Synthesis and cytotoxicity of novel 6,8,9-trisubstituted purine analogs against liver cancer cells.

A series of novel 6-(substituted phenyl piperazine)-8-(4-substituted phenyl)-9-cyclopentyl purines, 10-51, were synthesized by a four-step synthesis, achieving an overall yield of about 43 %. The reaction conditions were effectively optimized, and the final products were obtained with high purity and yield in all synthesis steps. The synthesized nucleobases were evaluated for their in vitro cytotoxic activities on selected human cancer cell lines (HUH7 (liver), HCT116 (colon), and MCF7 (breast)) using the Sulforhodamine B (SRB) assay. Among these analogs, compounds bearing 4-trifluoromethyl phenyl (19, 20 and 21), 4-methoxy phenyl (27) and 4-fluoro phenyl (34) substitutions at C-8 of purine were the most potent, and they were also analyzed in drug-resistance and drug-sensitive hepatocellular cancer cell (HCC) panels. Compound 19 displayed remarkable anticancer activities (IC50 = 2.9-9.3 µM) against Huh7, FOCUS, SNU475, SNU182, HepG2, and Hep3B cells compared to the positive control, Fludarabine. Additionally, the pharmacological properties and toxicity profiles of the molecules were investigated computationally by the Swiss-ADME and Pro-Tox II online tools, respectively. Results showed that our compounds have favorable physicochemical characteristics for oral bioavailability and do not reveal any toxicity endpoints such as carcinogenicity, immunotoxicity, mutagenicity, or cytotoxicity.

Exploration of novel 6,8,9-trisubstituted purine analogues: synthesis, in vitro biological evaluation, and their effect on human cancer cells.

Cancer, a leading global cause of mortality, demands continuous advancements in therapeutic strategies. This study focuses on the design and synthesis of a novel series of purine derivatives, specifically 6-(substituted phenyl piperazine)-8-(4-phenoxyphenyl)-9-cyclopentyl purine derivatives (5-11). The motivation behind this endeavor lies in addressing acquired resistance mechanisms in cancer cells, a significant hurdle in current treatment modalities. The synthesis, starting from 4,6-dichloro-5-nitropyrimidine, involves a multi-step process, resulting in seven new purine derivatives. Biological evaluation against human liver, colon, and breast cancer cells (Huh7, HCT116, and MCF7, respectively) was performed using the SRB assay. Among the synthesized analogs, compounds 5 and 6, exhibited notable cytotoxic activity, surpassing clinically used positive controls 5-Fluorouracil and Fludarabine in terms of efficacy. This research underscores the potential of purine derivatives with a phenyl group at the C-8 position as a scaffold for developing compounds with improved anticancer properties. The findings offer insights for future exploration and development of novel agents in cancer pharmaceutical research.

Targeting Ovarian Cancer with Chalcone Derivatives: Cytotoxicity and Apoptosis Induction in HGSOC Cells.

Ovarian cancer ranks as the eighth most prevalent form of cancer in women across the globe and stands as the third most frequent gynecological cancer, following cervical and endometrial cancers. Given its resistance to standard chemotherapy and high recurrence rates, there is an urgent imperative to discover novel compounds with potential as chemotherapeutic agents for treating ovarian cancer. Chalcones exhibit a wide array of biological properties, with a particular focus on their anti-cancer activities. In this research, we documented the synthesis and in vitro study of a small library of chalcone derivatives designed for use against high-grade serous ovarian cancer (HGSOC) cell lines, specifically OVCAR-3, OVSAHO, and KURAMOCHI. Our findings revealed that three of these compounds exhibited cytotoxic and anti-proliferative effects against all the tested HGSOC cell lines, achieving IC50 concentrations lower than 25 µM. Further investigations disclosed that these chalcones prompted an increase in the subG1 phase cell cycle and induced apoptosis in OVCAR-3 cells. In summary, our study underscores the potential of chalcones as promising agents for the treatment of ovarian cancer.

