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Apoptotic evasion by cancerous cells being one of the striking hallmarks of cancer has turned into a new arena of drug discovery. A large number of pathways reported that govern the apoptotic evasion have been reported. Fas-activated serine/threonine kinase (FASTK) is a member of Ser/Thr kinase family, and it has been implicated in the apoptotic evasion and, hence, the development of cancer. Keeping this in view, a series of novel thienopyrimidine-based chalcones have been synthesized and evaluated to modulate the FASTK mediated apoptotic evasion. Initial screening was done by enzyme inhibition assay and binding studies, which showed that out of 15 synthesized compounds, 3 thienopyrimidine-based chalcone derivatives possess considerably high binding affinity and enzyme inhibitory potential (nM range) for FASTK. Cell proliferation assessment of selected compounds was performed on HEK-293 and MCF-7 cells. For MCF-7 cells, compounds 2, 10, and 12 show IC values of 20.22 ± 1.50, 6.52 ± 0.82, and 8.20 ± 0.61 μM, respectively. Annexin-V and PI staining suggested that these molecules induce apoptosis in MCF-7 cells, arrest the cell cycle in the G0/G1 phase, and subsequently inhibit cell migration presumably by inhibiting FASTK and reactive oxygen species production. In conclusion, we have successfully designed, synthesized, and characterized thienopyrimidine-based chalcones that inhibit FASTK and induce apoptosis. These compounds may be exploited as potential anticancer agents.

We have developed a coarse-grained (CG) model of a polymer-clay system consisting of organically modified montmorillonite nanoclay as the nanoparticle in accordance with the MARTINI forcefield. We have used mechanical properties and cleavage free energy of clay particle to respectively parameterize bonded and nonbonded interaction parameters for an organically modified montmorillonite (oMMT) clay particle where intergallery Na + ions are replaced by tetramethylammonium (TMA) ions. The mechanical properties were determined from the slope of stress-strain curve and cleavage free energy was determined by allowing for full surface reconstruction corresponding to a slow equilibrium cleavage process. Individual dispersive and polar contributions to oMMT cleavage energy were used for determination of appropriate MARTINI bead types for CG oMMT sheet. The self-consistency of developed MARTINIFF 2 parameters for TMA-MMT -polymer system was verified by comparing estimates for select structural, thermodynamic, and dynamic properties obtained in all-atomistic simulations with that obtained in coarse-grained simulations. We have determined the influence of clay particle on properties of three polymer melts (polyethylene, polypropylene, and polystyrene) at two temperatures to establish transferability of the developed parameters. We have also shown that the effect of clay-polymer interactions on structure-property relationships in polymer-clay nanocomposite system is well captured by Rosenfeld's excess entropy scaling.Accordingly, we have defined each CG MMT bead as consisting of three heavy atoms, viz. / or / ( = ), and CG bead center was put at , , atom. This representation allowed us to preserve the 2:1 layered structure of phyllosilicates through interlayer and intralyer bonds between CG beads (Figure 1). We have used the smaller (fine grained) type-S representation for all three beads, as found to be suitable for ring structures in MARTINI parameterization. 29,40,44 Bonded Potential. We have used a single sheet of TMA-MMT placed in plane with bond connections across the periodic boundary (periodic sheet). The equilibrated structure of Na-MMT of size 3.11 nm × 2.71 nm (924 atoms in 6 × 6 × 1 array of unit cells) was taken from

Prostate cancer (PrCa) metastasis is the major cause of mortality and morbidity among men. Metastatic PrCa cells are typically adopted for aberrant glucose metabolism. Thus, chemophores that reprogram altered glucose metabolic machinery in cancer cells can be useful agent for the repression of PrCa metastasis. Herein, we report that cucurbitacin D (Cuc D) effectively inhibits glucose uptake and lactate production in metastatic PrCa cells via modulating glucose metabolism. This metabolic shift by Cuc D was correlated with decreased expression of GLUT1 by its direct binding as suggested by its proficient molecular docking (binding energy −8.5 kcal/mol). Cuc D treatment also altered the expression of key oncogenic proteins and miR-132 that are known to be involved in glucose metabolism. Cuc D (0.1 to 1 µM) treatment inhibited tumorigenic and metastatic potential of human PrCa cells via inducing apoptosis and cell cycle arrest in G2/M phase. Cuc D treatment also showed inhibition of tumor growth in PrCa xenograft mouse model with concomitant decrease in the expression of GLUT1, PCNA and restoration of miR-132. These results suggest that Cuc D is a novel modulator of glucose metabolism and could be a promising therapeutic modality for the attenuation of PrCa metastasis.

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Identifying novel molecules as potential kinase inhibitors are gaining significant attention globally. The present study suggests Myricetin as a potential inhibitor of microtubule‐affinity regulating kinase (MARK4), adding another molecule to the existing list of anticancer therapeutics. MARK4 regulates initial cell division steps and is a potent druggable target for various cancers. Structure‐based docking with 100 ns molecular dynamics simulation depicted activity of Myricetin in the active site pocket of MARK4 and the formation of a stable complex. The fluorescence‐based assay showed excellent affinity of Myricetin to MARK4 guided by static and dynamic quenching. Moreover, the assessment of enthalpy change (∆H) and entropy change (∆S) delineated electrostatic interactions as a dominant force in the MARK4‐myricetin interaction. Isothermal titration calorimetric measurements revealed spontaneous binding of Myricetin with MARK4. Further, the kinase assay depicted significant inhibition of MARK4 by Myricetin with IC50 = 3.11 µM. Additionally, cell proliferation studies established that Myricetin significantly inhibited the cancer cells (MCF‐7 and A549) proliferation, and inducing apoptosis. This study provides a solid rationale for developing Myricetin as a promising anticancer molecule in the MARK4 mediated malignancies.

This study aims to synthesize novel fused spiro-4H-pyran derivatives under green conditions to develop agents having antimicrobial activity. The synthesized compounds were initially screened for in vitro antibacterial activity against two Gram-positive and three Gram-negative bacterial strains, and all the compounds exhibited moderate to potent antibacterial activity. However, compound 4l showed significant inhibition toward all the bacterial strains, particularly against Streptococcus pneumoniae and Escherichia coli with minimum inhibitory concentration values of 125 μg/mL for each. The toxicity studies of selected compounds (4c, 4e, 4l, and 4m) using human red blood cells as well as human embryonic kidney (HEK-293) cells showed nontoxic behavior at desired concentration. Growth kinetic and time–kill curve studies of 4l against S. pneumoniae and E. coli supported its bactericidal nature. Interestingly, compound 4l showed a synergistic effect when used in combination with ciprofloxacin against selected strains. Biofilm formation in the presence of a lead compound, as assessed by XTT assay, showed complete disruption of the bacterial biofilm visualized by scanning electron microscopy. Overall, the findings suggest 4l to be considered as a promising lead for further development as an antibacterial agent.