Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

A series of 2-amino(chloro)-3-chloro-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. 1,4-Naphthoquinones 1 and 4 were found to be the most potent compounds affording IC50 values 5.2 times lower than the reference drug, ketoconazole. A quantitative structure-activity relationship (QSAR) model provided good predictive performance (R2 CV = 0.9783 and RMSECV = 0.0748) and indicated mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors as key descriptors governing the activity. To investigate the effects of structural modifications on aromatase inhibitory activity, the model was employed to predict the activities of an additional set of 39 structurally modified compounds constructed in silico. The prediction suggested that the 2,3-disubstitution of 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) is the most effective modification for potent activity (1a, 1b and 1c). Importantly, compound 1b was predicted to be more potent than its parent compound 1 (11.90-fold) and the reference drug, letrozole (1.03-fold). The study suggests the 1,4-naphthoquinone derivatives as promising compounds to be further developed as a novel class of aromatase inhibitors

Rational design of novel sirtuin 1 activators via structure-activity insights from application of QSAR modeling

Sirtuin 1 (SIRT1) enzyme regulates major cell activities, and its activation offers lucrative therapeutic potentials for aging diseases including Alzheimer’s disease (AD). Regarding the global aging society, continual attention has been given to various chemical scaffolds as a source for the discovery of novel SIRT1 activators since the discovery of the pioneer activator, resveratrol. Understanding structure-activity relationship (SAR) is essential for screening, designing as well as improving the properties of drugs. In this study, an in silico approach based on quantitative structure-activity relationship (QSAR) modeling, was employed for understanding the SAR of currently available SIRT1 fused-aromatic activators (i.e., imidazothiazole, oxazolopyridine, and azabenzimidazole analogs). Three QSAR models constructed using multiple linear regression (MLR) provided good predictive performance (R2 LOOCV = 0.729 - 0.863 and RMSELOOCV = 0.165 - 0.325). An additional novel set of 181 structurally modified compounds were rationally designed according to key descriptors deduced from the QSAR findings and their SIRT1 activities were predicted using the constructed models. In overview, the study provides insightful SAR findings of currently available SIRT1 activators that would be useful for guiding the rational design, screening, and development of further potent SIRT1 activators for managing age-related clinical conditions. A series of promising compounds as well as important scaffolds and molecular properties for potent SIRT1 activator were highlighted. This study demonstrated the efficacious role of QSAR-driven structural modification for the rational design of novel leads

R code of the Efficient Linear Method (ELM)

<p>R code of the Efficient Linear Method (ELM) for constructing QSAR/QSPR models that is readily interpretable.</p

Effects of barakol from Cassia siamea on neuroblastoma SH-SY5Y cell line: A potential combined therapy with doxorubicin

Management of neuroblastoma is challenging because of poor response to drugs, chemotherapy resistance, high relapse, and treatment failures. Doxorubicin is a potent anticancer drug commonly used for neuroblastoma treatment. However, doxorubicin induces considerable toxicities, particularly those caused by oxidative-related damage. To minimize drug-induced adverse effects, the combined use of anticancer drugs with natural-derived compounds possessing antioxidant properties has become an interesting treatment strategy. Barakol is a major compound found in Cassia siamea, an edible plant with antioxidant and anticancer properties. Therefore, barakol could potentially be used in combination with doxorubicin to synergize the anticancer effect, while minimizing the oxidative-related toxicities. Herein, the potential of barakol (0.0043–43.0 μM) to synergize the anticancer effect of low-dose doxorubicin (0.5 and 1.0 μM) was investigated. Results indicated that barakol could enhance the cytotoxic effect of low-dose doxorubicin by affecting the cell viability of the treated cells. Furthermore, the co-treatment with barakol and low-dose doxorubicin decreased the levels of intracellular ROS when compared with the control. Moreover, the antimetastatic effect of the barakol itself was studied through its ability to inhibit metalloproteinase-3 (MMP-3) activity and prevent cell migration. Results revealed that the barakol inhibited MMP-3 activity and prevented cell migration in time- and dose-dependent manners. Additionally, barakol was a non-cytotoxic agent against the normal tested cell line (MRC-5), which suggested its selectivity and safety. Taken together, barakol could be a promising compound to be further developed for combination treatment with low-dose doxorubicin to improve therapeutic effectiveness but decrease drug-induced toxicities. The inhibitory effects of barakol on MMP-3 activity and cancer cell migration also supported its potential to be developed as an antimetastatic agent

Navigating the chemical space of dipeptidyl peptidase-4 inhibitors

<p>Data set used in this study is provided in the Excel file.</p