DNA-targeting pyrroloquinoline-linked butenone and chalcones: synthesis and biological evaluation.
A series of conjugates of alpha,beta-unsaturated ketone systems, phenyl-butenone and diaryl-propenones (chalcones), with the tricyclic planar pyrroloquinoline nucleus were synthesised and evaluated for their anticancer properties. The aim was to target DNA by butenone and chalcones, and determine the occurrence of interactions with the macromolecule or related functional enzymes. The ability to inhibit cell growth was assayed on three human tumor cell lines, and the capacity to form molecular complexes with DNA was studied by linear flow dichroism (LD). The effect on the activity of the nuclear enzyme DNA topoisomerase II was also investigated. A noticeable cytotoxic effect was observed for all pyrroloquinoline-conjugated compounds 5 and 7a-c, particularly against human melanoma cell line JR8 (IC(50) 1.2-3.3 microM); the unconjugated chalcones (8a-c) and butenone had a lower or no effect at the tested concentrations. LD experiments confirmed the pyrroloquinoline nucleus as an efficacious carrier for intercalative complexation with DNA. The ability of pyrroloquinoline derivatives to intercalate between base pairs appears to inhibit the relaxation of supercoiled DNA by topoisomerase II, while they induce no significant DNA cleavage. Since the concentrations inhibiting the enzyme appear relatively high with respect to cytotoxicity, the effective intercalation could affect the activity of more DNA processing enzymes and these overall nuclear effects may induce cell death.
Dalla Via
Lisa
L
Department of Pharmaceutical Sciences, University of Padova, Padova, Italy.
Gia
Ornella
O
Chiarelotto
Gianfranco
G
Ferlin
Maria Grazia
MG
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002074:Butanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D006801:Humans; D011758:Pyrroles / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D002074:Butanones; D047188:Chalcones; D011758:Pyrroles; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C410406:pyrroloquinoline; D004247:DNA