1419320-91-4Relevant academic research and scientific papers
Characterization of novel aminobenzylcantharidinimides and related imides by proton NMR spectra and their effects on NO induction
Tseng, Ing-Jy,Lin, Pen-Yuan,Sheu, Shiow-Yunn,Tung, Wan-Ni,Lin, Ching-Tung,Lin, Mei-Hsiang
, p. 59 - 63 (2015)
Various acidic anhydrides including cantharidin were converted into corresponding aminobenzylcantharidinimide 3a and analogous imides 3b～k (at the ortho, meta, and para positions) with 35%～87% yields by reacting with aminobenzylamines and triethylamine. The two methyl side chains of cantharidinimides 3ao, 3am, and 3ap, and related imides had more than two chiral centers; the lone pair of electrons of nitrogen displayed a different chemical shift and coupling constant in H-NMR spectra when the amino group of benzylamine was in the ortho position. These cantharidinimides had parent aniline, pyridine, and naphthalene plane structures, and the primary amine nucleophilicity and basicity might reflect the inductive electron's negative effect on chemical shifts. We prepared cantharidinimides by heating the reactants cantharidin 1a, aliphatic and aromatic acid anhydrides, primary benzylic amines, and aniline derivatives to ca. 200 °C with 3 mL of dry toluene, and 1～2 mL of triethylamine in high-pressure sealed tubes (Buchi glasuster 0032) to produce cantharidinimides and their analogues in good yields. The para-aminobenzylic imides showed greater inhibition of nitric oxide (NO) synthesis by NO synthase (NOS) than did ortho- and meta-aminobenzylic imides. Compound 3fp, para-aminobenzylic norbonane-imide, had the most potent effect on inducible NOS among the tested compounds and showed 35% inhibition. Cantharidinimides and their analogue were prepared by heating the reactants cantharidin, aliphatic, aromatic acid anhydrides, and primary benzyl amines, aniline derivatives with 3 mL of dry toluene, and 1-2 mL of triethylamine in high-pressure sealed tube at 200 oC in good yields. The para-aminobenzylic imides showed greater inhibition of nitric oxide (NO) synthesis by NO synthase (NOS) than that of ortho- and meta-aminobenzylic imides did.
Modelling and Phenotypic Screening of NAP-6 and 10-Cl-BBQ, AhR Ligands Displaying Selective Breast Cancer Cytotoxicity in Vitro
Baker, Jennifer R.,Pollard, Brett L.,Lin, Andrew J. S.,Gilbert, Jayne,Paula, Stefan,Zhu, Xiao,Sakoff, Jennette A.,McCluskey, Adam
, p. 1499 - 1512 (2021/03/03)
To exploit the interaction of the aryl hydrocarbon receptor (AhR) pathway in developing breast-cancer-specific cytotoxic compounds, we examined the breast cancer selectivity and the docking pose of the AhR ligands (Z)-2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (NAP-6; 5) and 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ; 6). While the breast cancer selectivity of 5 in vitro is known, we discuss the SAR around this lead and, by using phenotypic cell-line screening and the MTT assay, show for the first time that 6 also presents with breast cancer selectivity, notably in the triple-negative (TN) receptor breast cancer cell line MDA-MB-468, the ER+ breast cancer cell lines T47D, ZR-75-1 and the HER2+ breast cancer cell line SKBR3 (GI50 values of 0.098, 0.97, 0.13 and 0.21 μM, respectively). Indeed, 6 is 55 times more potent in MDA-MB-468 cells than normal MCF10A breast cells (GI50 of 0.098 vs 5.4 μM) and more than 130 times more potent than in cell lines derived from pancreas, brain and prostate (GI50 of 0.098 vs 10–13 μM). Molecular docking poses of 5 and 6 together with analogue synthesis and phenotypic screening show the importance of the naphthalene moiety, and an ortho-disposed substituent on the N-phenyl moiety for biological activity.
Development of 1,8-naphthalimides as clathrin inhibitors
Macgregor, Kylie A.,Robertson, Mark J.,Young, Kelly A.,Von Kleist, Lisa,Stahlschmidt, Wiebke,Whiting, Ainslie,Chau, Ngoc,Robinson, Phillip J.,Haucke, Volker,McCluskey, Adam
, p. 131 - 143 (2014/02/14)
We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a ～17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as ～80-120 μM clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)- 1,8-naphthalimide, potassium salt (18, IC50 ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure-activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50≈ 6.9 μM, is the most potent clathrin terminal domain-amphiphysin inhibitor reported to date.
