proliferation and stemness marker expressions.

Results: Overexpression of CDH1 decreased Cyclin F expression and increased SIRT5 and CDH1 expressions in HCT116/HT29 cells. Up-regulation of CDH1 suppressed SIRT5 ubiquitination, promoted G0/G1 phase blockage in HCT116/HT29 cells, boosted cell proliferation into quiescence and enhanced cell stemness. siSIRT5 counteracted the regulatory effect of CDH1 overexpression on colorectal cancer cells.

Conclusion: CDH1 promotes the entry of colorectal cancer cells into quiescence and enhances stemness by dampening SIRT5 ubiquitination.

Objectives: According to the data, mutations in EGFR-related genes are the main cause of Non-Small Cell Lung Cancer (NSCLC), necessitating the development of new drug constructs for EGFR-TKIs particularly important. This study aimed to screen potential third-generation EGFR-TKIs to address the emerging drug resistance challenges in NSCLC.

Methods: In this study, virtual screening, molecular dynamics modeling, and bioactivity evaluation were carried out to find a potential EGFR inhibitor that could overcome the L858R/T790M mutation. At first, 12 potential compounds were screened step by step from about 250,000 structures by virtual screening. These 12 compounds were subjected to MTT antitumor activity evaluation and kinase inhibition assay to select compounds with strong antiproliferative effects on cancer cells. Then, the preferred compounds were subjected to time-dependent assay, scratch assay, AO staining assay, and hemolysis assay. Finally, the preferred compound was subjected to molecular docking and molecular dynamics simulation with 5HG7 protein.

Result: The IC50 of T22306 on H1975 cells was 9.17 μM. In further kinase evaluation, the kinase inhibition of EGFRL858R/T790M was 69.17%. In addition, time-dependent experiments and scratch and AO staining assays confirmed the potential of T22306 as an EGFR-TKI inhibitor, while hemolysis assays demonstrated no significant toxicity. Finally, molecular docking revealed the formation of critical hydrogen bonds between T22306 and LEU-718. Furthermore, molecular dynamics simulations showed that the T22306-5HG7 complex has a low binding energy (-117.73 ± 18.69 kJ/mol), thus suggesting that T22306 binds tightly to the target protein 5HG7.

Conclusion: In this study, we rapidly screened potential compounds against NSCLC with the help of virtual screening technology. Further in vitro experiments demonstrated that T22306 successfully overcame the L858R/T790M mutation and could be a potential epidermal growth factor receptor inhibitor.

Background: Hepatocellular Carcinoma (HCC) is a primary hepatic tumor and is one of the world's third most frequent malignancies after lung and colorectal. After stomach, lung, and colorectal cancers, it is the most common cause of cancer-related mortality. Since the Palaeolithic era, herbs have been used as an essential source of alternative drugs. Modern cancer treatments that use chemotherapeutic medications are made of chemicals derived from plants.

Objective: The present review is about the compilation of phytochemical extracts and molecules from 2020 to July 2024.

Methods: A detailed literature survey was conducted to compile data from PubMed, Sci Finder, Science Direct, Google, etc. Results: The identification of novel treatments and their combinations for usage in the adjuvant context potentially address significant unmet needs in the management of HCC. A large number of investigations have been carried out these days on plants. Numerous phytochemicals included in plant extract may possess anti-cancer properties, including the ability to induce cell cycle arrest, suppress cell proliferation, increase apoptosis, and obstruct migration, invasion, and metastasis. These approaches possess less hazardous and more effective treatment in HCC.

Conclusion: This article is the compilation of data about research on phytomolecules and herbal extracts from January 2020 to July 2024 for the treatment of HCC in vitro and in-vivo. Various mechanisms involved in the treatment are also explored in the article. The growing interest of researchers in investigating new approaches toward HCC management with phytomolecules is rapidly growing.

Background: 1,4-Naphthoquinone and its derivatives are recognized for their potent anticancer effects, establishing this pharmacophore as a key focus in cancer research. Their potential to modulate cellular pathways suggests they could be effective in developing new HuR inhibitors, targeting a protein crucial for regulating cancer-related gene expression. Compounds C1-C20 were designed by using Discovery Studio (DS) software.

