naphthoquinones and eleutherin

Cipura paludosa Aubl. (Iridaceae) is widely used in folk medicine to treat several ailments. Experimental studies have confirmed its anti-inflammatory, antinociceptive, and neuroprotective effects.. This study evaluates the possible antiproliferative potential of the crude methanol extract and three isolated compounds from the bulbs of C. paludosa.. Phytochemical analysis was carried out by conventional chromatographic techniques, and the resulting compounds were identified by NMR (1)H and (13)C. The antiproliferative activity was analysed using the sulforhodamine B assay.. Crude methanol extract of C. paludosa bulbs showed GI50 values of between 1.6 and 30.8 μg/mL. The naphthoquinone derivatives (eleutherine, isoeleutherine, and eleutherol) isolated from the bulbs of C. paludosa exhibited promising cytotoxicity against several human tumour cell lines, especially the two main compounds, eleutherine and isoeleutherine, against glioma and breast cancer cell lines, with TGI values of between 2.6 and 13.8 μg/mL.. Cipura paludosa bulbs produce active principles with relevant antiproliferative potential, such as naphthoquinone derivatives, identified as eleutherine, isoeleutherine, and eleutherol. This is the first report indicating C. paludosa with antiproliferative potential.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Furans; Humans; Inhibitory Concentration 50; Iridaceae; Medicine, Traditional; Molecular Structure; Naphthoquinones; Plant Extracts; Plant Roots

Previous studies with the bulbs of Cipura paludosa (Iridaceae) showed the presence of pyranonaphthoquinones, including eleutherine, isoeleutherine and eleutherol. The aim of this study was to evaluate the antifungal properties of these compounds. The activity was tested against the clinically relevant yeasts Candida albicans, C. tropicalis, Saccharomyces cerevisiae and Cryptococcus neoformans with the microbroth dilution method, following the guidelines of CLSI. Eleutherine, isoeleutherine and eleutherol all presented significant antifungal activity, especially the first two, the major components, with MIC values between 7.8 and 250 µg/mL. In conclusion, these results demonstrate that C. paludosa bulbs produce active principles with relevant antifungal potential, contributing, at least in part, to the antimicrobial effect evidenced for this plant and justifying its popular use against infections.

Topics: Antifungal Agents; Candida; Furans; Iridaceae; Microbial Sensitivity Tests; Molecular Structure; Naphthoquinones; Plant Roots

Previous studies from our group have indicated important biological properties of the ethanolic extract and isolated compounds from the bulbs of Cipura paludosa (Iridaceae), a native plant widely distributed in northern Brazil, including antioxidant, neuroprotective and anti-nociceptive activities. In the present study, the effects of the ethanolic extract and its two naphthoquinones (eleutherine and isoeleutherine) on the short- and long-term memory of adult rodents were assessed in social recognition and inhibitory avoidance tasks. Acute pre-training oral administration of the ethanolic extract improved the short-term social memory in rats as well as facilitated the step-down inhibitory avoidance short- and long-term memory in mice. Moreover, the co-administration of 'non-effective' doses of the extract of Cipura paludosa and the adenosine receptor antagonists caffeine (non-selective), DPCPX (adenosine A1 receptor antagonist) and ZM241385 (adenosine A2A receptor antagonist) improved the social recognition memory of rats. In the inhibitory avoidance task, the co-administration of sub-effective doses of the extract with caffeine or ZM241385, but not with DPCPX, improved the short- and long-term memory of mice. Finally, the acute oral administration of eleutherine and isoeleutherine facilitated the inhibitory avoidance short- and long-term memory in mice. These results demonstrate for the first time the cognitive-enhancing properties of the extract and isolated compounds from the bulbs of Cipura paludosa in rodents and suggest a possible involvement of adenosine A1 and A2A receptors in these effects.

Topics: Animals; Avoidance Learning; Brazil; Caffeine; Ethanol; Furans; Iridaceae; Male; Memory, Long-Term; Memory, Short-Term; Mice; Naphthoquinones; Plant Extracts; Plant Roots; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Receptor, Adenosine A1; Receptors, Adenosine A2; Triazines; Triazoles; Xanthines

