Design, Synthesis and Biological Evaluation of Lipophilic Analogs of Anethol Trithione

Abstract

16 ADT carboxylate esters were prepared and tested for their chemical characteristics, stability, bioavailability, potency and toxicity. Considering the good bioavailability, 3a was selected for the pharmacology test, and the result showed that the potency of 3a was remarkably higher than that of ATT. Additionally, 3a was also chosen for the acute toxicity test. The result indicated that the prodrug 3a was more safer than ATT. The study suggested the feasibility to improve the bioavailability of ATT by using prodrug strategy. Keywords: Synthesis, Anethol trithione, Lipophilicity, Bioavailability, Prodrugs, ATT, glutamyl cysteine synthetase, glutathione, GSH, IR, HNMR, ESI-MS, pyridine hydrochloride, HPLC, alanine transaminases, aspartate transaminases, AST, Acute Toxicity Test, maximum tolerated dose, YRT-3 melting point apparatus, IR spectra, Perkin-Elmer983, NMR spectra, INOVA400, Bruker AC-E200, Agilent 1946B ESI-MS instrument, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl acetate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl propionate, (E)-4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl but-2-enoate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl isobutyrate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl benzoate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-phenylacetate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl stearate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl pivalate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl cinnamate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-fluorobenzoate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 4-chlorobenzoate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 3-phenylpropanoate, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 3,3-diphenylpropan-oate, (3-thioxo-3H-1,2-dithiol-5-yl)phenyl 1,2,3,4-tetrahydro-naphthalene-1-carboxylate (3o), 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 5,6,7,8-tetrahydro-naphthalene-1-carboxylate, SPD-10A variable UV-VIS detector, ODS column, ICR mice