Anthrapyrazole anticancer agents. Synthesis and structure-activity relationships against murine leukemias

Abstract

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.

SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

“…However, we performed ethidium bromide displacement assays (35) but observed no competitive binding (data not shown), suggesting SP600125 is not a strong interchelator of DNA. Consistent with this finding, we observed no apoptotic cell death with SP600125, and anthrapyrazoles with unsubstituted side chains (e.g., SP600125) performed poorly in murine leukemia cell death assays compared with highly substituted structures such as mitoxantrone (24). This observation clearly supports further studies examining the effect of JNK inhibitors in proliferation and tumor progression.…”

SP600125 Inhibits Cap-dependent Translation Independently of the c-Jun N-terminal Kinase Pathway

“…mTOR directly phosphorylates two translational regulators, namely 4E-binding protein 1 (4EBP1) and p70 ribosomal protein S6 kinase (S6K), and subsequently activates translation initiation factors such as eukaryotic initiation factor (eIF) 4B and eIF4E (Ma and Blenis, 2009;Mamane et al, 2006). SP600125 {SP, anthra[1,9-cd]pyrazol-6(2H)one} is a small chemical compound originally identified during anticancer drug screening (Showalter et al, 1987). Since Bennett et al reported that SP strongly inhibited c-Jun Nterminal kinase (JNK) activity (Bennett et al, 2001), this compound has been recognized as a JNK inhibitor II to *To whom correspondence should be addressed: Hiroshi Kitamura, Department of Comparative and Experimental Medicine, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.…”

In vitro cytotoxic activity of anthrapyrazole analogues in human prostate DU-145 and testicular NTERA-2 carcinoma cells

“…Due to their planar aromatic structure, these compounds are also considered to be exceptional DNA complexing agents (2,3). Furthermore, studies have shown that the planar anthrapyrazole compounds can cause single and double strand breaks in DNA and are also potent and selective inhibitors of DNA synthesis (4)(5)(6).…”