Development of 9-(N-arylmethylamino) congeners of noscapine: the microtubule targeting drugs for the management of breast cancer.

Noscapine is a natural lead molecule with anticancer activity at a higher concentrations. So, there is an urge for the development of more potent derivatives of noscapine. In this study, we have approached for development of 9-N-arylmethylamino derivatives of noscapine that kills cancer cells without affecting the normal cells. They were designed by substituting N-aryl methyl pharmacophore at the C-9 position and screened out top-ranked three derivatives 13a-c using molecular docking. Further, their theoretical free energy of binding with tubulin was calculated followed by chemical synthesis and experimental validation. In vitro antiproliferative activity of noscapine and its 9-N-arylmethylamino derivatives (13a-c) was carried out using MCF-7 (a triple receptors positive) and MDA-MB-231 (a triple receptor negative) breast cancer cell lines. Further, cytotoxicity to normal cells was examined using human embryonic kidney cells (HEK cells). Inhibition to cell cycle progression and induction of apoptosis was monitored using FACS. The binding of noscapine and 13a-c with tubulin was examined using fluorescence quenching assay. The 9-N-arylmethylamino derivatives of noscapine (13a-c) were found to inhibit the proliferation of cancer cells at a much lower concentration (IC50 values range between 9.1 to 47.3 µM) compared to noscapine (IC50 value is 45.8-59.3 µM). Surprisingly, the proliferation of HEK cells was not inhibited even at a concentration of 100 µM (cytotoxicity is < 5%). These derivatives induced apoptosis by arresting cells at G2/M-phase and also bind to tubulin. The 9-(N-arylmethylamino) noscapinoids have the potential to be a novel therapeutic agent for the treatment of breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03445-3.

Assessment of groundwater geochemistry using multivariate water quality index and potential health risk in industrial belt of central Odisha, India.

Groundwater in India has been shown to have a variety of water quality issues, including fluoride, nitrate, and uranium pollution, all of which pose a health risk to humans. In the present study, a total of 106 groundwater samples from the Angul district of Odisha, an industrialized region in India, were analyzed for 14 different hydrochemical parameters. In almost 30%, 34.9%, and 4.7% of the groundwater samples, the concentrations of F-, NO3- and uranium, respectively, exceeded the permissible limit set by WHO. In addition to the fixed-weight groundwater quality index (GWQI), the entropy-weighted water quality index (EWQI), the principal component analysis (PCA) factor (or rotated factor) loading based water quality index (PCWQI) and human health risk assessment were used. Depending on the models, about 19.1 ± 0.9%, 70.5 ± 1.9% and 10.38 ± 1.9% of water samples were classified as "Excellent", "Good" and "Medium" quality, respectively, across four water quality indexes with a nominal rating disagreement of 11.3%. More than 90% of samples are unanimously classified as excellent or good across the WQI rating. For children and adults, approximately 54.7% and 24.5% of samples exceeded the permitted limit for F-, (hazard quotient HQ > 1), posing non-carcinogenic health hazards, respectively. In contrast, 71.7% and 34.9% of NO3- samples respectively, surpassed the allowed limit and caused non-carcinogenic health concerns for children and adults. In terms of carcinogenic HQ values, about 13.2% and 7.5% of samples exhibit an uranium related carcinogenic health risk in children and adults, respectively. The existence of significant amounts of Cl -, NO3-, and especially HCO3- ions in groundwater in some samples, as well as their positive interdependence, may increase uranium pollution in the future through uranium dissolution.

Hydro-geochemical analysis based on entropy and geostatistics model for delineation of anthropogenic ground water pollution for health risks assessment of Dhenkanal district, India.

Consumption of poor quality water causes serious human health hazards. Therefore, it is very crucial to investigate factors influencing the quality of groundwater and its suitability for drinking purpose. In the present study, groundwater quality of the Dhenkanal district of Odisha, India was characterized and the spatial distribution of different water quality parameters were analyzed using the multivariate statistics, entropy theory, and geostatistics techniques. In the present study 112 number of groundwater tube well samples were collected from the study area. The entropy theory revealed that SO42-, Mg+2 and Cl- were the most influencing parameters. A similar observation was also observed based on the correlation coefficient analysis. Groundwater quality index (GWQI) and entropy-weighted water quality index (EWQI) classifications indicated that 78.57 and 43.75% of the collected groundwater samples were categorized under excellent water quality, whereas, the rest of the samples were varying from good to medium drinking water quality. In addition, the result of EWQI classification offers more realistic assessment than that of GWQIs owing to its high precision, simplicity and without application of artificial weight. The correlation coefficient between Ca+2 and HCO3-, Mg+2 and PO4- were significantly high which might be due the presence of CaHCO3 and MgPO4 in the groundwater samples. The GWQI revealed a weak spatial dependence of groundwater quality.

Rational design, chemical synthesis and cellular evaluation of novel 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents.

We present a new class of derivatives of noscapine, 1,3-diynyl-noscapinoids of an antitussive plant alkaloid, noscapine based on our in silico efforts that binds tubulin and displays anticancer activity against a panel of breast cancer cells. Structure-activity analyses pointed the C-9 position of the isoquinoline ring which was modified by coupling of 1,3-diynyl structural motifs to rationally design and screened a series of novel 1,3-diynyl-noscapinoids (20-22) with robust binding affinity with tubulin. The selected 1,3-diynyl-noscapinoids, 20-22 revealed improved predicted binding energy of -6.568 kcal/mol for 20, -7.367 kcal/mol for 21 and -7.922 kcal/mol for 22, respectively in comparison to the lead molecule (-5.246 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast cancer cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 6.2 to 38.9 µM, which is 6.7 to 1.5 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrests cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrests cell cycle in the G2/M-phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.

Comparative evaluation of anti-angiogenic effects of noscapine derivatives.

Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumor progression. Synthetic derivatives of anti-cancer compound, noscapine (an opium alkaloid) such as Cl-noscapine, Br-noscapine and Folate-noscapine along with two of the reference compounds, TNP-470 and paclitaxel were examined for anti-angiogenic activities by using human umbilical vein endothelial cells (HUVECs). The noscapine derivatives showed anti-angiogenic activity albeit at high concentration compared to the reference compounds. All the tested compounds inhibited angiogenesis in a dose-dependent manner; the drug concentration causing 50% inhibition of cell survival was 11.87 µM for Cl-noscapine, 6.9 µM for Br-noscapine and 6.79 µM for folate-noscapine. Besides, all the noscapine derivatives significantly inhibited cord formation (IC50 for Cl-noscapine is 50.76 µM, for Br-noscapine is 90.08 µM and for folate-noscapine is 18.44 µM) as well as migration and invasion (IC50 value of Cl-noscapine is 28.01 µM, for Br-noscapine is 19.78 µM and for folate-noscapine is 10.76 µM) of endothelial cells. Based on these results, we speculated that the inhibitory effects on human endothelial cell proliferation of noscapine derivatives might be important for anti-angiogenesis.