Structure-based design and synthesis of acyclic and substituted heterocyclic phosphonates linearly linked to thiazolobenzimidazoles as potent hydrophilic antineoplastic agents

• Published in: Chemical papers Vol. 71; no. 10; pp. 1961 - 1973
• Main Authors: Abdou, Wafaa M., Shaddy, Abeer A., Kamel, Azza A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2017; Springer Nature B.V
• Subjects: Algorithms; Anticancer properties; Biochemistry; Biotechnology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chromophores; Colon; Esters; Industrial Chemistry/Chemical Engineering; Materials Science; Medicinal Chemistry; Molecular structure; Organic chemistry; Original Paper; Phosphonates; Phosphors; Reagents; Stereoselectivity; Substitutes; Nucleophilic substitutions; Heterocycles; Antitumor pro-drugs; Structure–activity relationships (SAR); Computer Program PASS 14; Nucleophilic addition
• ISSN: 2585-7290; 0366-6352; 1336-9075
• DOI: 10.1007/s11696-017-0190-z

As a contribution to our investigations to develop multidisciplinary entities of substituted heterocycle phosphor esters, in this paper, we prepared a series of thiazolobenzimidazoles incorporating phosphor esters of potential anticancer properties. Phosphoryl reagents were applied on E -3-( N,N -dimethylamino)-1-(3-methythiazolo[3,2- a ]benzoimidazol-2-yl)prop-2-en-1-one and 1-(3-methylthiazolo[3,2- a ]benzimidazol-2-yl)ethanone. The reactions proceeded under mild conditions to give an ensemble of 14 new phosphonates in good yields (68–74%). The stereoselective chemistry was studied by a series of heteronuclear 13 C[ 1 H]-n O e experiments. Based on the prediction studies in the early stage using PASS algorithm 14, the synthesized phosphonates were evaluated as antitumor candidates at a dose of 10 µmol/mL against human breast and human colon tumor (4 cultured cell lines each). Three products showed significant antineoplastic potency in relative to the standard drug, adriamycin. Permeability of the lead molecules was determined and the structure–activity relationship (SAR) was discussed to suggest a pro-drug chromophore. Furthermore, there was good coincidence of experimental data of antitumor properties and prediction results.