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl containing purine nucleobase analogs act as potent anticancer agents and induce apoptosis via inhibiting Src in hepatocellular carcinoma cells.

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl-containing purine nucleobase analogs were tested for their in vitro anticancer activity against human cancer cells. Compounds 15, 17-24, 49, and 56 with IC50 values less than 10 µM were selected for further examination on an enlarged panel of liver cancer cell lines. Experiments revealed that compound 19 utilizes its high cytotoxic potential (IC50 < 5 µM) to induce apoptosis in vitro. Compound 19 displayed a KINOMEscan selectivity score S35 of 0.02 and S10 of 0.01 and demonstrated a significant selectivity against anaplastic lymphoma kinase (ALK) and Bruton's tyrosine kinase (BTK) over other kinases. Compounds 19, 21, 22, 23, and 56 complexed with ALK, BTK, and (discoidin domain-containing receptor 2) DDR2 were analyzed structurally for binding site interactions and binding affinities via molecular docking and molecular dynamics simulations. Compounds 19 and 56 displayed similar interactions with the activation loop of the kinases, while only compound 19 reached toward the multiple subsites of the active site. Cell cycle and signaling pathway analyses exhibited that compound 19 decreases phosho-Src, phospho-Rb, cyclin E, and cdk2 levels in liver cancer cells, eventually inducing apoptosis.

Tetraphenylethylene-Based Photoluminescent Self-Assembled Nanoparticles: Preparation and Biological Evaluation.

The conjugation of tetraphenylethylene (TPE) with podophyllotoxin, N-desacetylthiocolchicine, and cabazitaxel through a sebacic acid linker led to the formation of fluorescent nanoparticles. Dynamic light scattering (DLS) and photoluminescence spectroscopy were used for the identification and characterization of the fluorescent nanoparticles. The biological evaluation was determined in three human ovarian (KURAMOCHI, OVCAR3, OVSAHO) and three human breast (MCF7, SKBR 3, and MDA-MB231) cancer cell lines. In the case of cabazitaxel, the nanoparticles maintained the activity of the parent drug, at the low nanomolar range, while exhibiting high blue fluorescence. The internalization of the fluorescent NPs into cells was detected using immunofluorescence assay.

COVID-19 Infection, Vaccination, and Antibody Levels: Investigating Correlations through a Cohort Study.

AIM: The objective of this study was to explore the potential correlation between COVID-19 infection or vaccination and levels of anti-nucleocapsid (anti-N) and anti-spike (anti-S) antibodies. METHODS: Among 6050 healthcare workers at the Ege University Hospital, a cohort study with 162 participants divided into three arms with 54 participants each was conducted. The three groups were selected as follows: those diagnosed with COVID-19 and not vaccinated (group 1), those diagnosed with COVID-19 and subsequently vaccinated with CoronaVac (group 2), and those not diagnosed with COVID-19 but vaccinated with two doses of CoronaVac (group 3). Antibody levels measured at the sixth month of follow-up were defined as the primary outcome. RESULTS: At the sixth month, all serum samples tested positive for anti-S. Anti-S levels were found to be significantly higher in group 2 than in the other groups (p < 0.001). There were no differences in antibody levels between groups 1 and 3 (p = 0.080). Average antibody levels were found to be lower in office workers and males. Anti-N antibodies were found to be positive in 85.1% of subjects at the sixth month. In group 2, anti-N antibodies were detected in all samples at the sixth month. Anti-N antibody levels were not significantly different between groups 1 and 2 (p = 0.165). Groups 1 and 2 had significantly higher antibody levels than group 3 (p < 0.001). CONCLUSIONS: Vaccination or infection provide protection for at least 6 months. Those who have previously been diagnosed with COVID-19 do not need to be vaccinated in the early period before their antibody levels decrease.

