DNA binding to guide the development of tetrahydroindeno[1,2-b]pyrido[4,3,2-de]quinoline derivatives as cytotoxic agents.
The tetrahydroindeno[1,2-b]pyrido[4,3,2-de]quinoline chromophore was initially designed as a DNA intercalating unit because of its planar structure. Unexpectedly, one molecule (15d) bearing two N-methylpiperazine chains on both sides of this condensed pentacyclic skeleton fits into the minor groove of DNA and preferentially recognizes AT-rich sequences. The monosubstituted compound 16d was identified as a potent cytotoxic DNA intercalator, whereas the disubstituted analogue 15d represents a new structural motif for the development of DNA sequence-reading small molecules.
Catoen-Chackal
Sarah
S
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Université de Lille 2, Rue du Professeur Laguesse, BP 83, 59006 Lille, France.
Facompré
Michael
M
Houssin
Raymond
R
Pommery
Nicole
N
Goossens
Jean-François
JF
Colson
Pierre
P
Bailly
Christian
C
Hénichart
Jean-Pierre
JP
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D018983:DNA Footprinting; D004354:Drug Screening Assays, Antitumor; D005470:Fluorometry; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044366:Transition Temperature
C488118:4,5-dimethoxy-10-(3-(4-methyl)piperazin-1-ylpropoxy)-1,2,3,12-tetrahydroindeno(1,2-b)pyrido(4,3,2-de)quinoline; C488117:4,5-dimethoxy-3-(2-(4-methyl)piperazin-1-ylacetyl)-10-(3-(4-methyl)piperazin-1-ylpropoxy)-1,2,3,12-tetrahydroindeno(1,2-b)pyrido(4,3,2-de)quinoline; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D010879:Piperazines; D011804:Quinolines; D004247:DNA