Tailoring of novel biologically active molecules based on N4-substituted sulfonamides bearing thiazole moiety exhibiting unique multi-addressable biological potentials

Nowadays, the growth of drug-resistant microbial strains (MDRs) is a serious public health threat worldwide. Moreover, tens of millions of people are annually diagnosed with cancer worldwide, and more than half of patients ultimately die. In the present study, a new series of 2-(4-substituted-thiazol-2-ylamino)acetamides and N-(4-substituted-thiazol-2-yl)acetamides incorporating sulfonamide moieties were designed, synthesized, well-characterized and successfully evaluated for their antimicrobial activity against multidrug resistant strains and screened for cytotoxic activity against normal lung fibroblast (WI-38), human lung carcinoma (A549), and human breast carcinoma (MDA-MB-231) cell lines. Fluorescence-activated cell sorting (FACS) analysis and molecular modeling study were performed to identify the mode of action of the novel synthesized compounds and their binding interactions with the active sites of dihydrofolate reductase enzyme (DHFR).     

Computational design and experimental discovery of an antiestrogenic peptide derived from alpha-fetoprotein

Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.     

In silico drug design and molecular docking of novel amidophosphonates and sulfamidophosphonates as inhibitors of urokinase-type plasminogen activator

Cancer is one of the most serious health problems worldwide, affecting individuals from different sexes, ages, and races. However, the most frequent cancer types in the world are lung, prostate, stomach, colorectal, and esophagus in men; and breast, lung, stomach, colorectal and cervical in women. Currently, the search for new active substances used in oral targeted therapies are legitimate and opens up the possibility of an "ambulatory shift" in cancer treatment. In order to design anti-tumor drug candidates endowed with oral bioavailability, we studied trough an in silico approach the oral bioavailability of newly synthesized biomolecules; α-sulfamidophosphonates and α-amidophosphonates as well as their mechanism of action on the new target urokinase-type plasminogen activator (uPA). The studied compounds have been found to meet the five criteria of. Lipinski's rule. The Osiris, Molinspiration and SWISS/ADME calculations related to the compounds (1d, 2a) have shown that these compounds could be good candidates for interacting with the different targets, they have convincing characteristics in relation to the standard drug used. It can be concluded that these compounds are biologically important and possessing molecular properties desirable for being a drug candidate for oral use.The molecular docking results of the studied compounds revealed a good ligand-target interactions, the compounds (1d, 2a) presented a possibility of interacting as an inhibitor of the anticancer target: urokinase-type plasminogen activator (uPA).     

Evaluation of novel coumarin-proline sulfonamide hybrids as anticancer and antidiabetic agents

Abstract

Cancer and diabetes are considered as two major diseases affecting human health worldwide. Various therapies are available for treatment of cancer and diabetes individually, peptide linkage containing proline sulfonamide can be a promising therapy for treatment of both cancer as well as diabetes. Here, we report design and synthesis of novel coumarin-proline sulfonamide derivatives as anticancer and antidiabetic agents. All the synthesized compounds were screened for their anticancer activity against lungs cancer cell line (A549) and breast cancer cell line (MCF7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye (MTT)assay and antidiabetic activity using DPP-IV inhibition assay. Compound 16b showed excellent activity against breast cancer cell line (MCF7) with IC₅₀ value of 1.07?µM. All compounds showed moderate DPP-IV inhibition.     

Anticancer activities of manganese-based photoactivatable CO-releasing complexes (PhotoCORMs) with benzimidazole derivative ligands

Carbon monoxide is an important signaling molecule which is produced by heme oxygenase-1. CO shows antiproliferative activity against cancer cells; hence, activation of HO-1 is a significant inhibition strategy against tumor formation and survival of cancer cells. In this work, manganese-based CO-releasing molecules (CORMs) were designed and synthesized to inhibit breast cancer cell proliferation. Human invasive ductal breast cancer cells (MCF-7) were treated with the synthesized CORMs to investigate the effect of the complexes on breast cancer survival under UV light. In vitro experiments indicated that the complexes inhibited breast cancer cell proliferation, and further, the antiproliferative effects were increased under UV light. Thus, these novel CORMs may provide a drug template for the treatment of invasive ductal breast cancer.     

