Synthesis and antiproliferative activity of some variously substituted acridine and azacridine derivatives.
A group of 9-substituted acridine and azacridine derivatives (m-AMSA analogues) were synthesised following classical procedures as potential antitumour agents with inhibitory effects on DNA topoisomerase II. Some were found to have noticeable cytotoxicity against human HL-60 and HeLa cells grown in culture. Their non-covalent interactions with calf thymus DNA have been studied using fluorescence quenching. We evaluated DNA damage produced by the tested compounds by means of DNA filter elution and protein precipitation techniques. Catalytic studies carried out with purified topoisomerase confirmed these agents as antitopoisomerase inhibitors. Chemotherapy of solid-tumour-bearing mice with tested compounds allowed an aza-analogue (compound IIIb), as potent as m-AMSA but less toxic towards the host, to be recognised.
Ferlin
M G
MG
Department of Pharmaceutical Sciences of Padua University, Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, Padova, Ital.
Marzano
C
C
Chiarelotto
G
G
Baccichetti
F
F
Bordin
F
F
D000166:Acridines / Q000737:chemistry*; D000677:Amsacrine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000166:Acridines; D000970:Antineoplastic Agents; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004247:DNA