title: Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2-carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors.
abstract: Series of 4-amino-6-(arylamino)-1,3,5-triazine-2-carbohydrazides (3a-e) and N'-phenyl-4,6-bis(arylamino)-1,3,5-triazine-2-carbohydrazides (6a-e), for ease of readership, we will abbreviate our compound names as 'new triazines', have been synthesized, based on the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ9 and 4-amino-N'-phenyl-6-(arylamino)-1,3,5-triazine-2-carbohydrazides. Synthesis of the target compounds was readily accomplished in two steps from either bis-aryl/aryl biguanides via reaction of phenylhydrazine or hydrazinehydrate with key 4-amino-6-bis(arylamino)/(arylamino)-1,3,5-triazine-2-carboxylate intermediates. These new triazine derivatives were evaluated for their abilities to inhibit Rad6B ubiquitin conjugation and in vitro anticancer activity against several human cancer cell lines: ovarian (OV90 and A2780), lung (H1299 and A549), breast (MCF-7 and MDA-MB231) and colon (HT29) cancer cells by MTS assays. All the 10 new triazines exhibited superior Rad6B inhibitory activities in comparison to selective Rad6 inhibitor TZ9 that was reported previously. Similarly, new triazines also showed better IC50 values in survival assays of various tumor cell lines. Particularly, new triazines 6a-c, exhibited lower IC50 (3.3-22 μM) values compared to TZ9.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Egypt. Electronic address: hendo1311@hotmail.com.
authors.forename: Hend
authors.initials: H
authors.lastname: Kothayer
authors.affiliation: Department of Oncologic Sciences, USA Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL 36604, USA.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Spencer
authors.affiliation: Department of Oncologic Sciences, USA Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL 36604, USA.
authors.forename: Kaushlendra
authors.initials: K
authors.lastname: Tripathi
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westwell
authors.affiliation: Department of Oncologic Sciences, USA Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL 36604, USA.
authors.forename: Komaraiah
authors.initials: K
authors.lastname: Palle
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; D014227:Triazines; C471546:UBE2B protein, human; D044763:Ubiquitin-Conjugating Enzymes
keywords: Anticancer; E2 ubiquitin conjugating enzyme; Rad6B; Triazines; Ubiquitination