Knipholone Anthrone Research Articles

Kniphofia foliosa Hochst, (Asphodelaceae)

This review gives the first comprehensive appraisal of Kniphofia foliosa Hochst, from the plant family Asphodelaceae: its botany, ethnomedicinal (with particular emphasis on the African communities), phytochemistry, and pharmacological potential. Particular emphasis is given to the biological and chemical properties. Peer review and literature search were done by conducting a logical and inclusive review. Indigenous cultures have used the plant among different ethnic groups in tropical Africa for medicinal and other purposes. The chemical compounds that have been isolated from K. foliosa include monomeric anthraquinones such as chrysophanol, islandicin, laccaic acid, aloe-emodin, and aloe-emodin acetate, which contain antileukaemic properties; dimeric anthraquinones such as asphodelin, knipholone, and chryslandicin; phenyl anthraquinones and anthrones, including knipholone anthrone, isoknipholone anthrone, knipholone, phenylanthrone knipholone anthrone and anthraquinone isoknipholone; oxanthrones such as isofoliosone and foliosone; and rare dimeric phenylanthraqunones joziknipholones A and B. The pharmacological studies on K. foliosa exhibited antimalarial, antioxidant, antibacterial, anti-HIV-1, and anti-leukotriene activities. From the above, it can be deduced that K. foliosa contains chemical constituents of pharmacological importance, contributing significantly to the development of new medicines.

The African natural product knipholone anthrone and its analogue anthralin (dithranol) enhance HIV-1 latency reversal

A sterilizing or functional cure for HIV is currently precluded by resting CD4+ T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple "shock-and-kill" agents, which in turn may inform ongoing LRA combination therapy efforts.

Biological activity and stability analyses of knipholone anthrone, a phenyl anthraquinone derivative isolated from Kniphofia foliosa Hochst.

Knipholone (1) and knipholone anthrone (2), isolated from the Ethiopian medicinal plant Kniphofia foliosa Hochst. are two phenyl anthraquinone derivatives, a compound class known for biological activity. In the present study, we describe the activity of both 1 and 2 in several biological assays including cytotoxicity against four human cell lines (Jurkat, HEK293, SH-SY5Y and HT-29), antiplasmodial activity against Plasmodium falciparum 3D7 strain, anthelmintic activity against the model organism Caenorhabditis elegans, antibacterial activity against Aliivibrio fischeri and Mycobacterium tuberculosis and anti-HIV-1 activity in peripheral blood mononuclear cells (PBMCs) infected with HIV-1c. In parallel, we investigated the stability of knipholone (2) in solution and in culture media. Compound 1 displays strong cytotoxicity against Jurkat, HEK293 and SH-SY5Y cells with growth inhibition ranging from approximately 62–95% when added to cells at 50 μM, whereas KA (2) exhibits weak to strong activity with 26, 48 and 70% inhibition of cell growth, respectively. Both 1 and 2 possess significant antiplasmodial activity against Plasmodium falciparum 3D7 strain with IC50 values of 1.9 and 0.7 μM, respectively. These results complement previously reported data on the cytotoxicity and antiplasmodial activity of 1 and 2. Furthermore, compound 2 showed HIV-1c replication inhibition (growth inhibition higher than 60% at tested concentrations 0.5, 5, 15 and 50 μg/ml and an EC50 value of 4.3 μM) associated with cytotoxicity against uninfected PBMCs. The stability study based on preincubation, HPLC and APCI-MS (atmospheric-pressure chemical ionization mass spectrometry) analysis indicates that compound 2 is unstable in culture media and readily oxidizes to form compound 1. Therefore, the biological activity attributed to 2 might be influenced by its degradation products in media including 1 and other possible dimers. Hence, bioactivity results previously reported from this compound should be taken with caution and checked if they differ from those of its degradation products. To the best of our knowledge, this is the first report on the anti-HIV activity and stability analysis of compound 2.

