title: Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA.
abstract: Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI(50) in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety of in vitro and cell-based assays all of the hybrids tested were shown to target topoisomerase II. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles matching both etoposide and the N-mustard compounds from which they were derived. These results supported the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA.
authors.affiliation: Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Yadav
authors.affiliation: Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.affiliation: Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Daywin
authors.initials: D
authors.lastname: Patel
authors.affiliation: College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Jack C
authors.initials: JC
authors.lastname: Yalowich
authors.affiliation: Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada. Electronic address: B_Hasinoff@UManitoba.ca.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Hasinoff
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005047:Etoposide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D062105:Molecular Docking Simulation; D009150:Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009150:Mustard Compounds; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin
keywords: Alkylator; Anticancer; COMPARE; DNA; Docking; Epipodophyllotoxin; Etoposide; Hybrid; K562 cells; Molecular modeling; Nitrogen mustard; Structure-based design; Topoisomerase II