Synthesis, antiproliferative and apoptosis-inducing effects of novel asiatic acid derivatives containing α-aminophosphonates

Abstract

A series of novel asiatic acid (AA) derivatives containing α-aminophosphonate were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against five cancer cell lines (A549, Hct-116, T24, Spca-2 and SK-OV-3 cell) and a normal cell line (HUVEC cell) were evaluated, employing standard MTT assay. Antitumor activities screening result indicated that many target compounds displayed moderate to high levels of antitumor activities compared with AA, 5-fluorouracil (5-FU) and cisplatin, and exhibited much lower cytotoxicy against normal cell than 5-FU and cisplatin. In addition, the mechanism of representative compound 3d was preliminarily investigated by AO/EB staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, flow cytometry and western blot.Compound 3d inducing apoptosis involved intracellular Ca 2+ production, the loss of mitochondrial membrane potential and intracellular reactive oxygen species (ROS) production. Western blot analysis also demonstrated that compound 3d treatment triggered the mitochondrial apoptotic pathway, indicating by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation.Moreover, the cell cycle analysis showed that compound 3d may confine T24 cells in G 1 /S phase mainly through the p53-dependent pathway. Together, these results implied a critical role of ROS, caspase-9 and p53 in compound 3d-inducing G 1 /S arrest and apoptosis of T24 cells.

Antimicrobial Effect of Asiatic Acid Against Clostridium difficile Is Associated With Disruption of Membrane Permeability

“…Prior to the drug administration, cytotoxicity of the compounds against host cells is needed to be evaluated ( Tharmalingam et al, 2018 ). IC 50 values for AA were reported to be greater than 100 μM (∼50 μg/ml) on human umbilical vein endothelial cells and kidney epithelial Vero cells ( Jirasripongpun et al, 2012 ; Huang et al, 2016 ), as well as no significant effect of the compound at the same concentration was observed on viability of human gastric mucosa epithelial cells ( Jing et al, 2016 ). Additionally, up to 165 mg/kg of AA was administered to the mice without any signal of side effects ( Krishnamurthy et al, 2009 ).…”

Ultrasound-promoted solvent-free synthesis of some new α-aminophosphonates as potential antioxidants

“…Due to their outstanding biological and physical characteristics together with their usefulness as intermediates in synthesis; AAPs have found a wide variety of applications in industry, agriculture and medicine (Moonen et al, 2004;Palacios et al, 2004;Schug and Lindner, 2005). They are discovered to be antibacterial (Subramanyam et al, 2017), antifungal (Yang et al, 2006), antiviral (Xu et al, 2006), anti-inflammatory agents (Sujatha et al, 2017), anti-HIV (Bhattacharya et al, 2012), anticancer (Bahrami et al, 2016), anti-proliferative and apoptosis inducing (Huang et al, 2016a(Huang et al, , 2016bLi et al, 2015), antitumor (Liu et al, 2017), herbicidal activity (Che et al, 2016) and insecticidal activity (Jiang et al, 2013;Liu et al, 2012). Addition of trialkyl or dialkylphosphite to imines is a successful technique to obtain them (Azizi et al, 2004;Heydari et al, 2009;Kassaee et al, 2009;Manjula et al, 2013;Yadav et al, 2001).…”

Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells

“…α-Aminophosphonic acids are structural bioisosteres of amino acids displaying a wide range of biological properties and applications in many areas ranging from agrochemistry to medicine [ 1 , 2 , 3 , 4 ]. Some of their varied applications include antitumor agents [ 5 , 6 , 7 ], potent antibiotics [ 8 , 9 ], as antibacterial agents [ 10 , 11 ], antiviral [ 12 ], and enzyme inhibitors [ 13 , 14 , 15 ] such as renin [ 14 , 16 ], or HIV protease [ 17 , 18 ], among others. Joined with their structural similarity to natural carboxylic acids, the intriguing properties of α-aminophosphonic acids also stem from the fact that the tetrahedral geometry of phosphonic acid functionality resembles in a stable manner the high-energy transition state of peptide bond hydrolysis [ 19 ].…”