Anti-cancer agents in medicinal chemistry最新文献

Background: Sulfonamide derivatives are well-reported hCA IX inhibitors; however, they inhibit all types of hCA without any selectivity, leading to severe adverse effects. Hence, developing a novel nonsulfonamide class of tumor-associated hCA IX inhibitors through non-classical inhibition may provide greater selectivity and better pharmacokinetics.

Objective: The objective of this study was to develop non-sulfonamide derivatives as potential human carbonic anhydrase (hCA) inhibitors and develop a new series of chromene-linked bis-indole derivatives.

Methods: We synthesized and characterized the chromene-linked bis-indole derivatives and further evaluated them against four hCA isoforms, i.e., hCA I, hCA II, hCA IX, and hCA XII, and determined the ADMET parameters by the In-silico method.

Results: Most of the compounds showed significantly greater affinity and selectivity towards the tumorassociated hCA IX over other hCA isoforms within the lower micromolar to submicromolar range. In particular, the bromo-substituted bis-indole derivative 6t showed an excellent inhibition of hCA IX isoform with an affinity (Ki) of 2.61 μM. In contrast, the cyano group substituted bis-indole derivative 6s and also displayed a strong inhibition of hCA IX isoform with an affinity (Ki) of 2.73 μM. Many other potential candidates, including 6g, 6i, 6k, 6m, 6o, 6p, and 6r, showed higher affinity at tumor-associated hCA IX with lower than 10 μM compared to other hCA isoforms.

Conclusion: Therefore, the chromene-linked bis-indole derivatives can serve as a novel non-sulfonamide class of tumor-associated hCA IX inhibitors.

Background: One of the growing diseases in today's human societies is cancer, which has become a major challenge, especially in industrialized and developing countries. Cancer treatments are diverse, but they usually use surgery, chemotherapy, and radiotherapy to improve patients. Existing drugs are usually expensive and, in some cases, are not effective due to drug resistance and side effects. Finding compounds of natural origin can be somewhat effective and useful in helping doctors to treat this disease. Ferula plants, which are traditionally used as spices or for medicinal purposes, can be a good source for finding anti-cancer compounds due to their various compounds, such as monoterpenes, sulfide compounds, and polyphenols. Several studies have shown that compounds found in Ferula plants have significant anticancer effects on various types of cancer cells.

Objective: This article was compiled with the aim of collecting evidence and articles related to the anti-cancer effects of three compounds obtained from these plants, namely Conferone, Diversin, and Ferutinin.

Methods: This review article was prepared by searching the terms Conferone, Diversin, Ferutinin and cancer and related information was collected through searching electronic databases such as ISI Web of Knowledge, PubMed and Google Scholar until the March of 2024.

Conclusion: The results of this review showed that relatively comprehensive studies have been conducted in this field and these studies have shown that these compounds can be used in the design of future anticancer drugs. Among the examined compounds, conferone showed that it has the best effect on cancer cells.

Background and objective: Benzothiazole derivatives, a class of heterocyclic compounds, exhibited diverse biological activities influenced by substituents in the thiazole ring. This study aimed to synthesize these compounds with two functional groups to investigate their potential as anticancer agents, particularly against breast cancer. While previous research demonstrated the efficacy of 2-substituted benzothiazoles against glioma and cervical and pancreatic cancer cells, there is a gap in studies targeting breast cancer.

Methods: The synthesized compounds were tested in vitro using MCF-7, MDA-MB-231, and MCF-10A cell lines, with Doxorubicin as the positive control. Various assays were conducted, including Annexin V/PI, cell cycle analysis, wound healing, and measurement of mitochondrial membrane potential. Protein expression of EGFR and transcription levels of apoptosis-related genes (Bax and Bcl-xL) and cancer progression-related genes (JAK, STAT3, ERK, AKT, mTOR) were analyzed. Additionally, the balance between antioxidants and oxidants was evaluated by measuring TAS and TOS levels.

Results: Our findings revealed that benzothiazole compounds significantly inhibited breast cancer cell growth by reducing cell motility, disrupting mitochondrial membrane potential, and inducing cell cycle arrest in the sub-G1 phase. These compounds increased reactive oxygen species accumulation, leading to cell death. Furthermore, they decreased EGFR protein levels, increased Bax gene transcription, and downregulated the expression of genes such as JAK, STAT3, ERK, AKT, and mTOR.

Conclusion: In conclusion, benzothiazole derivatives exhibited potent inhibitory effects on breast cancer in vitro by promoting apoptosis, downregulating EGFR activity, and modulating key signaling pathways, including JAK/STAT, ERK/MAPK, and PI3K/Akt/mTOR. These results highlighted the potential of benzothiazole derivatives as novel therapeutic agents for breast cancer treatment.

