title: 2,6-Di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones: novel, potent, cytotoxic, and DNA-binding agents.
abstract: DNA-binding agents with potential antitumor activities bearing two cationic side chains, the 2,6-di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4a-r), have been prepared either by reaction of the appropriate 2-(omega-aminoalkyl)-6-chloro-2,3-dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione with the appropriate (omega-aminoalkyl)hydrazine or by cyclization of the requisite N-6,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-6-carboxamide with phosgene. In vitro cytotoxic properties of these derivatives against three human colon adenocarcinoma cell lines (HT29, LoVo, and LoVo/Dx) and against some cell lines of the NCI panel are described and compared to that of reference drugs. Some of the new compounds showed outstanding potency while lacking cross-resistance with anthracyclines. Structure-activity relationships are discussed, and a mechanistic analysis is performed using the COMPARE procedure. The mechanism and efficiency of noncovalent DNA binding of these compounds are examined using gel electrophoresis and fluorometric techniques. The 2,6-di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4) constitute a new class of potent, cytotoxic DNA-binding agents not cross-resistant with doxorubicin.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy. antonini@camserv.unicam.it
authors.forename: Ippolito
authors.initials: I
authors.lastname: Antonini
authors.forename: Paolo
authors.initials: P
authors.lastname: Polucci
authors.forename: Amelia
authors.initials: A
authors.lastname: Magnano
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Ernesto
authors.initials: E
authors.lastname: Menta
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pescalli
authors.forename: Sante
authors.initials: S
authors.lastname: Martelli
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D005470:Fluorometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; D004247:DNA