Pharmacokinetic Profile Evaluation of Novel Combretastatin Derivative, LASSBio-1920, as a Promising Colorectal Anticancer Agent.

LASSBio-1920 was synthesized due to the poor solubility of its natural precursor, combretastatin A4 (CA4). The cytotoxic potential of the compound against human colorectal cancer cells (HCT-116) and non-small cell lung cancer cells (PC-9) was evaluated, yielding IC50 values of 0.06 and 0.07 µM, respectively. Its mechanism of action was analyzed by microscopy and flow cytometry, where LASSBio-1920 was found to induce apoptosis. Molecular docking simulations and the enzymatic inhibition study with wild-type (wt) EGFR indicated enzyme-substrate interactions similar to other tyrosine kinase inhibitors. We suggest that LASSBio-1920 is metabolized by O-demethylation and NADPH generation. LASSBio-1920 demonstrated excellent absorption in the gastrointestinal tract and high central nervous system (CNS) permeability. The pharmacokinetic parameters obtained by predictions indicated that the compound presents zero-order kinetics and, in a human module simulation, accumulates in the liver, heart, gut, and spleen. The pharmacokinetic parameters obtained will serve as the basis to initiate in vivo studies regarding LASSBio-1920's antitumor potential.

Characterization of the binding interaction between atrazine and human serum albumin: Fluorescence spectroscopy, molecular dynamics and quantum biochemistry.

Atrazine (ATR), one of the most used herbicides worldwide, causes persistent contamination of water and soil due to its high resistance to degradation. ATR is associated with low fertility and increased risk of prostate cancer in humans, as well as birth defects, low birth weight and premature delivery. Describing ATR binding to human serum albumin (HSA) is clinically relevant to future studies about pharmacokinetics, pharmacodynamics and toxicity of ATR, as albumin is the most abundant carrier protein in plasma and binds important small biological molecules. In this work we characterize, for the first time, the binding of ATR to HSA by using fluorescence spectroscopy and performing simulations using molecular docking, classical molecular dynamics and quantum biochemistry based on density functional theory (DFT). We determine the most likely binding sites of ATR to HSA, highlighting the fatty acid binding site FA8 (located between subdomains IA-IB-IIA and IIB-IIIA-IIIB) as the most important one, and evaluate each nearby amino acid residue contribution to the binding interactions explaining the fluorescence quenching due to ATR complexation with HSA. The stabilization of the ATR/FA8 complex was also aided by the interaction between the atrazine ring and SER454 (hydrogen bond) and LEU481(alkyl interaction).