Background: PC is among the cancer types with high incidence and mortality. New and effective strategies are being sought for the treatment of deadly cancers, such as PC. In this context, the use of nanocarrier systems containing titanium dioxide can improve treatment outcomes and increase the effectiveness of anticancer drugs.

Objective: This study aimed to evaluate the cytotoxic activity of doxorubicin (DOX) and paclitaxel (PTX) drugs on the prostate cancer (PC) cell line by attaching them to pegylated titanium dioxide nanoparticles and to examine their effect on the expression levels of dual-specificity phosphatase (DUSP) genes.

Methods: Free DOX and PTX drugs, DOX and PTX compounds bound to the pegylated titanium dioxide system were applied to DU-145 cells, a PC cell line, under in vitro conditions, and MTT analysis was performed. Additionally, the IC50 values of these compounds were analyzed. In addition, the expression levels of DUSP1, DUSP2, DUSP4, DUSP6, and DUSP10 genes were measured using RT-PCR. Additionally, bioinformatics and molecular docking analyses were performed on DUSP proteins.

Results: The cytotoxic activity of PTX compound bound to PEGylated TiO2 was found to be higher than that of DOX compound bound to PEGylated TiO2. Additionally, when the expression levels were compared to the control group, the expression levels of DUSPs were found to be lower in the drugs of the drug carrier systems.

Conclusion: Accordingly, it was predicted that the pegylated titanium dioxide nano-based carrier could be effective in PC.

Background: Cancer is regarded as one of the main causes of death globally. Future predictions indicate that the death rate from cancer will keep rising, which may reach 11.4 million in 2030. Carcinogenesis refers to the phenomenon of transforming a normal cell into a cancer cell. Cancer is characterized by unregulated and uncontrolled cell division due to alterations at the molecular and genetic levels. Gene mutations can speed up the rate of cell division, which leads to cancer. Metastasis entails the dissemination of cancer cells from the primary site to distant regions of the body via the circulatory or lymphatic systems.

Objective: This review is mainly focusing on the anticancer properties of terpenoids. In the case of human beings, several types of cancers can be treated clinically based on the form and phase of the cancer. So, there are different types of treatment regimens available for the management of cancer, such as immunotherapy, hormonal therapy, radiation therapy, and chemotherapy.

Methods: Several problems are associated with cancer therapy, including chemoresistance, severe toxicity, relapse, and metastasis. To minimize these complications, natural products like terpenoids seem to be beneficial for the effective management of cancer.

Results: Experimental results revealed that the anticancer potential of terpenoids is due to activation of apoptosis and stimulation of cell cycle arrest. Some of the terpenoids exhibit anticancer effects by inhibiting angiogenesis and metastasis via the regulation of several signaling pathways intracellularly. Certain terpenoids have been shown to work in concert with anticancer medications (doxorubicin, cisplatin, paclitaxel, and 5-fluorouracil) to provide synergistic effects. These terpenoids have also been shown to be effective against cancer cells that are resistant to several drug therapies.

Conclusion: The current study will focus on signaling pathways and mode of action of several types of terpenoids as anticancer agents. Further, it will provide insights into the ongoing clinical trials and prospective pathways for the advancement of terpenoids as possible anti-cancer agents.

Background: Mesoionic compound MI-D possesses important biological activities, such as antiinflammatory and antitumoral against melanoma and hepatocarcinoma. Glioblastoma is the most aggressive and common central nervous system tumor in adults. Currently, chemotherapies are not entirely effective, and the survival of patients diagnosed with glioblastoma is extremely short.

Objective: In this study, we aimed to evaluate the cytotoxicity of MI-D in noninvasive A172 glioblastoma cells and establish which changes in functions linked to energy provision are associated with this effect.

Methods: Cells A172 were cultured under glycolysis and phosphorylation oxidative conditions and evaluated: viability by the MTT method, oxygen consumption by high-resolution respirometry, levels of pyruvate, lactate, citrate, and ATP, and glutaminase and citrate synthase activities by spectrophotometric methods.

Results: Under glycolysis-dependent conditions, MI-D caused significant cytotoxic effects with impaired cell respiration, reducing the maximal capacity of the electron transport chain. However, A172 cells were more susceptible to MI-D effects under oxidative phosphorylation-dependent conditions. At the IC25, inhibition of basal and maximal respiration of A172 cells was observed, without stimulation of the glycolytic pathway or Krebs cycle, along with inhibition of the activity of glutaminase enzyme, resulting in a 30% ATP deficit. Additionally, independent of metabolic conditions, MI-D treatment induced cell death in A172 cells by apoptosis machinery/ processes.