Biomarker-targeted fluorescent probes for breast cancer imaging

This review summarized fluorescent probes for breast cancer imaging according to different biomarkers probes recognized.     

Green-synthesized Zinc oxide nanoparticle,an efficient safe anticancer compound for human breast MCF7 cancer cells

There are many types of researches investigating anticancer therapeutics for breast cancer therapy. Zinc oxide nanoparticles (ZnONPs) as an efficient drug delivery system, has been widely being used in various biomedical applications. In the current study, we synthesized ZnONP applying Rheum rhaponticum Waste (RRW) as a novel bio-platform to investigate its anticancer impacts on MCF7 breast cancer cells compared with normal Human HFF and HDF cells. In this regard, RRW was triggered to synthesize the ZnONPs. Then, they were characterized by XRD, FTIR, TEM, and SEM analysis. Next, the MCF-7, HFF, and HDF cell lines were cultured and treated as the following plane: Incubation of all cell lines for 72, 48, and 24 hours at the presence of different ZnONPs doses. Finally, the cell morphology, BCL2- BAX genes expression profile and AO/PI-fluorescent cell staining on the 48-hour incubated cells were analyzed to check the ZnONP apoptotic activity. Moreover, the ZnONP antioxidant activity was analyzed by a DPPH antioxidant test. We produced the 30 nm ZnONPs which significantly increased the BAX and decreased the BCL-2 gene expression. According to the results including the Sub G1 enhancement peaks, apoptotic hallmarks, MTT assay, and the AO/PI-fluorescent stained cells, ZnONPs can specifically induce apoptotic death in MCF7 breast cancer cells compared with normal HFF and HDF cells. The IC₅₀ values of MCF-7 in 72, 48, and 24 hr were measured at 8, 11, and 12 μg/ml in 72, 48, and 24 hr, respectively. This is while the mentioned values in the normal cells (HFF, HDF) were estimated at higher treatment doses. In conclusion, we suggest that the ZnONPs have the potential to be applied as a safe cell-specific apoptosis inducer in breast cancer treatment. However, there are many challenges that need to be clarified for applying them as an efficient anticancer agent.     

Gold nanoparticles synthesized from Curcuma wenyujin inhibits HER-2/neu transcription in breast cancer cells (MDA-MB-231/HER2)

Breast cancer is the second leading cancer diagnosed globally and every year about two million new incidences were accounted. Curcuma wenyujin, a rhizome grown abundantly in china and used in various traditional Chinese medicines. Recent times the research on anticancer property of Curcuma wenyujin is extensively on progress and it is proved by many researchers. The major drawback of herbal drugs are their limited bio-availability, to overcome this we formulated a herbal gold nanodrug with Curcuma wenyujin (CW-AuNPs) and examined its anticancer potential against breast cancer cells. The cytotoxic effect of synthesized CW-AuNPs against MDA-MB231/HER2 cell line was inspected by MTT assay and the dosage for further analysis was calculated. The apoptosis triggered by CW-AuNPs was investigated by intracellular ROS and caspases levels in CW-AuNPs treated MDA-MB231/HER2 cell line. Over expression of HER2/neu, oncogene leads to meager prognosis in most of the breast cancer patients. Therefore in the current exploration, we investigated the inhibitory potential of CW-AuNPs against the expression of HER2/neu in breast cancer cell line by immunocytochemical and immunoblotting analysis. Our results of UV-Spec, FTIR, TEM and Atomic force investigation confirms, the synthesized nanodrug CW-AuNPs satisfies the characteristic features of a nanodrug. The results authentically proves that CW-AuNPs possessed the potent anticancer activity, increases ROS in breast cancer cells which in turn inhibits the HER2/neu, key oncogene expression and inhibited the cancer cell proliferation.     

