title: Design, synthesis and in vitro anticancer evaluation of 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides.
abstract: Series of substituted 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides have been synthesised, based on molecular modelling of candidate structures related to the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ8 and TZ9. Synthesis of the target compounds was readily accomplished in two steps from aryl biguanides via reaction of phenylhydrazine or benzylamines with key 4-amino-6-(arylamino)-1,3,5-triazine-2-carboxylate intermediates. These new triazine derivatives were tested for in vitro anticancer activity against the Rad6B expressing human breast cancer cell lines MDA-MB-231 and MCF-7. Active compounds, such as the triazinyl-carbohydrazides 3a-e, were found to exhibit low micromolar IC50 values particularly in the Rad6B-overexpressing MDA-MB-231 cell line.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK; Faculty of Pharmacy, Zagazig University, Egypt.
authors.forename: Hend
authors.initials: H
authors.lastname: Kothayer
authors.forename: Abdalla A
authors.initials: AA
authors.lastname: Elshanawani
authors.forename: Mansour E
authors.initials: ME
authors.lastname: Abu Kull
authors.forename: Osama I
authors.initials: OI
authors.lastname: El-Sabbagh
authors.forename: Malathy P V
authors.initials: MP
authors.lastname: Shekhar
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Arwyn T
authors.initials: AT
authors.lastname: Jones
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westwell
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D006834:Hydrazines; D014227:Triazines; C471546:UBE2B protein, human; D044763:Ubiquitin-Conjugating Enzymes; C019289:carbohydrazide
keywords: Breast cancer; E2 ubiquitin conjugating enzyme; MCF-7; MDA-MB-231; Rad6B; Triazines