Further SAR studies on bicyclic basic merbarone analogues as potent antiproliferative agents

Andrea Spallarossa; Chiara Rotolo; Claudia Sissi; Giuseppe Marson; Maria Laura Greco; Angelo Ranise; Paolo La Colla; Bernardetta Busonera; Roberta Loddo

doi:10.1016/j.bmc.2013.08.056

Further SAR studies on bicyclic basic merbarone analogues as potent antiproliferative agents

Bioorg Med Chem. 2013 Nov 1;21(21):6328-36. doi: 10.1016/j.bmc.2013.08.056. Epub 2013 Sep 6.

Authors

Andrea Spallarossa¹, Chiara Rotolo, Claudia Sissi, Giuseppe Marson, Maria Laura Greco, Angelo Ranise, Paolo La Colla, Bernardetta Busonera, Roberta Loddo

Affiliation

¹ 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.

PMID: 24063907
DOI: 10.1016/j.bmc.2013.08.056

Abstract

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.

Keywords: Antiproliferative agents; Pyrimidopyrimidine derivatives; Topoisomerase II inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / toxicity
Bridged Bicyclo Compounds / chemistry*
Cell Line
Cell Proliferation / drug effects
DNA Topoisomerases, Type II / metabolism
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / metabolism
Drug Screening Assays, Antitumor
HeLa Cells
Humans
MCF-7 Cells
Pyrimidines / chemical synthesis
Pyrimidines / toxicity
Structure-Activity Relationship
Thiobarbiturates / chemical synthesis
Thiobarbiturates / chemistry*
Thiobarbiturates / toxicity
Thiones / chemical synthesis
Thiones / toxicity
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry*
Topoisomerase II Inhibitors / toxicity

Substances

((2-(dimethylamino)ethyl)amino)-5-imino-1,3,6-triphenyl-5,6-dihydropyrimido(4,5-d)pyrimidine-2,4(1H,3H)-dithione
Antigens, Neoplasm
Antineoplastic Agents
Bridged Bicyclo Compounds
DNA-Binding Proteins
Pyrimidines
Thiobarbiturates
Thiones
Topoisomerase II Inhibitors
DNA Topoisomerases, Type II
merbarone