Further SAR studies on bicyclic basic merbarone analogues as potent antiproliferative agents.
Pyrimidopyrimidine derivatives 1 were prepared as rigid thioanalogues of merbarone (a catalytic topoisomerase II inhibitor) and screened as antiproliferative agents against different tumor cell lines. A number of the synthesized compounds emerged as cytotoxic in cell-based assays (MT-4, HeLa and MCF-7 cells) at low micromolar concentrations. In a National Cancer Institute screening, selected member of the series showed a broad spectrum of antiproliferative activity against various tumours (melanoma, renal, CNS, colon and breast cancers). The acid-base and steric properties of the substituent at position 7 of the pyrimidopyrimidine scaffold deeply affected potency. Enzymatic assays evidenced that a subset of tested derivatives efficiently inhibit topoisomerase IIα accordingly to merbarone mechanism of action. However this property does not fully rationalize the cytotoxicity data of the full ligand panel, suggesting that different target(s) should be additionally involved.
Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, Università degli Studi di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. Electronic address: andrea.spallarossa@unige.it.
Andrea
A
Spallarossa
Chiara
C
Rotolo
Claudia
C
Sissi
Giuseppe
G
Marson
Maria Laura
ML
Greco
Angelo
A
Ranise
Paolo
P
La Colla
Bernardetta
B
Busonera
Roberta
R
Loddo
D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D011743:Pyrimidines / Q000138:chemical synthesis / Q000633:toxicity; D013329:Structure-Activity Relationship; D013858:Thiobarbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013871:Thiones / Q000138:chemical synthesis / Q000633:toxicity; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
C588111:((2-(dimethylamino)ethyl)amino)-5-imino-1,3,6-triphenyl-5,6-dihydropyrimido(4,5-d)pyrimidine-2,4(1H,3H)-dithione; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D004268:DNA-Binding Proteins; D011743:Pyrimidines; D013858:Thiobarbiturates; D013871:Thiones; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; C045459:merbarone
Antiproliferative agents; Pyrimidopyrimidine derivatives; Topoisomerase II inhibitors