Aspergillus Carneus metabolite Averufanin induced cell cycle arrest and apoptotic cell death on cancer cell lines via inducing DNA damage.

Cancer is one of the leading causes of death worldwide, accounting for nearly 10 million deaths in 2020. Current treatment methods include hormone therapy, γ-radiation, immunotherapy, and chemotherapy. Although chemotherapy is the most effective treatment, there are major obstacles posed by resistance mechanisms of cancer cells and side-effects of the drugs, thus the search for novel anti-cancer compounds, especially from natural sources, is crucial for cancer pharmaceutics research. One natural source worthy of investigation is fungal species. In this study, the cytotoxicity of 5 metabolic compounds isolated from filamentous fungus Aspergillus Carneus. Arugosin C, Averufin, Averufanin, Nidurifin and Versicolorin C were analyzed using NCI-SRB assay on 10 different cell lines of breast cancer, ovarian cancer, glioblastoma and non-tumorigenic cell lines. Averufanin showed highest cytotoxicity with lowest IC50 concentrations especially on breast cancer cells. Therefore, Averufanin was further investigated to enlighten cell death and molecular mechanisms of action involved. Cell cycle analysis showed increase in SubG1 phase suggesting apoptosis induction which was further confirmed by Annexin V and Caspase 3/7 Assays. H2A.X staining revealed accumulation of DNA damage in cells treated with Averufanin and finally western blot analysis validated DNA damage response and downstream effects of Averufanin treatment in various signaling pathways. Consequently, this study shows that Averufanin compound induces cell cycle arrest and cell death via apoptosis through causing DNA damage and can be contemplated and further explored as a new therapeutic strategy in breast cancer.

Low serum allopregnanolone levels in children with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) has increasing evidence for the role of neurohormones in its etiopathogenesis. It has been suggested that the effects of neurosteroids on the brain in the early developmental period may predispose to neurodevelopmental pathologies. In our study, we examined serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and allopregnanolone levels in children with ADHD and whether these neurosteroids differ in the presence of specific learning disorder (SLD) and oppositional defiant disorder (ODD) comorbidities (ADHD+SLD and ADHD+ODD). We also investigated the relationship between neurosteroid levels and the severity of ADHD symptoms. Thirty-five prepubertal children with ADHD and 33 prepubertal healthy children, all aged 6-10 years, were included in this study. The severity of ADHD symptoms was assessed with the parent-rated and teacher-rated Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S). Serum allopregnanolone levels were significantly lower in the ADHD group compared to healthy controls. When analyzed according to comorbidity status, serum allopregnanolone levels were lower in ADHD+SLD and ADHD+ODD groups compared to healthy controls. However, when compared to healthy children, serum DHEA and DHEA-S levels in children with ADHD were not significantly different. Serum allopregnanolone levels were negatively associated with teacher-rated T-DSM-IV-S hyperactivity/impulsivity scores for all participants only. These findings suggest that allopregnanolone may play a role in the pathophysiology of ADHD, especially in the presence of ODD and SLD comorbidities.

Design, Synthesis and Biological Evaluation of Novel Triazolothiadiazoles Derived from NSAIDs as Anticancer Agents.

BACKGROUND: Although transplantation, surgical resection, and tumor ablation are treatment options available following early diagnosis of HCC, poor prognosis and high recurrence rates restrict the efficacy of these approaches. Hence, small molecules with high selectivity and bioactivity are urgently required. OBJECTIVE: This study presents the synthesis of a series of new triazolothiadiazole derivatives (1a-3j) with NSAID moieties and their cytotoxic bioactivities. METHODS: The new synthetic derivatives (1-3; 1a-3j) and NSAIDs ibuprofen, naproxen, and flurbiprofen that commonly used in clinics were screened against human liver (Huh7), breast (MCF7), and colon (HCT116) carcinoma cell lines under in vitro conditions via NCI-sulforhodamine B assay. RESULTS: The 4-methoxyphenyl substituted condensed derivatives 1h, 2h, and 3h were the most active compounds. Based on its high potency, compound 3h was selected for the further biological evaluation of hepatocellular carcinoma cell lines, and the mechanisms underlying cell death induced by 3h were determined. The results revealed that compound 3h induced apoptosis and cell cycle arrest in the sub G1 phase in human liver cancer cells. CONCLUSION: These new small molecules may be used for the development of new lead compounds.

