Synthesis and cytotoxic activity of a new series of topoisomerase I inhibitors.
A series of structurally simple analogues of natural topopyrone C were synthesized and tested for cytotoxic and topoisomerase I inhibitory activities. The removal of the hydroxyl groups at the 5 and 9 positions resulted in an increased cytotoxic potency and ability to stabilize topoisomerase-mediated cleavage. In addition, the results suggest that some structural features, such as the pyrone ring and a polar group in position 11, are fundamental for topoisomerase I inhibitory effect. These structural requirements are also consistent with the cytotoxic activity.
Dallavalle
Sabrina
S
Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, via Celoria 2, 20133 Milano, Italy.
Gattinoni
Sonia
S
Mazzini
Stefania
S
Scaglioni
Leonardo
L
Merlini
Lucio
L
Tinelli
Stella
S
Beretta
Giovanni L
GL
Zunino
Franco
F
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011753:Pyrones; D059004:Topoisomerase I Inhibitors; C417104:topopyrone C; D004247:DNA; D004264:DNA Topoisomerases, Type I