Antiplasmodial Quinones from the Rhizomes of Kniphofia Foliosa

Extracts of the rhizomes of Kniphofia foliosa exhibited antiplasmodial activities against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 3-5 microg/mL. A phenyloxanthrone, named 10-acetonylknipholone cyclooxanthrone (1) and an anthraquinone-anthrone dimer, chryslandicin 10-methyl ether (2), were isolated from the rhizomes, along with known quinones, including the rare phenylanthraquinone dimers, joziknipholones A and B. The structures of these compounds were determined based on spectroscopic data. This is the second report on the occurrence of the dimeric phenylanthraquinones in nature. In an in vitro antiplasmodial assay of the isolated compounds, activity was observed for phenylanthraquinones, anthraquinone-anthrone dimers and dimeric phenylanthraquinones, with joziknipholone A being the most active. The new compound, 10-acetonylknipholone cyclooxanthrone, also showed anti-plasmodial activity. In an in vivo assay, knipholone anthrone displayed marginal antimalarial activity.

Knipholone anthrone from Kniphofia foliosa induces a rapid onset of necrotic cell death in cancer cells

The present study examines the comparative cytotoxicity of knipholone (KP) and knipholone anthrone (KA) in leukaemic and melonocyte cancer cell lines. It was found that KA induces a rapid onset of cytotoxicity with IC 50 values ranging from 0.5 to 3.3 μM. In comparison to KA, KP was 70–480-times less toxic to cancer cells. Morphological and biochemical studies revealed that the cytotoxicity of KA was coupled with a quick loss of membrane integrity leading to necrotic cell death. The study identified KA as a new class of natural potential anticancer agent with a wide range of toxicological and pharmacological implications.

Differential cytotoxic and prooxidnant activity of knipholone and knipholone anthrone

Knipholone (KP) and knipholone anthrone (KA) are natural 4-phenylanthraquinone structural analogues with established differential biological effects including in vitro antioxidant [1] and antimicrobial properties [2]. The present study was designed to investigate the comparative in vitro cytotoxic activity and the possible mechanism of action of these two compounds. We demonstrated that KA is by order of magnitude more cytotoxic to mammalian cells than KP. In parallel with the demonstrated cytotoxic effect, KA but not KP induces prooxidative DNA damage in the presence of copper ions. In order to establish the possible involvement of reactive oxygen species in the KA-mediated prooxidative effect, we investigated the protective effect of several metal chelators and reactive oxygen species scavengers. Our data suggest that reactive oxygen species such as hydrogen peroxide are involved and a good correlation between prooxidative action, antioxidant effect and cytotoxicity is established for these two structural analogues. The chemistry, pharmacology and potential medicinal/toxicological potential of these compounds are discussed.

Prooxidant action of knipholone anthrone: Copper dependent reactive oxygen species generation and DNA damage

Knipholone (KP) and knipholone anthrone (KA) are natural 4-phenylanthraquinone structural analogues with established differential biological activities including in vitro antioxidant and cytotoxic properties. By using DNA damage as an experimental model, the comparative Cu(II)-dependent prooxidant action of these two compounds were studied. In the presence of Cu(II) ions, the antioxidant KA (3.1–200 μM) but not KP (6–384 μM) caused a concentration-dependent pBR322 plasmid DNA strand scission. The DNA damage induced by KA could be abolished by reactive oxygen species scavengers, glutathione and catalase as well as EDTA and a specific Cu(I) chelator bathocuproine disulfonic acid. In addition to Cu(II) chelating activity, KA readily reduces Cu(II) to Cu(I). Copper-dependent generation of reactive oxygen species and the subsequent macromolecular damage may be involved in the antimicrobial and cytotoxic activity of KA.

Joziknipholones A and B: The First Dimeric Phenylanthraquinones, from the Roots of Bulbine frutescens

From the roots of the African plant Bulbine frutescens (Asphodelaceae), two unprecedented novel dimeric phenylanthraquinones, named joziknipholones A and B, possessing axial and centrochirality, were isolated, together with six known compounds. Structural elucidation of the new metabolites was achieved by spectroscopic and chiroptical methods, by reductive cleavage of the central bond between the monomeric phenylanthraquinone and -anthrone portions with sodium dithionite, and by quantum chemical CD calculations. Based on the recently revised absolute axial configuration of the parent phenylanthraquinones, knipholone and knipholone anthrone, the new dimers were attributed to possess the P-configuration (i.e., with the acetyl portions below the anthraquinone plane) at both axes in the case of joziknipholone A, whereas in joziknipholone B, the knipholone part was found to be M-configured. Joziknipholones A and B are active against the chloroquine resistant strain K1 of the malaria pathogen, Plasmodium falciparum, and show moderate activity against murine leukemic lymphoma L5178y cells.