Homologous Recombination Repair Mechanisms in Serous Endometrial Cancer.

Serous endometrial cancer (SEC) resembles high-grade serous ovarian cancer (HGSOC) genetically and clinically, with recurrent copy number alterations, TP53 mutations and a poor prognosis. Thus, SEC patients may benefit from targeted treatments used in HGSOC, e.g., PARP inhibitors. However, the preclinical and clinical knowledge about SEC is scarce, and the exact role of defective DNA repair in this tumor subgroup is largely unknown. We aimed to outline the prevalence of homologous recombination repair deficiency (HRD), copy-number alterations, and somatic mutations in SEC. OncoScan SNP arrays were applied to 19 tumors in a consecutive SEC series to calculate HRD scores and explore global copy-number profiles and genomic aberrations. Copy-number signatures were established and targeted sequencing of 27 HRD-associated genes was performed. All factors were examined in relation to HRD scores to investigate potential drivers of the HRD phenotype. Ten of the 19 SEC tumors (53%) had an HRD score > 42, considered to reflect an HRD phenotype. Higher HRD score was associated with loss of heterozygosity in key HRD genes, and copy-number signatures associated with non-BRCA1/2 dependent HRD in HGSOC. A high number of SECs display an HRD phenotype. It remains to be elucidated whether this also confers PARP inhibitor sensitivity.

Artificial Intelligence-Assisted Loop Mediated Isothermal Amplification (AI-LAMP) for Rapid Detection of SARS-CoV-2.

Until vaccines and effective therapeutics become available, the practical solution to transit safely out of the current coronavirus disease 19 (CoVID-19) lockdown may include the implementation of an effective testing, tracing and tracking system. However, this requires a reliable and clinically validated diagnostic platform for the sensitive and specific identification of SARS-CoV-2. Here, we report on the development of a de novo, high-resolution and comparative genomics guided reverse-transcribed loop-mediated isothermal amplification (LAMP) assay. To further enhance the assay performance and to remove any subjectivity associated with operator interpretation of results, we engineered a novel hand-held smart diagnostic device. The robust diagnostic device was further furnished with automated image acquisition and processing algorithms and the collated data was processed through artificial intelligence (AI) pipelines to further reduce the assay run time and the subjectivity of the colorimetric LAMP detection. This advanced AI algorithm-implemented LAMP (ai-LAMP) assay, targeting the RNA-dependent RNA polymerase gene, showed high analytical sensitivity and specificity for SARS-CoV-2. A total of ~200 coronavirus disease (CoVID-19)-suspected NHS patient samples were tested using the platform and it was shown to be reliable, highly specific and significantly more sensitive than the current gold standard qRT-PCR. Therefore, this system could provide an efficient and cost-effective platform to detect SARS-CoV-2 in resource-limited laboratories.

A small library of chalcones induce liver cancer cell death through Akt phosphorylation inhibition.

Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity ([Formula: see text]) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NF[Formula: see text]B-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NF[Formula: see text]B-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development.

The tumor microenvironment of pancreatic adenocarcinoma and immune checkpoint inhibitor resistance: a perplex relationship.

Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease. Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes, limited progress is achieved for the use of immunotherapeutics in this challenging cancer. Immune checkpoint inhibitors, thus far, single-agent or in combination, have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer. The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity. In this review article, we elaborate on the biology of pancreatic cancer microenvironment, its highly complicated interaction with cancer cells, and the immune system. We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.

Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.