Development and Effects of Influenza Antiviral Drugs

Influenza virus is a highly contagious zoonotic respiratory disease that causes seasonal outbreaks each year and unpredictable pandemics occasionally with high morbidity and mortality rates, posing a great threat to public health worldwide. Besides the limited effect of vaccines, the problem is exacerbated by the lack of drugs with strong antiviral activity against all flu strains. Currently, there are two classes of antiviral drugs available that are chemosynthetic and approved against influenza A virus for prophylactic and therapeutic treatment, but the appearance of drug-resistant virus strains is a serious issue that strikes at the core of influenza control. There is therefore an urgent need to develop new antiviral drugs. Many reports have shown that the development of novel bioactive plant extracts and microbial extracts has significant advantages in influenza treatment. This paper comprehensively reviews the development and effects of chemosynthetic drugs, plant extracts, and microbial extracts with influenza antiviral activity, hoping to provide some references for novel antiviral drug design and promising alternative candidates for further anti-influenza drug development.     

Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer

Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15–20% of BC and is extremely aggressive resulting in reduced survival rate, which is mainly due to the low therapeutic efficacy of available treatments. Photodynamic therapy (PDT) is an interesting therapeutic approach in the treatment of cancer; the photosensitizers with good absorption in the therapeutic window, combined with their specific targeting of cancer cells, have received particular interest. This review aims to revisit the latest developments on chlorin-based photoactive molecules for targeted therapy in TNBC. Photodynamic therapy, alone or combined with other therapies (such as chemotherapy or photothermal therapy), has potential to be a safe and a promising approach against TNBC.     

核酸适配体在癌症诊断中的研究进展

核酸适配体是通过指数富集配体系统进化技术(SELEX)从体外合成的寡核苷酸文库中筛选得到的短的寡核苷酸分子(ssDNA或RNA).核酸适配体能够通过折叠成特定的空间结构与靶标分子进行特异性结合,与抗体相比,适配体具有高亲和力、易修饰、低成本、易于合成和低免疫原性等优势,可以针对细胞、蛋白质、组织、生长因子进行癌症生物标...     

Synthesis of Folate Conjugated Fluorescent Nanoparticle Probe and Its Application in Cervical Cancer Cell Imaging

Abstract

Cervical cancer is the second most common cancer in women worldwide with 80% of cases arising in the developing world, following cancer of the breast. The mortality associated with cervical cancer can be reduced if this disease is detected in a timely fashion. In this study, a folate conjugated fluorescent nanoparticle (FCFN) probe was used to detect cervical cancer cells. Fluorescent nanoparticles (FNs), with excellent characteristics such as nontoxicity and photostability, were first synthesized with a simple, cost-effective, and environmentally friendly modified St?ber synthesis method and then successfully modified with folate. This kind of fluorescence probe based on FCFNs has been used to detect cervical cancer cells with fluorescence microscopy imaging technology. The experimental results demonstrate that the FCFNs can effectively recognize cervical cancer cells and exhibit good sensitivity and exceptional photostability; they would provide a novel way for the diagnosis and curative effect observation of cervical cancer cells and offer a new method in detecting folate receptors (FR).     

