2,3-Dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione derivatives, a class of cytotoxic agents active on multidrug-resistant cell lines: synthesis, biological evaluation, and structure-activity relationships.
A series of DNA-intercalating potential antitumor agents, (amino)alkyl-substituted 2,3-dihydro-1H,7H-pyrimido[5,6, 1-de]acridine-1,3,7-triones, has been prepared by aminolysis of the corresponding 6-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward eight tumor cell lines, including human colon adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubicin-resistant)) and human ovarian carcinoma (A2780 sensitive, A2780cisR (cisplatin-resistant), CH1, CH1cisR (cisplatin-resistant), and SKOV-3) cells, are described and compared to that of reference drugs. The cytotoxic activity often parallels the observed DNA affinities, for almost all the target compounds. Interesting structure-activity relationships have been found. The octanol/water partition coefficients have also been calculated, but there was no correlation either with cytotoxicity values or with resistance index. Three highly DNA-affinic analogues, 9 and 15f,15h, have been identified with a useful broad spectrum of cytotoxic activity.
Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
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I
Antonini
P
P
Polucci
L R
LR
Kelland
E
E
Menta
N
N
Pescalli
S
S
Martelli
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005453:Fluorescence; D006801:Humans; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C120307:6-((2-aminoethyl)amino)-2-(2-(dimethylamino)ethyl)-2,3-dihydro-1H,7H-pyrimido(5,6,1-de)acridine-1,3,7-trione; C120308:9-amino-2-(2-(dimethylamino)ethyl)-6-((2-(dimethylamino)ethyl)amino)-2,3-dihydro-1H,7H-pyrimido(5,6,1-de)acridine-1,3,7-trione; C120309:9-hydroxy-2-(2-(dimethylamino)ethyl)-6-((2-(dimethylamino)ethyl)amino)-2,3-dihydro-1H,7H-pyrimido(5,6,1-de)acridine-1,3,7-trione; D000166:Acridines; D000970:Antineoplastic Agents; D011744:Pyrimidinones; D004247:DNA