Cipura paludosa (Iridaceae) is a plant that is distributed in the north region of Brazil. Its bulbs are used in folk medicine to treat inflammation and pain. Four naphthalene derivatives have been isolated from the bulbs of this plant. Three of them have been identified as the known naphthalene derivatives, eleutherine, iso-eleutherine, and hongkonin. The structure of the fourth and new component was determined as 11-hydroxyeleutherine by extensive NMR study. In addition, the IN VIVO effect of the two major compounds, eleutherine and iso-eleutherine, was evaluated in carrageenan-induced hypernociception and inflammation in mice. Eleutherine and iso-eleutherine (1.04-34.92 µmol/kg), dosed intraperitoneally (i.p.) or orally (p.o.), decreased the carrageenan-induced paw oedema (i.p. - inhibitions of 36 ± 7 % and 58 ± 14 %, respectively; p.o. - inhibitions of 36 ± 7 % and 58 ± 14 %, respectively). Iso-eleutherine, but not eleutherine, significantly reduced (inhibitions of 39 ± 4 %) the plasma extravasation induced by intradermal (i.d.) injection of carrageenan. Likewise, eleutherine and iso-eleutherine (1.04-34.92 µmol/kg, i.p. or p.o.) were also effective in preventing the carrageenan-induced hypernociceptive response (i.p. - inhibition of 59 ± 4 % and 63 ± 1 %, respectively; p.o. - inhibitions of 36 ± 7 % and 58 ± 14 %, respectively). It was also suggested that the anti-inflammatory and anti-hypernociceptive effects of eleutherine or iso-eleutherine partly depend on the interference with the synthesis or activity of mast cell products, kinins, cytokine, chemokines, prostanoids, or sympathetic amines. Our findings show that two major compounds of C. paludosa contain pharmacologically active constituents that possess antinociceptive and anti-inflammatory activity, justifying, at least in part, its popular therapeutic use for treating conditions associated with pain.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brazil; Carrageenan; Drug Evaluation, Preclinical; Edema; Female; Inflammation; Injections, Intraperitoneal; Iridaceae; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Naphthoquinones; Pain; Plant Roots; Plants, Medicinal

A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors.

Topics: Antineoplastic Agents; Enzyme Inhibitors; Naphthoquinones; Saccharomyces cerevisiae; Topoisomerase II Inhibitors

Natural compounds possessing naphthopyran moiety have been attracted by their anti-bacterial, anti-fungal, and anti-viral activities, as well as anti-tumor activities. Although chemical structures were critical for the potential biological activities, the detailed functional mechanisms remained unclear. Here, we have studied the effects of naphthopyran derivatives (eleutherin, isoeleutherin, and eleutherinol) on T helper cell-mediated immune responses to understand the mechanisms of their anti-microbial and anti-tumor activities. The study revealed that isoeleutherin, which has 1,4-naphthoquinone ring with alpha-methyl group, selectively and specifically stimulated IFNgamma production through the activation of T-bet gene transcription, thus enhancing Th1-mediated immune responses. However, a natural naphthopyran-4-one, eleutherinol dramatically inhibited both IFNgamma and IL-2 productions during Th cell activation by suppressing the gene transcriptions of cytokines. Therefore, we suggest that the chemical modification and chirality of naphthopyran moiety in isoeleutherin and eleutherinol may be critical for the selective modulation of T helper cell-mediated immune responses.

Topics: Animals; CD4 Antigens; Cytokines; Furans; Humans; Immunologic Factors; Interferon-gamma; Interleukin-2; Lymphocyte Activation; Mice; Naphthols; Naphthoquinones; Pyrans; Pyrones; Receptors, Antigen, T-Cell; T-Box Domain Proteins; T-Lymphocytes, Helper-Inducer; Transcription, Genetic

A new synthetic approach to enantiopure pyranonaphthoquinones is described. (S)-Mellein 10, prepared in 6 steps from (S)-propylene oxide 16, is converted stereospecifically to the (1R,3S)-dimethylpyran 15. The pyran 15 is then converted to the benzoquinone 14, which undergoes regiospecific Diels-Alder reactions with a variety of oxygenated butadienes to give pyranonaphthoquinones including ventiloquinones E, G, L, eleutherin and ent-deoxyquinone A.

Topics: Benzopyrans; Indicators and Reagents; Models, Molecular; Molecular Conformation; Naphthoquinones; Pyrans; Quinones

Pyranonaphthoquinones have diverse biological activities against Gram-positive bacteria, fungi, and mycoplasms, and, recently, there has also been an increasing interest in their anti-cancer activity. This study includes three derivatives: eleutherin (compound 1), beta lapachone (compound 2), and its structural isomer, alpha lapachone (compound 3). The mechanism of topoisomerase II inhibition by the three derivatives was examined systematically with respect to the steps of the catalytic cycle of the enzyme. Etoposide, the prototypical enzyme poison, was used as a control and in combination with compounds 1-3 to localize their mechanism of action. The study revealed that eleutherin (1) and beta lapachone (2) inhibited topoisomerase II by inducing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an "irreversible" inhibitor of topoisomerase II, compound 1 merely slowed the catalytic cycle of the enzyme. alpha Lapachone (3), on the other hand, inhibited initial non-covalent binding of topoisomerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from DNA. Compound 3 was an "irreversible" inhibitor of topoisomerase II. The diverse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoquinone derivatives reveal novel ways to target the enzyme with potential for anti-cancer drug design.

Topics: Adenosine Triphosphate; Bacteria; Binding Sites; Catalysis; DNA; DNA Topoisomerases, Type II; Enzyme Inhibitors; Fungi; Mercaptoethanol; Naphthoquinones; Topoisomerase II Inhibitors