Novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity

Bi, Xiangdong; Lopez, Christina; Bacchi, Cyrus J.; Rattendi, Donna; Woster, Patrick M.

doi:10.1016/j.bmcl.2006.03.048

Cited by 56 publications

(66 citation statements)

References 34 publications

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“…Panepoxydone and hypnophilin inhibited TR in the same concentration range of a series of synthesized polyaminoguanidines and polyaminobiguanides (IC 50 values from 0.95 to 69.47 µM) (Bi et al 2006). Under our assay conditions, hypnophilin inhibits TR in the low micromolar range (IC 50 = 1 µM), making it about three times more active than the reference compound clomipramine (IC 50 = 3 µM), a known inhibitor of TR.…”

Section: Discussionmentioning

confidence: 89%

A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation

Cota

Rosa

Fagundes

et al. 2008

Mem. Inst. Oswaldo Cruz

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The fungus Lentinus strigosus (Pegler 1983) (Polyporaceae, basidiomycete) was selected in a screen for inhibitory activity on Trypanosoma cruzi trypanothione reductase (TR). The crude extract of L. strigosus was able to completely inhibit TR at 20 µg/ml. Two triquinane sesquiterpenoids (dihydrohypnophilin and hypnophilin), in addition to two panepoxydol derivatives (neopanepoxydol and panepoxydone), were isolated using a bioassay-guided fractionation protocol. Hypnophilin and panepoxydone displayed IC 50 values of 0.8 and 38.9 µM in the TR assay, respectively, while the other two compounds were inactive. The activity of hypnophilin was confirmed in a secondary assay with the intracellular amastigote forms of T. cruzi, in which it presented an IC 50 value of 2.5 µM. Quantitative flow cytometry experiments demonstrated that hypnophilin at 4 µM also reduced the proliferation of human peripheral blood monocluear cells (PBMC) stimulated with phytohemaglutinin, without any apparent interference on the viability of lymphocytes and monocytes. As the host immune response plays a pivotal role in the adverse events triggered by antigen release during treatment with trypanocidal drugs, the ability of hypnophilin to kill the intracellular forms of T. cruzi while modulating human PBMC proliferation suggests that this terpenoid may be a promising prototype for the development of new chemotherapeutical agents for Chagas disease. Key words: fungal natural products -Chagas disease -drug discovery -immunomodulators -BasidiomycotaChagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects millions of people in Latin America, having an enormous economic and social impact in the endemic areas. These patients rely on treatment with nitrofuran (nifurtimox; Bayer) or nitroimidazol (benznidazole; Roche), medicines that display little or no activity in chronic infections, in spite of their beneficial effect during the acute phase of the disease (Cançado 2002, Coura & Castro 2002. However, significant differences in the therapeutic effectiveness are observed between these two drugs, especially when considering distinct geographical areas, which is probably due to the occurrence of naturally resistant and susceptible T. cruzi strains (Filardi & Brener 1987, Toledo et al. 2003. Furthermore, both drugs cause several side effects that contribute to their reduced use in clinical medicine (Cançado 1985). Thus, new compounds are needed to develop more effective medicines to treat Chagas disease, espe- cially in its chronic phase, is needed (Schmidt & KrauthSiegel 2002, Nwaka & Ridley 2003. However, due to low profit prospects, the development of new trypanocidal drugs is not attractive to the pharmaceutical industry (Nwaka & Ridley 2003). Thus, this endeavor is being conducted mainly in academic laboratories (Fairlamb 1999).Among the many different strategies for drug discovery, screening the local biodiversity for bioactive natural products using appropriate bioassays is an interesting alternative for researchers in affec...

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Section: Discussionmentioning

confidence: 89%

A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation

Cota

Rosa

Fagundes

et al. 2008

Mem. Inst. Oswaldo Cruz

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“…1A, 1a-1g) and biguanide (Fig. 1B, 2a-2f ) polyamine analogues (17) was tested for the ability to inhibit recombinant LSD1 in vitro. Nine compounds were found to inhibit demethylase activity by Ͼ50% at 1 M (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Biguanide and bisguanidine polyamine analogues were synthesized as reported previously (17). Stock solutions (10 mM in double distilled H 2 O) of each compound were diluted with medium to the desired concentrations for specific experiments.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes

Huang

Greene

Murray-Stewart

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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287

334

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Epigenetic chromatin modification is a major regulator of eukaryotic gene expression, and aberrant epigenetic silencing of gene expression contributes to tumorigenesis. Histone modifications include acetylation, phosphorylation, and methylation, resulting in a combination of histone marks known collectively as the histone code. The chromatin marks at a given promoter determine, in part, whether specific promoters are in an open/active conformation or closed/repressed conformation. Dimethyl-lysine 4 histone H3 (H3K4me2) is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by the lysine-specific demethylase 1 (LSD1), a homologue of polyamine oxidases, may broadly repress gene expression. We now report that novel biguanide and bisguanidine polyamine analogues are potent inhibitors of LSD1. These analogues inhibit LSD1 in human colon carcinoma cells and affect a reexpression of multiple, aberrantly silenced genes important in the development of colon cancer, including members of the secreted frizzle-related proteins (SFRPs) and the GATA family of transcription factors. Furthermore, we demonstrate by chromatin immunoprecipitation analysis that the reexpression is concurrent with increased H3K4me2 and acetyl-H3K9 marks, decreased H3K9me1 and H3K9me2 repressive marks. We thus define important new agents for reversing aberrant repression of gene transcription.chromatin ͉ histone ͉ lysine demethylase ͉ methylation

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“…As compounds bearing guanidine groups were shown to inhibit both SMO and other polyamine oxidases, a pioneer series of (bis)guanidines and (bis)biguanides, previously synthesized as potential antitrypanosomal agents, 49 were tested as inhibitors of LSD1 (Fig. 5).…”

Section: Polyamine Analoguesmentioning

confidence: 99%

Targeting Histone Demethylases: A New Avenue for the Fight against Cancer

2011

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In addition to genetic disorders, epigenetic alterations have been shown to be involved in cancer, through misregulation of histone modifications. Miswriting, misreading, and mis-erasing of histone acetylation as well as methylation marks can be actually associated with oncogenesis and tumor proliferation. Historically, methylation of Arg and Lys residues has been considered a stable, irreversible process due to the slow turnover of methyl groups in chromatin. The discovery in recent years of a large number of histone Lys demethylases (KDMs, belonging to either the amino oxidase or the JmjC family) totally changed this point of view and suggested a new role for dynamic histone methylation in biological processes. Since overexpression, alteration, or mutation of a number of KDMs has been found in many types of cancers, such enzymes could represent diagnostic tools as well as epigenetic targets to modulate for obtaining novel therapeutic weapons against cancer. The first little steps in this direction are described here.

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Novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity

Cited by 56 publications

References 34 publications

A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation

A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation

Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes

Targeting Histone Demethylases: A New Avenue for the Fight against Cancer

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