Structure−Activity Relationships for Pyrido-, Imidazo-, Pyrazolo-, Pyrazino-, and Pyrrolophenazinecarboxamides as Topoisomerase-Targeted Anticancer Agents

Abstract

Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines. A 4-methoxypyrido[4,3-a]phenazine (IC(50)s 2.5-26 nM) gave modest (ca. 5 day) growth delays in H69/P xenografts with oral dosing.

Synthesis and Antitumor Activity of 5-Trifluoromethyl-2,4- dihydropyrazol-3-one Nucleosides

“…The trifluoromethylsubstituted compounds have been reported to possess biological activities as herbicides [16], fungicides [17], analgesic agents [18], antipyretic agents [19], and inhibitors for platelet aggregation [20]. Recently, much attention has been focused on pyrazoles as antvirial and anticancer agents after the discovery of the pyrazole C-glycoside pyrazofurin [21,22]. This report describes the synthesis and anticancer evaluation of several trifluoromethyl-substituted pyrazole N-nucleosides.…”

Synthesis and Antiproliferative Activity of New Aminoisoquinolinylurea Derivatives against Melanoma Cell Line

“…Nitration of 1-chloroisoquinoline (2) using a mixture of nitric and sulfuric acids gave 1-chloro-5-nitroisoquinoline (3). 20 Treatment of 3 with 7 N ammonia solution in methanol led to nucleophilic displacement and formation of 1-amino-5-nitroisoquinoline (4). Reaction of 4 with the appropriate aryl isocyanate derivatives afforded the corresponding diarylurea derivatives 5a-t.…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…Lastly, suksdorfin (96), another natural compound isolated from the fruit of Lomatium suksdorfii, exhibits a significant anti-HIV activity as it inhibits the viral replication in the T-cell line with an EC50 in the 2.5 µM range [116] (Figure 8). In a similar approach, Wang et al [118] have reported a new one-pot two-step tandem synthesis of highly functionalized benzo[a]pyrano [2,3- [119][120][121]. This reaction was achieved by the simple condensation of 2-hydroxynaphthalene-1,4-dione (104), diamines 105, aldehydes 107 and malonitrile (108).…”

“…In a similar approach, Wang et al [118] have reported a new one-pot two-step tandem synthesis of highly functionalized benzo[a]pyrano [2,3- [119][120][121]. This reaction was achieved by the simple condensation of 2-hydroxynaphthalene-1,4-dione (104), diamines 105, aldehydes 107 and malonitrile (108).…”