Preparation, Characterization, and In vitro Evaluation of Curcumin- and Resveratrol-Loaded Solid Lipid Nanoparticles.

Curcumin and resveratrol are natural compounds with significant anticancer activity; however, their bioavailability is limited due to poor solubility. This study aimed to overcome the solubility problem by means of solid lipid nanoparticles (SLN). 2-Hydroxypropyl ß-cyclodextrin (HPßCD) was selected from a range of polymers based on miscibility and molecular interactions. SLNs were obtained by probe sonication and freeze-drying curcumin-resveratrol with/without HPßCD incorporated in gelucire 50/13. SLNs were characterized by dynamic light scattering (DLS), zeta potential, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and physical stability. The in vitro release of drugs from the SLNs was performed by the direct dispersion method and analyzed using a validated UV-visible method. In vitro efficacy was tested using a colorectal cancer cell line. Curcumin-resveratrol-gelucire 50/13-HPßCD (CRG-CD) and curcumin-resveratrol-gelucire 50/13(CRG) SLNs showed a particle size from 100 to 150 nm and were not in the crystalline state per PXRD results. MDSC results complimented PXRD results by the absence of melting endotherm of curcumin; TGA showed no weight loss, confirming the absence of organic solvent residual, and the shape of the SLNs was confirmed as spherical by SEM. CRG SLNs were stable for 21 days with respect to particle size and zeta potential. MTT assay indicated better IC50 value for CRG as compared to CRG-CD. Hence, novel SLNs of curcumin and resveratrol incorporated in gelucire 50/13 and HPßCD were prepared and characterized to improve their bioavailability and anticancer activity.

Thienopyrimidine derivatives exert their anticancer efficacy via apoptosis induction, oxidative stress and mitotic catastrophe.

In this study, a series of 13 structural variants of thieno[2,3d]pyrimidine derivatives (6a-6m) were synthesized and screened for cytotoxicity in a panel of colorectal, ovarian, and brain cancer cell lines. The selectivity of the compounds was assessed by determining the cytotoxicity in normal epithelial cell line (CHO). The most potent compound, 6j, was efficacious (with IC50 range of 0.6-1.2 µM) in colon (HCT116 and HCT15), brain (LN-229 and GBM-10) and ovarian (A2780 and OV2008) cancer cell lines. In contrast, in the normal cell line (CHO), the IC50 values for 6j were 14 ± 1.3 µM. Compound 6j significantly inhibited the clonogenic potential of HCT116, OV2008 and A2780 cell lines in concentration - dependent (0.5-4 µM) manner. Also, 6j induced 1) formation of reactive oxygen species; 2) apoptosis and 3) mitotic catastrophe in HCT116 and OV2008 cells (IC50 = 0.5-2 µM). Furthermore, apoptosis was the predominant mechanism of death in A2780 cells. The cytotoxicity of 6j in wild type HCT116 cells was similar to that in HCT116 cells lacking the apoptotic genes for Bax, Bak, or Bak and Bax, indicating that 6j induces mitotic catastrophe as alternative mechanism of death when when certain apoptotic proteins are absent. In summary, this study has identified a lead molecule, 6j, that selectively induces oxidative stress, apoptosis and mitotic catastrophe in specific cancer (colon and ovarian) cell lines.

N-(1H-Pyrazol-3-yl)quinazolin-4-amines as a novel class of casein kinase 1δ/ε inhibitors: Synthesis, biological evaluation and molecular modeling studies.

Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/ß, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.