Linked Life Data

11311063

Source:http://linkedlifedata.com/resource/pubmed/id/11311063

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2001-4-20
pubmed:abstractText
Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH(2))(n)()NR(CH(2))(m)NR(CH(2))(n) linkers of varying length (carboxamide N-N distances from 11.0 to 18.4 A) and rigidity were prepared by reaction of 9-methylphenazine-1-carboxylic acid imidazolide with the appropriate polyamines. The compounds were evaluated for growth inhibitory properties in P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia with low levels of topoisomerase II (topo II). The compounds all had IC(50) ratios of <1 in the resistant Jurkat lines, consistent with topo II inhibition not being the primary mechanism of action. Analogues joined by an (CH(2))(2)NR(CH(2))(2)NR(CH(2))(2) linker were extremely potent cytotoxins, with selectivity toward the human cell lines, but absolute potencies declined sharply from R = H through R = Me to R = Pr and Bu. In contrast, (CH(2))(2)NR(CH(2))(3)NR(CH(2))(2) compounds showed reverse effects, with the R = Me analogue being more potent than the R = H one as well as being the most potent in the series [IC(50) in JL(C) cells 0.08 nM; superior to that for the clinical bis(naphthalimide) LU 79553]. Overall, the IC(50)s of analogues with linker chains (CH(2))(n)NH(CH(2))(m)NH(CH(2))(n) were inversely proportional to linker length. Constraining the rigidity of the linker chain by incorporating a piperazine ring did not decrease potency significantly. A representative compound bound tightly to DNA with high selectivity for GC sites, compatible with recent work suggesting that compounds of this type place their side chains in the major groove, making specific contacts with guanine bases. Representative compounds were susceptible to transport mediated resistance, being much less effective in cells that overexpressed P-glycoprotein. Overall the results suggest these compounds have a similar mode of action, mediated primarily by poisoning of topo I (possibly with some involvement of topo II). The bis(9-methylphenazine-1-carboxamides) show very high in vitro growth inhibitory potencies compared to their monomeric analogues. Two compounds showed in vivo activity in murine colon 38 syngeneic and HT29 human colon tumor xenograft models using intraperitoneal dosing.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
44
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1407-15
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:11311063-Amides, pubmed-meshheading:11311063-Animals, pubmed-meshheading:11311063-Antineoplastic Agents, pubmed-meshheading:11311063-Cations, Divalent, pubmed-meshheading:11311063-DNA, Superhelical, pubmed-meshheading:11311063-DNA Topoisomerases, Type I, pubmed-meshheading:11311063-DNA Topoisomerases, Type II, pubmed-meshheading:11311063-Drug Screening Assays, Antitumor, pubmed-meshheading:11311063-Enzyme Inhibitors, pubmed-meshheading:11311063-Humans, pubmed-meshheading:11311063-Inhibitory Concentration 50, pubmed-meshheading:11311063-Mice, pubmed-meshheading:11311063-Mice, Inbred C57BL, pubmed-meshheading:11311063-Mice, Nude, pubmed-meshheading:11311063-Phenazines, pubmed-meshheading:11311063-Structure-Activity Relationship, pubmed-meshheading:11311063-Topoisomerase I Inhibitors, pubmed-meshheading:11311063-Topoisomerase II Inhibitors, pubmed-meshheading:11311063-Transplantation, Heterologous, pubmed-meshheading:11311063-Tumor Cells, Cultured
pubmed:year
2001
pubmed:articleTitle
Dicationic bis(9-methylphenazine-1-carboxamides): relationships between biological activity and linker chain structure for a series of potent topoisomerase targeted anticancer drugs.
pubmed:affiliation
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1000, New Zealand.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't