Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis

Díaz-Carballo, David; Ueberla, K.; Kleff, Veronika; Ergün, Sezen Güntekin; Malak, Sascha; Freistuehler, Michael; Somogyi, S.; Kücherer, Claudia; Bardenheuer, Walter; Strumberg, Dirk

doi:10.5414/cpp48670

Cited by 22 publications

(15 citation statements)

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“…Despite Nem and GutA sharing some structural core elements, the mechanism of action involved in their anti-leishmanial activity seems to be different. This was also observed with other APD, the 7-epi-nemorosone and plukenetione A, which caused anti-retroviral activities by different mechanism of action (Diaz-Carballo et al 2010). In scientific literature, other cellular targets have been suggested for APD, including kinases (Diaz-Carballo et al 2012), G₀/G₁ phase of cell cycle (Popolo et al 2011) and microtubule inhibition (Roux et al 2000).…”

Section: Discussionsupporting

confidence: 60%

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Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

et al. 2015

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Nemorosone (Nem) and guttiferone A (GutA) are acyl phloroglucinol derivatives (APD) that are present in different natural products. For both compounds anti-cancer and anti-microbial properties have been reported. In particular, an anti-leishmanial activity of both compounds was demonstrated. The aim of this study was to explore the possible role of mitochondria in the anti-leishmanial activity of Nem and GutA in comparison with their action on mammalian mitochondria. Both APD inhibited the growth of promastigotes of Leishmania tarentolae (LtP) with half maximal inhibitory concentration (IC50) values of 0·67 ± 0·17 and 6·2 ± 2·6 μ m; while IC50 values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29·5 ± 3·7 and 9·2 ± 0·9 μ m, respectively. Nemorosone strongly inhibited LtP oxygen consumption, caused species-specific inhibition (P < 0·05) of succinate:ubiquinone oxidoreductase (complex II) from LtP-mitochondria and significantly increased (P < 0·05) the mitochondrial superoxide production. In contrast, GutA caused only a moderate reduction of respiration in LtP and triggered less superoxide radical production in LtP compared with Nem. In addition, GutA inhibited mitochondrial complex III in bovine heart submitochondrial particles, which is possibly involved in its mammalian toxicity. Both compounds demonstrated at low micromolar concentrations an effect on the mitochondrial membrane potential in LtP. The present study suggests that Nem caused its anti-leishmanial action due to specific inhibition of complexes II/III of mitochondrial respiratory chain of Leishmania parasites that could be responsible for increased production of reactive oxygen species that triggers parasite death.

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Section: Discussionsupporting

confidence: 60%

“…A, which caused anti-retroviral activities by different mechanism of action (Diaz-Carballo et al 2010). In scientific literature, other cellular targets have been suggested for APD, including kinases (Diaz-Carballo et al 2012), G₀/G₁ phase of cell cycle (Popolo et al 2011) and microtubule inhibition (Roux et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

et al. 2015

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“…We already reported on the antitumoral and antiretroviral activity of these drugs, which we found to inhibit HIV. Moreover, PPAPs were recently described as selective agents in highly resistant neuroblastoma entities [ 40 – 43 ], exerting a pleiotropic effect that involves the downregulation of transcription factors which may interact with viral promoters like Myc, Myb and Stat1/3 [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

Díaz-Carballo¹,

Acikelli²,

Klein³

et al. 2015

J Exp Clin Cancer Res

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BackgroundEndoretroviruses account for circa 8 % of all transposable elements found in the genome of humans and other animals. They represent a genetic footprint of ancestral germ-cell infections of exoviruses that is transmittable to the progeny by Mendelian segregation. Traces of human endogenous retroviruses are physiologically expressed in ovarial, testicular and placental tissues as well as in stem cells. In addition, a number of these fossil viral elements have also been related to carcinogenesis. However, a relation between endoretroviruses expression and chemoresistance has not been reported yet.MethodsTwenty colorectal carcinoma patient samples were scrutinized for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In order to search for differential expression of these elements in chemotherapy refractory cells, a resistant HCT8 colon carcinoma subline was developed by serial etoposide exposure. Endoretroviral elements were detected by immunocytochemical staining, qPCR and ELISA. IC50-values of antiviral and cytostatic drugs in HCT8 cells were determined by MTT proliferation assay. The antivirals-cytostatics interaction was evaluated by the isobologram method.ResultsIn this work, we show for the first time that HERV-WE1, HERV-FRD1, HERV-31, and HERV-V1 are a) simultaneously expressed in treatment-naïve colon carcinoma cells and b) upregulated after cytostatic exposure, suggesting that these retroviral elements are intimately related to chemotherapy resistance. We found a number of antiviral drugs to have cytotoxic activity and the ability to force the downregulation of HERV proteins in vitro. We also demonstrate that the use of different antiviral compounds alone or in combination with anticancer agents results in a synergistic antiproliferative effect and downregulation of different endoretroviral elements in highly chemotherapy-resistant colorectal tumor cells.ConclusionsEnhanced HERV-expression is associated with chemoresistance in colon carcinomas which can be overcome by antiviral drugs alone or in combination with anticancer drugs. Therefore, the introduction of antiviral compounds to the current chemotherapy regimens potentially improves patient outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0199-5) contains supplementary material, which is available to authorized users.

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“…1,2 As such, their laboratory syntheses have received considerable attention. 3 PPAPs are highly regarded for their biological activities 1 which include anticancer, 2b−2e,2g,2h antiviral, 2f and antibacterial 2i properties.…”

Section: Introductionmentioning

confidence: 99%

“…2 Such an approach to PPAP core structures would take advantage of biosynthetic, innate reactivity 8,9 (phloroglucinol dearomatization, allylic alkylation) and utilize the predictably reactive reagent 2 which has been utilized extensively in conjunctive bond-forming processes. 10 Herein, we report our initial discoveries enabling the rapid construction of diverse PPAP analogs for biological evaluation through this modular and step-economic sequence.…”

Section: Introductionmentioning

confidence: 99%

Rapid Synthesis of Polyprenylated Acylphloroglucinol Analogs via Dearomative Conjunctive Allylic Annulation

2014

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Polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. Herein, we present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via double decarboxylative allylation (DcA) of acylphloroglucinol scaffolds to access allyl-desoxyhumulones followed by dearomative conjunctive allylic alkylation (DCAA).

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Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis

Cited by 22 publications

References 0 publications

Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

Rapid Synthesis of Polyprenylated Acylphloroglucinol Analogs via Dearomative Conjunctive Allylic Annulation

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