Review: Radionuclide Molecular Imaging Targeting HER2 in Breast Cancer with a Focus on Molecular Probes into Clinical Trials and Small Peptides

As the most frequently occurring cancer worldwide, breast cancer (BC) is the leading cause of cancer-related death in women. The overexpression of HER2 (human epidermal growth factor receptor 2) is found in about 15% of BC patients, and it is often associated with a poor prognosis due to the effect on cell proliferation, migration, invasion, and survival. As a result of the heterogeneity of BC, molecular imaging with HER2 probes can non-invasively, in real time, and quantitatively reflect the expression status of HER2 in tumors. This will provide a new approach for patients to choose treatment options and monitor treatment response. Furthermore, radionuclide molecular imaging has the potential of repetitive measurements, and it can help solve the problem of heterogeneous expression and conversion of HER2 status during disease progression or treatment. Different imaging probes of targeting proteins, such as monoclonal antibodies, antibody fragments, nanobodies, and affibodies, are currently in preclinical and clinical development. Moreover, in recent years, HER2-specific peptides have been widely developed for molecular imaging techniques for HER2-positive cancers. This article summarized different types of molecular probes targeting HER2 used in current clinical applications and the developmental trend of some HER2-specific peptides.     

An Insight into the Anti-Angiogenic and Anti-Metastatic Effects of Oridonin: Current Knowledge and Future Potential

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients’ outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin’s anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action.     

Fecal Metabolic Profiling of Breast Cancer Patients during Neoadjuvant Chemotherapy Reveals Potential Biomarkers

Breast cancer (BC) is the most common form of cancer among women worldwide. Despite the huge advancements in its treatment, the exact etiology of breast cancer still remains unresolved. There is an increasing interest in the role of the gut microbiome in modulating the anti-cancer therapeutic response. It seems that alteration of the microbiome-derived metabolome potentially promotes carcinogenesis. Taken together, metabolomics has arisen as a fascinating new omics field to screen promising metabolic biomarkers. In this study, fecal metabolite profiling was performed using NMR spectroscopy, to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy (NAC) for breast cancer. Metabolic profiles of feces from patients (n = 8) following chemotherapy treatment cycles were studied. Interestingly, amino acids were found to be upregulated, while lactate and fumaric acid were downregulated in patients under the second and third cycles compared with patients before treatment. Furthermore, short-chain fatty acids (SCFAs) were significantly differentiated between the studied groups. These results strongly suggest that chemotherapy treatment plays a key role in modulating the fecal metabolomic profile of BC patients. In conclusion, we demonstrate the feasibility of identifying specific fecal metabolic profiles reflecting biochemical changes that occur during the chemotherapy treatment. These data give an interesting insight that may complement and improve clinical tools for BC monitoring.     

Ruthenium Complexes as Promising Candidates against Lung Cancer

Lung cancer is one of the most common malignancies with the highest mortality rate and the second-highest incidence rate after breast cancer, posing a serious threat to human health. The accidental discovery of the antitumor properties of cisplatin in the early 1960s aroused a growing interest in metal-based compounds for cancer treatment. However, the clinical application of cisplatin is limited by serious side effects and drug resistance. Therefore, other transition metal complexes have been developed for the treatment of different malignant cancers. Among them, Ru(II/III)-based complexes have emerged as promising anticancer drug candidates due to their potential anticancer properties and selective cytotoxic activity. In this review, we summarized the latest developments of Ru(II/III) complexes against lung cancer, focusing mainly on the mechanisms of their biological activities, including induction of apoptosis, necroptosis, autophagy, cell cycle arrest, inhibition of cell proliferation, and invasion and metastasis of lung cancer cells.     

Distinguishing breast cancer cells using surface-enhanced Raman scattering

The detection and identification of epidermal growth factor receptor 2 (HER2)-positive breast cancer cells is crucial for the clinic therapy of breast cancer. For the aim of the detection, a novel surface-enhanced Raman scattering (SERS) probe for distinguishing breast cancers at different HER2 statuses is reported in this paper. In such a probe, anti-HER2 antibody-conjugated silver nanoparticles have been synthesized for specific targeting of HER2-positive breast cancer cells. More importantly, different from the previously reported SERS probe for targeting cancer cells, p-mercaptobenzoic acid is utilized as both the Raman reporter and the conjugation agent for attaching antibody molecules, which leads to a much simplified structure. For investigating the ability of such a probe to distinguish breast cancer cells, SKBR3 and MCF7 cells were chosen as two model systems, which are HER2-positive- and HER2-negative-expressing cells, respectively. The experimental results reveal that SKBR3 cells exhibit much stronger SERS signals than MCF7 cells, indicating that the probe could be utilized to distinguish breast cancer cells at different HER2 statuses. This kind of SERS probe holds a potential for a direct detection of living breast cancer cells with the advantages of easy fabrication, high SERS sensitivity, and biocompatibility.     

