Identification of novel anti-cancer agents by the synthesis and cellular screening of a noscapine-based library.

Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z' > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC50 values of 5 µM and 1.5 µM, respectively. Both hit molecules have a five-fold and seventeen-fold higher potency, compared with that of lead compound noscapine (IC50 26 µM). The identified active derivatives retain the tubulin-binding ability of noscapine. Further testing of both hit molecules, alongside the natural product against additional cancer cell lines (HepG2, HeLa and PC3 cells) confirmed our initial findings. Both molecules have improved anti-proliferative properties when compared to the initial natural product, noscapine.

Distribution of Dietary Risk Factors in Iran: National and Sub-National Burden of Disease.

BACKGROUND: Non-communicable diseases (NCDs) are one of the greatest threats to public health, and have been related to poor quality dietary patterns. This study was conducted to determine the distribution of dietary risk factors in Iran. METHODS: Cross-sectional data was gathered between April and November 2016 from 30,541 eligible adults (out of 31 050 individuals who were selected through systematic proportional to size cluster random sampling) living in urban and rural areas, using the WHO-based STEPs risk factor questionnaire. Low intakes of fruits, vegetables, dairy products, and fish, and high intakes of salty processed food (SPF), as well as daily intake of hydrogenated fat (HF) were considered as nutritional risk factors. RESULTS: At the national level, 82.8% (95% CI: 82.4-83.2), 57.8% (95% CI: 57.2-58.4), 80.6% (95% CI: 80.1-81) and 90.3% (95% CI: 90-90.6) of participants of all age groups had sub-optimal intakes of fruits, vegetables, dairy products and fish, respectively. Furthermore, 12.8% (95% CI: 12.4-13.1), and 29.4% (95% CI: 28.9-29.9) of respondents had high SPF intakes and HF use, respectively. At the sub-national level, the highest distribution of suboptimal intake of fruits (97.2%; 95% CI:96-98.3), vegetables (79.2%; 95% CI: 76.3-82.1) and dairy products (92.9%; 95% CI: 91-94.7) was observed in Sistan and Baluchistan. Except for Boushehr and Hormozgan, the majority of the population of other provinces consumed fish less than twice a week. Similarly, the high intake of SPF was found mostly in the population of Yazd (23.7; 95% CI: 20.2-27.2). HF consumption was the highest in North Khorasan (64.2%; 95% CI: 60.3-68.1). CONCLUSION: These findings highlight the widespread distribution of dietary risk factors in Iran, which should be a priority for the people and the politicians in order to prevent NCDs.

Discovery of noscapine derivatives as potential ß-tubulin inhibitors.

Twenty novel 1,2,3-triazole noscapine derivatives were synthesized starting from noscapine by consecutive N-demethylation, reduction of lactone ring, N-propargylation and Huisgen 1,3-dipolar cycloaddition reaction. In order to select the most promising molecules to subject to further biophysical and biological evaluation, a molecular docking analysis round was performed using noscapine as reference compound. The molecules featuring docking predicted binding affinity better than that of noscapine were then subjected to MTT assay against MCF7 cell line. The obtained results disclosed that all the selected triazole derivatives exhibited a remarkably lower cell viability compared to noscapine in the range of 20 µM in 48 h. In an attempt to correlate the biological activity with the ability to bind tubulin, the surface plasmon resonance (SPR) assay was employed. Compounds 8a, 8h, 9c, 9f and 9j were able to bind tubulin with affinity constant values in the nanomolar range and higher if compared to noscapine. Integrating computational predictions and experimental evaluation, two promising compounds (8h and 9c) were identified, whose relevant cytotoxicity was supposed to be correlated with tubulin binding affinity. These findings shed lights onto structural modifications of noscapine toward the identification of more potent cytotoxic agents targeting tubulin.