Conclusion: The impairment of mitochondrial respiration by MI-D under the condition sustained by oxidative phosphorylation may enhance the cytotoxic effect on A172 glioma cells, although the mechanism of cell death relies on apoptosis.

Introduction/objective: Metastatic melanoma resists current pharmacological regimens that act through apoptosis. This indicates that therapies acting via non-apoptotic cell-death pathways could be pursued. Doramectin has shown promising results in another cancer of neural crest origin, neuroblastoma, through the inhibition of growth via autophagy. Our research hypothesis is that doramectin induces autophagy in B16F10 melanoma cells.

Methods: Cells were treated with doramectin (15 uM) or a combination of both doramectin and a cell-death inhibitor, compared to untreated control cells (media), and then analyzed with MTT analysis. Likewise, MDC analysis was completed to detect autophagy involvement with doramectin treatment. Flow cytometry and TUNEL Assay were conducted to observe cell death-related effects.

Results: MTT analysis of doramectin-treated cells displayed a decrease in cell growth compared to control. Apoptotic morphology was prominent in melanoma cells treated with doramectin. Increased autophagy was not detected by fluorometric microscopic analysis. Flow cytometry analysis of doramectin-treated cells showed apoptosis as a major mode of cell death with some necrosis.

Conclusion: Doramectin induces a novel cell-death mechanism in melanoma compared to other forms of cancer and should be studied as an effective anti-cancer agent for melanoma treatment.

Ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation, is increasingly recognized for its role in cancer development and as a potential therapeutic target. This review consolidates insights into the molecular mechanisms underpinning ferroptosis and evaluates the therapeutic potential of small-molecule inducers, such as erastin, RSL3, sulfasalazine, and sorafenib, which selectively trigger ferroptosis in cancer cells. It highlights the distinct morphological and molecular signatures of ferroptosis, its complex interplay with iron, lipid, and amino acid metabolic pathways, and the resultant implications for cancer treatment strategies. Strategic manipulation of the ferroptosis pathway offers a groundbreaking approach to cancer treatment, potentially circumventing the resistance that cancers develop against traditional apoptosis-inducing agents. Furthermore, it also emphasizes the necessity of refining these small molecules for clinical application and exploring their synergistic potential when combined with current therapies to augment overall treatment efficacy and improve patient outcomes. Ferroptosis thus emerges as a promising avenue in the realm of cancer therapy. Moving forward, research endeavors should focus on a more nuanced understanding of the interconnections between ferroptosis and other cell death modalities. Additionally, comprehensive evaluations of the long-term safety and therapeutic indices of the involved compounds are imperative. Such investigations are poised to herald a transformative shift in the paradigm of oncology, paving the way for innovative and targeted interventions.

Background: Tender Coconut Water (TCW) is a nutrient-rich dietary supplement that contains in bioactive secondary metabolites and phytohormones with anti-oxidative and anti-inflammatory properties. Studies on TCW's anti-cancer properties are limited and the mechanism of its anti-cancer effects have not been defined.

Objective: In the present study, we investigate TCW for its anti-cancer properties and, using untargeted metabolomics, we identify components form TCW with potential anti-cancer activity.

Methodology: Cell viability assay, BrdU incorporation assay, soft-agar assay, flow-cytometery, and Western blotting were used to analyze TCW's anticancer properties and to identify mechanism of action. Liquid chromatography- Tandem Mass Spectroscopy (LC-MS/MS) was used to identify TCW components.

Results: TCW decreased the viability and anchorage-independent growth of HepG2 hepatocellular carcinoma (HCC) cells and caused S-phase cell cycle arrest. TCW inhibited AKT and ERK phosphorylation leading to reduced ZEB1 protein, increased E-cadherin, and reduced N-cadherin protein expression in HepG2 cells, thus reversing the 'epithelial-to-mesenchymal' (EMT) transition. TCW also decreased the viability of Hep3B hepatoma, HCT-15 colon, MCF-7 and T47D luminal A breast cancer (BC) and MDA-MB-231 and MDA-MB-468 triplenegative BC cells. Importantly, TCW did not inhibit the viability of MCF-10A normal breast epithelial cells. Untargeted metabolomics analysis of TCW identified 271 metabolites, primarily lipids and lipid-like molecules, phenylpropanoids and polyketides, and organic oxygen compounds. We demonstrate that three components from TCW: 3-hydroxy-1-(4-hydroxyphenyl)propan-1-one, iondole-3-carbox aldehyde and caffeic acid inhibit the growth of cancer cells.

Conclusion: TCW and its components exhibit anti-cancer effects. TCW inhibits the viability of HepG2 hepatocellular carcinoma cells by reversing the EMT process through inhibition of AKT and ERK signalling.