Diaziquone

Abstract: SK-MEL-5 is a human melanoma cell line that has been used in several researches to explore new therapies against melanoma.Based on this study we report on the development of quant. structure-activity relationship (QSAR) model and mol. docking simulation able to predict the cytotoxic effect of diverse chem. compounds on this cancer cell line.The dataset of seventy-two (72) cytotoxic compounds were downloaded from the National Cancer Institute database.It contains the data of compounds for which cytotoxicity results expressed by pGI₅₀ was recorded.The QSAR model was built using fifty (50) compounds and the best-generated model based on multiple linear regression showed, resp. good quality of fits [R² (0.864), R²_adjusted (0.846), Q²_cv (0.841) and R²_pred (0.885)].The model′s predictive ability was determined by a test set of twenty-two (22) compounds and the applicability domain was assessed through leveraged approach.Compounds 41 and 69 were selected as templates for in silico design because they had high pGI₅₀ activity and are within the model′s applicability domain.The obtained information from the model was explored to design novel compounds by introducing various substituents.Moreover, the designed compounds were docked into the active site of the protein (PDB CODE: 3OG7) which is responsible for melanoma cancer to elucidate their binding mode.Ia (- 12.4 kcal mol^-1) and IIb (- 12.3 kcal mol^-1) showed a better binding affinity for the target when compared with (vemurafenib, - 11.3 kcal mol^-1) the known inhibitor of the target (V600E-BRAF).These results may be of great help in early anticancer drug discovery.

Leptospermum flavescens has been used traditionally in Malaysia to treat various ailments such as constipation, hypertension, diabetes and cancer.

To investigate the potential protective effects of L. flavescens in pancreatic β cells through inhibition of apoptosis and autophagy cell death mechanisms in in vitro and in vivo models.

L. flavescens leaves were extracted using solvent in increasing polarities: hexane, ethyl acetate, methanol and water. All extracts were tested for INS-1 β cells viability stimulated by streptozotocin (STZ). The extract which promotes the highest cell protective activity was further evaluated for insulin secretion, apoptosis and autophagy signaling pathways. Then, the acute toxicity of extract was carried out in SD rats according to OECD 423 guideline. The active extract was tested in diabetic rats where the pancreatic β islets were evaluated for insulin, apoptosis and autophagy protein.

The methanolic extract of L. flavescens (MELF) was found to increase INS-1 β cells viability and insulin secretion against STZ. In addition, MELF has been shown to inhibit INS-1 β cells apoptosis and autophagy activity. Notably, there was no toxicity observed in SD rats when administered with MELF. Furthermore, MELF exhibited anti-hyperglycemic activity in diabetic rats where apoptosis and autophagy protein expression was found to be suppressed in pancreatic β islets.

MELF was found to protect pancreatic β cells function from STZ-induced apoptosis and autophagy in in vitro and in vivo.