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 diaminotriazinylmethyl 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 (H1299and 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 to 22 μM) values compared to TZ9.

UbcH10 a Major Actor in Cancerogenesis and a Potential Tool for Diagnosis and Therapy

“…There must be more specific UPS inhibitors targeting the core of ubiquitination's specificity that reside in E2s or E3s components of the UPS system. A recent promising attempts have been made recently to target E1 enzymes [58], but the turning point could come from the studies about conjugating enzymes an ligases [59][60][61][62][63], hoping to get a specific inhibitor for UbcH10 to be placed alongside the specific siRNA or microRNA (miRNA) used so far. So far, only one study has been carried out to search for specific UbcH10 inhibitors but has stopped in the selection from ligand libraries identifying two candidate compounds that are waiting to be tested in vitro [64].…”

RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance

“…To test whether pharmacological inhibition of RAD6 can attenuate its ubiquitination signaling mediated acquired chemoresistance and stemness in OC cells, we examined TZ9 [4-Amino-6-(phenylamino)-[1,3,5]triazin-2-yl)methyl-4-nitrobenzoate], a previously identified RAD6-specific inhibitor ( Fig 4A ) 33 , 34 . Exposure of OV90 cells to TZ9 induced γH2AX foci, a marker of DNA double strand breaks (DSB) and stalled replication forks ( Fig 4B ).…”

Design, synthesis, anticancer, antibacterial, and antifungal evaluation of 4‐aminoquinoline‐1,3,5‐triazine derivatives

“…In this regard, 4‐aminoquinoline and 1,3,5‐triazine have gained a lot of attention from the researchers because of an extensive array of pharmacological properties, such as antibacterial, antimalarial, anti‐inflammatory, antifungal, anti‐HIV, anti‐diabetic, and against cystic fibrosis . More recently, these pharmacophores showed excellent anticancer activity . Thus, in the present study, we intended to synthesize a single skeleton comprised of 4‐aminoquinoline and 1,3,5‐triazine with subsequent screening against cancer, bacterial and fungal micro‐organisms.…”