Placement of alkyl substituents on the C-7 piperazine ring of fluoroquinolones: dramatic differential effects on mammalian topoisomerase II and DNA gyrase
| Autor: | Suzanne L. Haskell, Melinda S. Moynihan, Mcguirk Paul R, Thomas D. Gootz |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
medicine.drug_class
Stereochemistry Molecular Conformation Crystallography X-Ray Cleavage (embryo) DNA gyrase Structure-Activity Relationship chemistry.chemical_compound Anti-Infective Agents medicine Animals Topoisomerase II Inhibitors Pharmacology (medical) Etoposide Antibacterial agent Pharmacology biology Chemistry Topoisomerase DNA Quinolone Infectious Diseases Sparfloxacin Biochemistry biology.protein Topoisomerase-II Inhibitor Fluoroquinolones Research Article medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 38:130-133 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | quinolone wereprepared andtested inaDNA cleavage assaywithcalf thymus topoisomerase II.Positioning ofthemethyl groups on theC-7piperazineringinfluenced potency against themammalianenzyme;thecis-3,5-dimethyl configuration didnotstimulate cleavage atdrugconcentrations less thanorequal to2,000 ,uM,whilethetrans configuration was active atdruglevels as lowas 36p,M.Removalofthecis-methyl groupsproduced a compound that was onlysixfold less potent thantheantitumor agent etoposide instimulating enzyme-mediated DNA cleavage. Thecis- andtrans-methyl substitutions on thepiperazine thatconferred potency against the mammalian typeII enzyme hadlittle effect on bacterial DNA gyrasecleavage activity, suggesting that an asymmetric barrier exists withthemammalianenzymewhichinfluences productive quinolone interaction, favoring theless bulky trans-3,5-dimethylpiperazine substituent atC-7. Quinolones areantibacterial agents thattarget DNA gyrase(atypeIItopoisomerase) astheir primary mechanism of activity. Thesimilarities inthebiochemical mechanisms and aminoacid sequencesbetweenDNA gyraseandmammalian topoisomerase 11 (6)haveprompted several investigators to determine whetherquinolones couldexhibit potent inhibitoryeffects on theeukaryotic enzyme.Whilethequinolones approved forclinical use as antibacterial agents are not potentinhibitors ofeukaryotic topoisomerase II,theexperimental quinolones CP-115,953 andCP-67,804 haverecently beenshowntoinduceenzyme-mediated DNA cleavage in vitro atconcentrations comparable tothoseoftheanticancer agentetoposide (8,9).Relative activity against themammalian topoisomerase paralleled thecytotoxic potency ofthese novelquinolones against cultured eukaryotic cells (2,8).Our previous studies haveshownthatthe6,8-difluoro-1-cyclopropyl substitution pattern on thequinolone nucleus imparts potenttopoisomerase IIactivity (1,8).Recently, a new 7-(cis-3,5-dimethylpiperazinyl)-6,8-difluoro-5-amino-1-cyclopropyl-substituted quinolone (AT-4140, sparfloxacin) has beendescribed (7). Inour studies, thisquinolone isnot potentatinducing topoisomerase II-mediated DNA cleavage,even though ithasthe6,8-difluoro-1-cyclopropyl structure.Inordertodefine thestructural parameters thatinfluence topoisomerase II potencywithinthisseries, several substituted analogs were prepared andtested ina DNA cleavage assay withenzyme purified fromcalfthymus. Results suggest that an asymmetric barrier thataffects the potencyofquinolones against this eukaryotic topoisomerase II exists on theenzyme.A bulky cis-3,5-dimethyl piperazine substituent attheC-7position inthisseries appears to markedly reducepotencyforinducing enzyme-mediated DNA cleavage. (This workwas presented inpartattheFourth Conference |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|