Antonow, D and Kaliszczak, M and Kang, GD and Coffils, M and Tiberghien, AC and Cooper, N and Barata, T and Heidelberger, S and James, CH and Zloh, M and Jenkins, TC and Reszka, AP and Neidle, S and Guichard, SM and Jodrell, DI and Hartley, JA and Howard, PW and Thurston, DE (2010) Structure-Activity Relationships of Monomeric C2-Aryl Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Antitumor Agents. J MED CHEM , 53 (7) 2927 - 2941. 10.1021/jm901722v.
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A comprehensive SA R investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.
|Title:||Structure-Activity Relationships of Monomeric C2-Aryl Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Antitumor Agents|
|Keywords:||CROSS-LINKING AGENT, DNA-BINDING REACTIVITY, IN-VITRO, BIOLOGICAL-ACTIVITY, PYRROLOBENZODIAZEPINE PBD, MOLECULAR-MECHANICS, SJG-136 NSC-694501, CELL-LINES, CYTOTOXICITY, PHARMACOLOGY|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutical and Biological Chemistry|
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute > Research Department of Oncology
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