PMID: 11311063Apr 20, 2001Paper

Dicationic bis(9-methylphenazine-1-carboxamides): relationships between biological activity and linker chain structure for a series of potent topoisomerase targeted anticancer drugs

Journal of Medicinal Chemistry
S A GamageW A Denny

Abstract

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 link...Continue Reading

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Citations

Mar 12, 2009·Cancer Chemotherapy and Pharmacology·Steven J WolfDaniel R Catchpoole
Dec 12, 2001·Bioorganic & Medicinal Chemistry·Julie A SpicerWilliam A Denny
Mar 3, 2004·Chemical & Pharmaceutical Bulletin·Jaskiran KaurRamesh Chandra
Jun 28, 2014·Nature Communications·Kathryn A WhiteheadDaniel G Anderson
May 3, 2012·Medicinal Research Reviews·Chung-Hang LeungDik-Lung Ma
May 13, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Marta SzumilakAgnieszka W Piastowska-Ciesielska
Feb 18, 2012·Natural Product Reports·A CimminoR Kiss
Jul 7, 2018·Beilstein Journal of Organic Chemistry·Sayantan BhaduriDev P Arya
Aug 20, 2004·The Journal of Biological Chemistry·Jixun DaiDanzhou Yang
Sep 26, 2002·Chemical Communications : Chem Comm·Gilles LavalBernard T Golding
Jan 16, 2007·Molecular Cancer Therapeutics·Chandanamali PunchihewaDanzhou Yang
Aug 12, 2005·Molecular Cancer Therapeutics·Sarah A ByersDavid H Price
Mar 11, 2004·Chemical Reviews·Jane Buus Laursen, John Nielsen
Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Adam J BuricDanzhou Yang
Oct 8, 2003·Biochemistry·Carolina CarrascoChristian Bailly
Jun 27, 2003·Journal of Medicinal Chemistry·Ippolito AntoniniSante Martelli

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