title: DNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid neocryptolepine.
abstract: Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II. In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety. The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine. The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer. The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug.
authors.affiliation: INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, Lille, France. bailly@lille.inserm.fr
authors.forename: C
authors.initials: C
authors.lastname: Bailly
authors.forename: W
authors.initials: W
authors.lastname: Laine
authors.forename: B
authors.initials: B
authors.lastname: Baldeyrou
authors.forename: M C
authors.initials: MC
authors.lastname: De Pauw-Gillet
authors.forename: P
authors.initials: P
authors.lastname: Colson
authors.forename: C
authors.initials: C
authors.lastname: Houssier
authors.forename: K
authors.initials: K
authors.lastname: Cimanga
authors.forename: S
authors.initials: S
authors.lastname: Van Miert
authors.forename: A J
authors.initials: AJ
authors.lastname: Vlietinck
authors.forename: L
authors.initials: L
authors.lastname: Pieters
mesh_terms: D000470:Alkaloids / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000633:toxicity*; D002417:Cattle; D002942:Circular Dichroism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D018983:DNA Footprinting; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles; D007364:Intercalating Agents / Q000378:metabolism / Q000633:toxicity*; D007624:KB Cells; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D011804:Quinolines; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D026121:Indole Alkaloids; D007211:Indoles; D007364:Intercalating Agents; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C414982:neocryptolepine; C024015:cryptolepine; D004247:DNA; D004250:DNA Topoisomerases, Type II