Methods: In this study, a systematic approach involves scaffold hopping followed by additional research such as molecular docking, ADMET, drug-likeness, toxicity prediction, molecular dynamic (MD) simulation, and binding free energy analysis was used to discover novel Human Antigen R (HuR) inhibitors.

Results: In molecular docking, 1,4-Naphthoquinone derivatives showed better interactions with the HuR protein compared to that of the conventional HuR inhibitor MS-444. Among twenty 1,4-Naphthoquinone derivatives, most of the compounds showed favorable pharmacokinetic characteristics. In the toxicity prediction model, most of the designed compounds were neither mutagenic nor carcinogenic. According to MD simulation, C5 is more stable than MS-444.

Conclusion: The designed 1,4-Naphthoquinone derivatives have been found to be crucial structural motifs for the discovery of novel HuR inhibitors, which was well supported by the in-silico screening and molecular modeling methods.

Background: The tetracyclic indoloquinoline ring system has attracted considerable interest in the recent past due to its broad spectrum of biological activities and its binding to various types of nucleic acids.

Objective: This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II.

Methods: Several compounds derived from 6-amino-11H-indolo[3,2-c]quinoline with diverse groups on the quinoline ring have been successfully synthesized according to a previously established protocol where all the synthesized indolo[3,2-c]quinoline derivatives were evaluated in vitro against A549, HCT-116, BALB/3T3, and MV4-11 cell lines using MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl- tetrazolium bromide) assay. These derivatives were then screened for their topo I and II inhibitory activities.

Results: The tested compounds were more effective at killing MV4-11 leukemia cells than the standard cancer drug cisplatin, as shown by the fact that their IC50 values were less than 0.9 μM. On the other hand, cisplatin revealed an IC50 value of 2.36 μM. Moreover, they exhibited inhibitory activity against both Topoisomerase (Topo) I and II. The most potent compound, 5g, demonstrated a suppressive impact on topoisomerase I, with an IC50 value of 2.9 μM compared to the positive control Camptothecin (IC50 1.64 μM) and compound 8 displayed remarkable topoisomerase II inhibitory activity with an IC50 of 6.82 μM compared to the positive control Doxorubicin (IC50 6.49 μM). The cell cycle study for compounds 5g and 8 revealed that cell cycle arrest occurred at the G1/S and S phases, respectively. Compounds 5g and 8 showed a high selectivity index, which suggests that they could be used to develop low-toxicity chemotherapeutic agents.

Conclusion: The results of this study demonstrate that compounds 5g and 8 can be considered promising candidates for further anti-cancer drug development, which might be related to inhibiting TOPO I and TOPO II activities.

Background: Cancer chemotherapy is one of the best ways to treat the patients with cancer as they can remove cancer cells, which can't be remove by radiation or surgery.

Aims: Our study is focused on identifying potent chemotherapeutic drugs with minor or no adverse side effects. Therefore, in this study, we aimed to synthesize ethyl 4-[(4-methylbenzyl)oxy] benzoate complex, a macrocyclic aromatic compound followed by testing its antineoplastic activity against Ehrlich ascites carcinoma (EAC) human breast cancer (MCF7) cells.

Methods: In vitro and in vivo assays were used for monitoring, cytotoxicity, tumor weight, survival time, tumor cell growth inhibition, and hematological parameters to investigate the anticancer effectiveness of the tested compound. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to examine the expression of growth and apoptotic related genes. Haematological and biochemical parameters were assessed to examine the host toxicity in mice.

Results: The compound exhibited notable anticancer activity against both EAC and MCF7cells. It showed 40.70 and 58.98 % cell growth inhibition at the doses of 0.5 and 1.00 mg/kg, respectively in comparison to that of control EAC-bearing mice (p < 0.0001). The result is comparable with clinically used chemotherapeutic drugs cisplatin (59.2% growth inhibition at the dose of 1.0 mg/kg body weight). A four folds reduction of tumor weight (volume) of treated group at higher dose (1.0 mg/kg/day) was noted in comparison to that of untreated EAC-bearing mice. Also, the mean survival time of treated mice (1.00 mg/kg) increased by more than 83.07% when compared to that of control EAC-bearing mice (p<0.001). In addition, EAC-bearing control mice showed drastic deterioration of RBC, WBC, and % of hemoglobin, however, in the treated mice these parameters were restored towards normal levels. A dose dependent reduction of growth and proliferation of MCF7 cells was noted in compound treated cells. Most importantly, apoptosis of MCF7 was induced followed by activation of pro-apoptotic genes (p53, Bax, Parp, Caspase-3, -8, -9) and inactivation of antiapoptotic, e.g. Bcl2 gene. Toxicological studies reveal that there were changes in hematological (RBC, WBC, % of Hb) and biochemical (serum glucose, cholesterol, creatinine, SGOT, SGPT) parameters during the treatment period, however, the parameters returned towards normal levels after the treatment period, indicating no or minor toxic effect of the compound on the host.