Identification of Potential Markers Related to Neoadjuvant Chemotherapy Sensitivity of Breast Cancer by SELDI-TOF MS

Neoadjuvant chemotherapy (NACT) is known to be beneficial for patients with locally advanced breast cancer. However, there is still no unified standard on the evaluation of NACT. To identify the potential markers related to NACT sensitivity of breast cancer, in the present study, we examined the protein spectrum of breast cancer tissues before and after NACT using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Totally, 87 protein samples were extracted from tissues of breast cancer, with 30 from patients before NACT, 30 from patients after NACT, and 27 from patients without any treatment. To eliminate confounding factors a couple of tissue samples from the same patient were mixed. SELDI-TOF MS analysis demonstrated that the intensities of eight different protein peaks, i.e., 26,055.46, 17,898.94, 8,949.50, 11,652.02, 11,053.48, 38,546.56, 5,825.89, and 22,250.63 Da, were higher in samples after NACT than those before NACT. Although further experiments are needed to prove the reliability of the proteins identified in this study, our results will help the establishment of protein model based on drug resistance-related protein peaks to screen whether a patient is suitable for adopting NACT and to improve cancer treatment.     

Cellular Uptake of the ATSM−Cu(II) Complex under Hypoxic Conditions

The Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) complex (ATSM−Cu(II)) has been suggested as a promising positron emission tomography (PET) agent for hypoxia imaging. Several in-vivo studies have shown its potential to detect hypoxic tumors. However, its uptake mechanism and its specificity to various cancer cell lines have been less studied. Herein, we tested ATSM−Cu(II) toxicity, uptake, and reduction, using four different cell types: (1) mouse breast cancer cells (DA-3), (2) human embryonic kidney cells (HEK-293), (3) breast cancer cells (MCF-7), and (4) cervical cancer cells (Hela) under normoxic and hypoxic conditions. We showed that ATSM−Cu(II) is toxic to breast cancer cells under normoxic and hypoxic conditions; however, it is not toxic to normal HEK-293 non-cancer cells. We showed that the Cu(I) content in breast cancer cell after treatment with ATSM−Cu(II) under hypoxic conditions is higher than in normal cells, despite that the uptake of ATSM−Cu(II) is a bit higher in normal cells than in breast cancer cells. This study suggests that the redox potential of ATSM−Cu(II) is higher in breast cancer cells than in normal cells; thus, its toxicity to cancer cells is increased.     

Rhodium Nanoparticles as a Novel Photosensitizing Agent in Photodynamic Therapy against Cancer

Photodynamic therapy (PDT) is a promising alternative treatment for different types of cancer due to its high selectivity, which prevents healthy tissues from being damaged. The use of nanomaterials in PDT has several advantages over classical photosensitizing agents, due to their unique properties and their capacity for functionalization. Especially interesting is the use of metallic nanoparticles, which are capable of absorbing electromagnetic radiation and either transferring this energy to oxygen molecules for the generation of reactive oxygen species (ROS) or dissipating it as heat. Although previous reports have demonstrated the capacity of Rh derivatives to serve as anti-tumor drugs, to the best of our knowledge there have been no studies on the potential use of small-sized Rh nanoparticles as photosensitizers in PDT. In this study, 5 nm Rh nanoparticles have been synthesized and their potential in PDT has been evaluated. The results show that treatment with Rh nanoparticles followed by NIR irradiation induces apoptosis in cancer cells through a p53-independent mechanism.