title: Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex.
abstract: Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53(+/+) colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53(-/-) SW480; the lung cancer cell line p53(-/-) H1299; mouse embryonic fibroblasts (MEF) p53(+/+) and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53(+/+) cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo.
authors.forename: Mohamed Salah
authors.initials: MS
authors.lastname: Rezk
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abdel-Halim
authors.forename: Adam
authors.initials: A
authors.lastname: Keeton
authors.forename: Derek
authors.initials: D
authors.lastname: Franklin
authors.forename: Matthias
authors.initials: M
authors.lastname: Bauer
authors.forename: Frank Michael
authors.initials: FM
authors.lastname: Boeckler
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
authors.forename: Rolf Wolfgang
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gary Anthony
authors.initials: GA
authors.lastname: Piazza
authors.forename: Ashraf Hassan
authors.initials: AH
authors.lastname: Abadi
mesh_terms: D000818:Animals; 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; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases