title: A structure-based 3D-QSAR study of anthrapyrazole analogues of the anticancer agents losoxantrone and piroxantrone.
abstract: A series of 13 anthrapyrazole compounds that are analogues of piroxantrone and losoxantrone were synthesized, and their cell growth inhibitory effects, DNA binding, topoisomerase IIalpha mediated (EC 5.99.1.3) cleavage of DNA, and inhibition of DNA topoisomerase IIalpha decatenation catalytic activities were determined. Cell growth inhibitory activity was well-correlated with DNA binding, suggesting that these compounds may act by targeting DNA. However, cell growth inhibition was not well-correlated with the inhibition of topoisomerase IIalpha catalytic activity, suggesting that these anthrapyrazoles did not act solely by inhibiting the catalytic activity of topoisomerase II. Most of the analogues were able to induce DNA cleavage, and thus, it was concluded that they acted, at least in part, as topoisomerase II poisons. Structure-based three-dimensional quantitative structure-activity analyses (3D-QSAR) were carried out on the aligned structures of the anthrapyrazoles docked into DNA using comparative molecular field analysis (CoMFA) and comparative molecular similarity index (CoMSIA) analyses in order to determine the structural features responsible for their activity. Both CoMFA and CoMSIA yielded statistically significant models upon partial least-squares analyses. The 3D-QSAR analyses showed that hydrogen-bond donor interactions and electrostatic interactions with the protonated amino side chains of the anthrapyrazoles led to high cell growth inhibitory activity.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.forename: Lynn J
authors.initials: LJ
authors.lastname: Guziec
authors.forename: Frank S
authors.initials: FS
authors.lastname: Guziec
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Larson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lang
authors.forename: Jack C
authors.initials: JC
authors.lastname: Yalowich
authors.forename: Brian B
authors.initials: BB
authors.lastname: Hasinoff
mesh_terms: D018943:Anthracyclines / Q000737:chemistry; D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000187:drug effects; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D047069:Pyrazolones / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D018943:Anthracyclines; D000880:Anthraquinones; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone; D004247:DNA; C055925:anthrapyrazole; D004250:DNA Topoisomerases, Type II; C046659:piroxantrone