N4-(omega-Aminoalkyl)-1-[(omega-aminoalkyl)amino]-4- acridinecarboxamides: novel, potent, cytotoxic, and DNA-binding agents.
A series of DNA-binding potential antitumor agents, (omega-aminoalkyl)-4-acridinecarboxamides, has been prepared either by reduction of the corresponding (omega-aminoalkyl)-9-oxo-9, 10-dihydro-4-acridinecarboxamides with aluminum amalgam or by aminolysis of the corresponding (omega-aminoalkyl)-1-chloro-4-acridinecarboxamides with the suitable amine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780-sensitive, A2780cisR cisplatin-resistant, CH1-sensitive, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. One highly DNA affinic analogue (3a) has been identified with a useful broad spectrum of cytotoxic activity in the 4-7 nM range (mean IC(50) of 6 nM).
Antonini
I
I
Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy. antonini@camserv.unicam.it
Polucci
P
P
Kelland
L R
LR
Spinelli
S
S
Pescalli
N
N
Martelli
S
S
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005470:Fluorometry; D006801:Humans; D020128:Inhibitory Concentration 50; D014407:Tumor Cells, Cultured
D000166:Acridines; D000970:Antineoplastic Agents; C418113:N4-(2-(dimethylamino)ethyl)-1-((2-(dimethylamino)ethyl)amino)-4-acridinecarboxamide; D004247:DNA