A three-dimensional quantitative structure-activity analysis of a new class of bisphenol topoisomerase IIalpha inhibitors.
After the identification of a new lead bisphenol compound that had good topoisomerase IIalpha (EC 5.99.1.3) inhibitory activity, a series of bisphenol analogs were synthesized and tested to identify the structural features that were responsible for their activity. The bisphenols represent a new structural class of topoisomerase II inhibitor that potently inhibited the growth of Chinese hamster ovary and K562 leukemia cells in the low micromolar range. The fact that cell growth inhibition was significantly correlated with topoisomerase IIalpha inhibition suggests that the catalytic inhibition of topoisomerase IIalpha probably contributed to their growth inhibitory activity. Only one of the bisphenols (O3OH) tested significantly induced topoisomerase IIalpha-mediated cleavage of DNA. Most of the bisphenols displayed only low-fold cross-resistance to a K562 subline containing reduced levels of topoisomerase IIalpha Thus, it is likely that most of the bisphenols inhibited cell growth, not by acting as topoisomerase II poisons, but rather by acting as catalytic inhibitors of topoisomerase IIalpha. Three-dimensional quantitative structure-activity analysis (3D-QSAR) was carried out on the bisphenols using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to determine the structural features responsible for their activity. The CoMSIA analysis of the topoisomerase IIalpha inhibitory activity yielded a statistically significant model upon partial least-squares analyses. The 3D-QSAR CoMSIA analysis showed that polar meta hydrogen bond acceptor substituents on the phenyl rings favored inhibition of topoisomerase IIalpha. For the hydrogen bond donor field, para- and meta-substituted hydroxyl groups favored inhibition. Hydrophobic substituents on the bridge atoms disfavored inhibition.
Faculty of Pharmacy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. b_hasinoff@umanitoba.ca
Hong
H
Liang
Xing
X
Wu
Jack C
JC
Yalowich
Brian B
BB
Hasinoff
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000145:classification; D000970:Antineoplastic Agents / Q000633:toxicity; D016466:CHO Cells; D002384:Catalysis; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000145:classification; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000145:classification; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D021281:Quantitative Structure-Activity Relationship; D011929:Razoxane / Q000737:chemistry; D055672:Static Electricity; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D005047:Etoposide; D004317:Doxorubicin; D004247:DNA; D004250:DNA Topoisomerases, Type II