title: DNA interstrand crosslinking agents: synthesis, DNA interactions, and cytotoxicity of dimeric achiral seco-amino-CBI and conjugates of achiral seco-amino-CBI with pyrrolobenzodiazepine (PBD).
abstract: The design and synthesis of three novel bisalkylating agents derived from the achiral seco-duocarmycin or CC-1065 analogs and pyrrolobenzodiazepines (PBDs) are described: achiral seco-CBI (cyclopropanebenz[e]indoline)-PBD 11, achiral seco-CI-PBD 12, and achiral seco-CBI dimer 13. Compounds 11 and 12 demonstrated enhanced cytotoxicity over the monomer counterparts against the growth of P815 murine mastocytoma cells in culture. Conjugate 11 was found to covalently react with adenine-N3 positions within the minor groove at AT-rich sequences and to produce DNA interstrand crosslinks. Both compounds were found to induce apoptosis in P815 cells. Due to its poor water solubility, dimer 13 did not give any appreciable DNA binding or cytotoxicity.
authors.affiliation: Department of Chemistry, Furman University, 3300 Pointsett Highway, Greenville, SC 29613, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Purnell
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Amanda
authors.initials: A
authors.lastname: O'kelley
authors.forename: Carly
authors.initials: C
authors.lastname: Price
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Summerville
authors.forename: Stephen
authors.initials: S
authors.lastname: Hudson
authors.forename: Caroline
authors.initials: C
authors.lastname: O'hare
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Asao
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D003432:Cross-Linking Reagents; D003521:Cyclopropanes; D007211:Indoles; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; C057812:indoline; D004247:DNA; C030797:cyclopropane