Conclusion: The compound has promising anticancer activity with no or minimum host toxic effects. Thus, it has the potential to be formulated as an effective chemo-agent, however, further preclinical and clinical research is imperative using animal and human models.

Objectives: Our study aimed to explore the effects of quercetin on glioma stem cells in patients with brain tumors.

Methods: Human glioblastoma cell line, U373MG, or glioma stem cell lines, were treated with quercetin. Cell viability was determined by using the cell counting kit 8 assays. Cell apoptosis was determined by using the Annexin-V reagent. Western blotting and qPCR were used to detect the protein and mRNA levels of cyclindependent kinase inhibitor 2A (p16INK4a). Chromatin immunoprecipitation analysis was used to determine the enrichment of H3K27me3 on the p16-INK4 locus with or without quercetin.

Results: Treatment with quercetin inhibited cell viability and induced cell apoptosis in U373MG cells. Moreover, treatment with quercetin inhibited the cell viability of four glioma stem cell lines (G3, G10, G15, and G17) from brain tumor samples at high concentrations while having no obvious effects for the other two glioma stem cell lines (G9 and G21). Treatment with quercetin increased the mRNA and protein levels of p16- INK4 in glioma stem cell lines. The study of the underlying mechanism revealed that treatment with quercetin reduced H3K27me3 (an epigenetic modification to the DNA packaging protein histone H3) levels at the p16-INK4 locus.

Conclusions: In conclusion, quercetin inhibits glioma cell growth by activating p16-INK4 gene expression through epigenetic regulation.

Antibody-drug conjugates (ADCs) are a groundbreaking advancement in targeted cancer therapy, combining the precision of monoclonal antibodies with the potency of cytotoxic drugs. This review first outlines the components of ADCs and their mechanisms of action before providing a comprehensive overview of the current state of ADC technology. It covers both FDA-approved ADCs and those in various stages of clinical development, as well as future research directions. The review also explores recent innovations, such as bispecific antibodies and pro-body-drug conjugates, which offer promising new strategies for improving efficacy and minimizing off-target effects. The review emphasizes the need for ongoing research to optimize ADC design and develop novel approaches to enhance their therapeutic potential.

Background: Despite ongoing advances and introducing innovative therapeutic approaches for the treatment of multiple myeloma (MM), relapses are common, with low overall survival rates. G protein-coupled receptor, class C, group 5, and member D (GPRC5D) has been expressed in several myeloma cell lines and has demonstrated encouraging outcomes results in in-vitro studies as a potential target for immunotherapies.

Objective: We aimed to investigate the safety and efficacy of GPRC5D-targeted CAR T cell therapies in MM patients.

Methods: On August 24, 2023, the databases of PubMed, Scopus, Embase, and Web of Science were systematically searched for pertinent studies. After completing a two-step title/abstract and full-text screening process, the eligible studies were included.

Results: Following the screening of 107 articles, four studies of 130 multiple myeloma patients treated with GPRC5D-targeted CAR T-cell therapy were included. The meta-analyses showed an ORR of 87% (95% CI [81- 93%]), with 74% (95% CI [65-73%]) for those with prior BCMA-targeted therapy and 88% (95% CI [78-99%]) for those without. PR was 25%, VGPR 33%, and CR/sCR 48%, with 65% achieving MRD-negativity. In terms of safety, hematologic AEs were common, with anemia reported in 86% of patients. Non-hematologic common AEs included CRS (83%, 5% grade ≥3) and hypocalcemia (63%, 10% grade ≥3). No significant publication bias was detected.

Conclusion: GPRC5D is an active and safe target that shows promising results in the treatment of relapsed and/or refractory (R/R) MM and heavily pretreated patients.