Simaomicin (LL-D42067), a novel antibiotic from actinomadura madurae. I. Taxonomy, fermentation and biological activity.

Maiese, William M.; Korshalla, J.; Goodman, Joseph J.; Torrey, M. J.; Kantor, S.; Labeda, David P.; Greenstein, Michael

doi:10.7164/antibiotics.43.1059

Cited by 30 publications

(28 citation statements)

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“…Simaomicin a is a polycyclic xanthone antibiotic, and it is known that it exhibits inhibitory activities against Grampositive bacteria and coccidia [7]. However, its mode of action is not clearly understood.…”

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confidence: 99%

Selective and Potent In Vitro Antimalarial Activities Found in Four Microbial Metabolites

Ishiyama

Sekiguchi

et al. 2007

J Antibiot

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Antimalarial activities have been identified in four microbial metabolites through a screening programme of existing compounds in the Kitasato Institute chemical library. Hedamycin showed selective and potent activity against both drug-resistant and drug-sensitive strains of Plasmodium falciparum. Simaomicin a exhibited remarkably strong antimalarial activity, although its activity against a drug-resistant strain was weaker than that against a drugsensitive strain. The antimalarial effects of triacsins C and D are also reported. Keywords antimalarialantibiotics, hedamycin, simaomicin a , triacsin, Plasmodium falciparum, drugresistant strain As a result of our on-going program of screening soil microorganisms and renewed testing of compounds lodged in the antibiotic library of the Kitasato Institute for Life Sciences, we have previously reported on various microbial metabolites that exhibit potent antimalarial activities [1ϳ5]. We have now discovered four more compounds that possess antimalarial characteristics. Hedamycin, simaomicin a , triacsin C and triacsin D, all from the antibiotic library of the Kitasato Institute, display potent antimalarial activity in vitro. We report here the antimalarial profiles of these four compounds (Fig. 1) [6ϳ8] in comparison with those of clinically-used antimalarial drugs.In vitro activities against Plasmodium falciparum strains K1 (drug-resistant) and FCR3 (drug-sensitive), and cytotoxicity against human diploid embryonic cell line MRC-5 of these compounds, were measured as described previously [1].Hedamycin showed weak activity against both the K1 and FCR3 strain of P. falciparum, similar to the activity of chloroquine for K1 strain (Table 1). The IC 50 value of chloroquine to the K1 strain is 10-fold higher than to the FCR3 strain, indicating that the antimalarial action of hedamycin is different from that of chloroquine. Although the compound does not meet the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) criteria for whole cell screening (IC 50 Ͻ0.1 mg/ml for P. falcipurum K1 strain), it could be a promising lead if the activity could be improved since it has low cytotoxicity (IC 50 Ͼ25 mg/ml).Simaomicin a showed the most potent activity against both drug-resistant K1 and drug-sensitive FCR3. The IC 50 values of the compound were remarkably lower than those of the clinically-used antimalarial drugs, artemether, artemisinin and chloroquine. The cytotoxicity of the compound was weaker (IC 50 ϭ4 ng/ml) than its antimalarial activities. Simaomicin a was 4.6-fold less active against the K1 strain than the FCR3 strain. Although simaomicin a showed considerably more potent antimalarial activity than that of the other compounds, the presence of a polycyclic xanthone structure containing an isoquinoline moiety may

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confidence: 99%

Selective and Potent In Vitro Antimalarial Activities Found in Four Microbial Metabolites

Ishiyama

Sekiguchi

et al. 2007

J Antibiot

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“…1,2 These microbial metabolites arise biosynthetically from multiple cyclizations from a single polyacetate chain, accounting for the high degree of oxygenation on the aromatic and heteroaromatic rings. 3 Structurally related natural products include simaomicin α, 4 actinoplanone, 5 SCH-56036 6 and kigamicin A. 7 Additionally, natural products such as cervinomycin A2 8 and FD-594 9 feature aromatic F-rings as part of a xanthone moiety.…”

Section: Introductionmentioning

confidence: 99%

“…In particular, they generally show broad-spectrum toxicity including anti-cancer, antibiotic and anti-fungal activity. Simaomicin α has shown activity preventing coccidiosis in chickens, 4b and was found to induce G1 arrest in cultured cancer cells. 4c Likewise, the kigamicins have demonstrated efficacy in inhibiting tumor growth in immunocompromised mice.…”

Section: Introductionmentioning

confidence: 99%

“…Simaomicin α has shown activity preventing coccidiosis in chickens, 4b and was found to induce G1 arrest in cultured cancer cells. 4c Likewise, the kigamicins have demonstrated efficacy in inhibiting tumor growth in immunocompromised mice. 7c Despite these promising biological activities, little is understood regarding the mechanism by which polycyclic tetrahydroxanthone natural products kill microbial and mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives

Rujirawanich

Kim

et al. 2016

J. Am. Chem. Soc.

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Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nM cytotoxicity towards multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro.

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“…Claviceps purpurea, Aspergillus aculeatus, Phoma terrestris -see Figure 1) containing a xanthenone unit [1,2] we have examined a methodology for the one-step formation of tetrahydroxanthenone moieties 2 from a salicylic aldehyde 3 and a cyclohex-2-enone 4 (Scheme 1). [3] The xanthenone's tricyclic structural feature is found in a wide variety of other fungal metabolites such as diversonol (5), [4,5] the beticolins 6, [6] simaomicins 7, [7] phomoxanthones [8] 8, and rugulotrosins 9, [9] most of which show very interesting biological activities ( Figure 1). [10] So far, only few stereoselective syntheses of natural products containing tetrahydroxanthenone units have been reported.…”

Section: Introductionmentioning

confidence: 99%

The Domino Oxa‐Michael Addition–Aldol Reaction: Access to Variably Substituted Tetrahydroxanthenones

et al. 2006

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Tetrahydroxanthenones represent the core of many natural products, most of which exhibit interesting biological activities. In the course of our synthetic efforts towards the total synthesis of the secalonic acids, which contain two of these tricyclic units, we have investigated the influence of substituents on the one‐step domino oxa‐Michael addition–aldol reaction leading to tetrahydroxanthenones. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Simaomicin (LL-D42067), a novel antibiotic from actinomadura madurae. I. Taxonomy, fermentation and biological activity.

Cited by 30 publications

References 10 publications

Selective and Potent In Vitro Antimalarial Activities Found in Four Microbial Metabolites

Selective and Potent In Vitro Antimalarial Activities Found in Four Microbial Metabolites

Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives

The Domino Oxa‐Michael Addition–Aldol Reaction: Access to Variably Substituted Tetrahydroxanthenones

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