76226-58-9Relevant articles and documents
Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway
Elmenoufy, Ahmed H.,Gentile, Francesco,Jay, David,Karimi-Busheri, Feridoun,Yang, Xiaoyan,Soueidan, Olivier M.,Mani, Rajam S.,Ciniero, Gloria,Tuszynski, Jack A.,Weinfeld, Michael,West, Frederick G.
, (2020)
The structure-specific ERCC1-XPF endonuclease is essential for repairing bulky DNA lesions and helix distortions induced by UV radiation, which forms cyclobutane pyrimidine dimers (CPDs), or chemicals that crosslink DNA strands such as cyclophosphamide and platinum-based chemotherapeutic agents. Inhibition of the ERCC1-XPF endonuclease activity has been shown to sensitize cancer cells to these chemotherapeutic agents. In this study, we have conducted a structure activity relationship analysis based around the previously identified hit compound, 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin1-yl)methyl)phenol (F06), as a reference compound. Three different series of compounds have been rationally designed and successfully synthesized through various modifications on three different sites of F06 based on the corresponding suggestions of the previous pharmacophore model. The in vitro screening results revealed that 2-chloro-9-((3-((4-(2-(dimethylamino)ethyl)piperazin-1-yl)methyl)-4-hydroxyphenyl)amino)acridin-2-ol (B9) has a potent inhibitory effect on the ERCC1-XPF activity (IC50 = 0.49 μM), showing 3-fold improvement in inhibition activity compared to F06. In addition, B9 not only displayed better binding affinity to the ERCC1-XPF complex but also had the capacity to potentiate the cytotoxicity effect of UV radiation and inhibiting the nucleotide excision repair, by the inhibition of removal of CPDs, and cyclophosphamide toxicity to colorectal cancer cells.
Computer-aided drug design of small molecule inhibitors of the ERCC1-XPF protein–protein interaction
Barakat, Khaled H.,Ciniero, Gloria,Elmenoufy, Ahmed H.,Gentile, Francesco,Jay, David,Karimi-Busheri, Feridoun,Tuszynski, Jack A.,Weinfeld, Michael,West, Frederick G.
, (2020/02/04)
The heterodimer of DNA excision repair protein ERCC-1 and DNA repair endonuclease XPF (ERCC1-XPF) is a 5′–3′ structure-specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1-XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum-based and cross-linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1-XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi-step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half-maximum inhibitory concentration (IC50) value of 0.49 μM for the inhibition of ERCC1-XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1-XPF complex.
Microwave-induced Mannich reaction - Synthesis of some Mannich derivatives of p-aminophenol
Mahesh,Perumal, R. Venkatesha
, p. 1012 - 1014 (2007/10/03)
Mono and bis substituted dialkylamino alkyl-p-aminophenol 3 are prepared by treating paracetamol 1 with formaldehyde and appropriate secondary amines followed by deacetylation using 6 M HCI in unmodified domestic microwave oven in unsealed borosil vessels
