A new triazolothiadiazine derivative inhibits stemness and induces cell death in HCC by oxidative stress dependent JNK pathway activation.

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, and resistant to both conventional and targeted chemotherapy. Recently, nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the incidence and mortality of different types of cancers. Here, we investigated the cellular bioactivities of a series of triazolothiadiazine derivatives on HCC, which have been previously reported as potent analgesic/anti-inflammatory compounds. From the initially tested 32 triazolothiadiazine NSAID derivatives, 3 compounds were selected based on their IC50 values for further molecular assays on 9 different HCC cell lines. 7b, which was the most potent compound, induced G2/M phase cell cycle arrest and apoptosis in HCC cells. Cell death was due to oxidative stress-induced JNK protein activation, which involved the dynamic involvement of ASK1, MKK7, and c-Jun proteins. Moreover, 7b treated nude mice had a significantly decreased tumor volume and prolonged disease-free survival. 7b also inhibited the migration of HCC cells and enrichment of liver cancer stem cells (LCSCs) alone or in combination with sorafenib. With its ability to act on proliferation, stemness and the migration of HCC cells, 7b can be considered for the therapeutics of HCC, which has an increased incidence rate of ~ 3% annually.

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.

Bioequivalence study of two favipiravir tablet formulations in healthy male subjects.

OBJECTIVE: The global pandemic called COVID-19 has dragged the world into a healthcare crisis, and favipiravir is one of the most prescribed agents against the virus so far. Favipiravir is a repurposed antiviral agent in treatment of SARS-CoV-2 infection, and to meet the current need, pharmaceutical companies are working for manufacturing licensed generic favipiravir. For getting the marketing authorization, the bioequivalence of the generic product must be proven first. The aim of this study is to demonstrate the bioequivalence of a new favipiravir tablet formulation as compared to the reference tablet formulation in healthy male subjects under fasting conditions. MATERIALS AND METHODS: To prove the bioequivalence, a randomized, single oral dose, cross-over, two-period study was carried out in 30 healthy subjects under fasting conditions. Plasma favipiravir levels were quantified by using an in-house-developed high performance liquid chromatography with mass spectrometry detector (LC-MSD) method. RESULTS: The 90% CIs for the test/reference geometric mean ratios of the Cmax and AUC0-tlast were 88.02 - 103.11% and 98.19 - 102.06%, respectively. CONCLUSION: This single-dose study has shown that the test and reference favipiravir products met the required bioequivalence criteria. Besides, both products were well tolerated and safe.

Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins.

Newly designed triazolothiadiazines incorporating with structural motifs of nonsteroidal analgesic anti-inflammatory drugs were synthesized and screened for their bioactivity against epithelial cancer cells. Compounds with bioactivities less then ∼5µM (IC50) were further analyzed and showed to induce apoptotic cell death and SubG1 cell cycle arrest in liver cancer cells. Among this group, two compounds (1g and 1h) were then studied to identify the mechanism of action. These molecules triggered oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition as demonstrated by downstream targets such as GSK3ß, ß-catenin and cyclin D1. QSAR and molecular docking models provide insight into the mechanism of inhibition and indicate the optimal direction of future synthetic efforts. Furthermore, molecular docking results were confirmed with in vitro COX bioactivity studies. This study demonstrates that the novel triazolothiadiazine derivatives are promising drug candidates for epithelial cancers, especially liver cancer.