Modulation of Anopheles gambiae Epsilon glutathione transferase activity by plant natural products in vitro

Elevated glutathione transferase (GST) E2 activity is associated with DDT resistance in the mosquito Anopheles gambiae. The search for chemomodulators that inhibit the function of AgGSTE2 would enhance the insecticidal activity of DDT. Therefore, we examined the interaction of novel natural plant products with heterologously expressed An. gambiae GSTE 2 in vitro. Five of the ten compounds, epiphyllocoumarin (Tral-1), knipholone anthrone, isofuranonaphthoquinones (Mr 13/2, Mr13/4) and the polyprenylated benzophenone (GG1) were shown to be potent inhibitors of AgGSTE2 with IC50 values of 1.5 μM, 3.5 μM, 4 μM, 4.3 μM and 4.8 μM respectively. Non-competitive inhibition was obtained for Tral 1 and GG1 with regards to GSH (Ki of 0.24 μM and 0.14 μM respectively). Competitive inhibition for Tral1 was obtained with CDNB (Ki = 0.4 μM) whilst GG1 produced mixed type of inhibition. The Ki and Ki' for GSH for Tral-1 and GG1 were 0.2 μM and 0.1 μM respectively. These results suggest that the novel natural plant products, particularly Tral-1, represent potent AgGSTE2 in vitro inhibitors.

The absolute axial configurations of knipholone and knipholone anthrone by TDDFT and DFT/MRCI CD calculations: a revision

Triggered by a seemingly inconsistent twisting direction in the atroposelective ring cleavage reaction of biaryl lactones by using the ‘lactone concept’, the absolute axial configurations of the most important phenylanthraquinones, knipholone ( 1), and knipholone anthrone ( 2) were reassigned on the basis of renewed quantum chemical circular dichroism (CD) calculations using advanced, higher-level methods, viz. a time-dependent DFT (TDDFT) and a multireference configurational interaction approach (DFT/MRCI). Additional confirmation of the new configurational assignment of 1 and 2 was achieved by their stereochemically unambiguous interconversion, and further corroborated by the transformation of 1 into an ‘leuco’ phenylanthracene derivative 3, i.e., a compound with a substantially different chromophore, whose absolute configuration was independently assigned again by quantum chemical CD calculations. Accordingly, the dextrorotatory enantiomer of knipholone, (+)- 1, and its anthrone, (+)- 2, has the P-configuration, while the laevorotatory forms, (−)- 1 and (−)- 2 (which likewise exist in nature), are M-configured. From this new configurational assignment, the absolute axial stereostructures of a whole series of further naturally occurring phenylanthraquinones may now be deduced.

Antioxidant activity of Knipholone anthrone

Knipholone anthrone (KA), isolated from an Ethiopian medicinal plant, Kniphofia foliosa, Hochst (Asphodelaceae) has been shown to display a potent antiprotozoal activity and a relatively little cytotoxic effect on mammalin cells. In the present study, the antioxidant potential of KA was assessed using a variety of in vitro assay models. KA displayed a concentration-dependant scavenging effect against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. The IC 50 values obtained for KA and the positive control (−)-epicatechin (EC) in the DPPH assay were 22 ± 1.5 and 8.7 ± 0.9 μM (mean ± SEM; n = 3 separate experiments), respectively. KA displayed a better activity than EC in scavenging superoxide anions and preventing deoxyribose degradation by hydroxyl radicals. KA appeared to form a complex with Fe 2+, displayed a concentration-dependant reducing power, and also protected (at concentrations of 4.4 μM and above) isolated DNA from damage induced by Fenton reaction-generated hydroxyl radicals.

Elucidation of the absolute configuration of knipholone and knipholone anthrone by quantum chemical CD calculations

The absolute configuration of knipholone, an axially chiral phenylanthraquinone from Kriphofia, Bulbine, and Bulbinella species, has been established as M by quantum chemical CD calculations. For further evidence, the absolute stereostructure of the related compound knipholone, which has a significantly different chromophor, was likewise elucidated. The fact that both natural biaryls compounds were independently attributed the same absolute configuration, underlines the reliability of the results and the value of the applied method.

Knipholone anthrone from Kniphofia foliosa

A new anthrone named knipholone anthrone was isolated from the stem of Kniphofia foliosa. Its structure was determined by spectral analysis as well as conversion to knipholone.