Pyranonaphthoquinone Derivatives Research Articles

Discovery of pyranonaphthoquinones and an eighteen-membered ring macrolide from the rhizospheric soil-derived fungus Phialocephala sp. YUD18001 by OSMAC strategy

Two new pyranonaphthoquinones, phialoyxinones A (1) and B (2), a new eighteen-membered ring lactone, phialoyxtone (3), and five known pyranonaphthoquinone derivatives were identified from the fungus Phialocephala sp. YUD18001, which was isolated from the rhizospheric soil associated with Gastrodia elata. Their structures were unequivocally established by a comprehensive interpretation of the spectroscopic data, with the stereochemistry for 1–3 was defined by a combination of TDDFT calculations, and the DP4+ probability analysis based on NMR chemical shift calculations. All of the new compounds 1–3 were evaluated for cytotoxicity and acetylcholinesterase inhibitory, compound 2 exhibited in vitro cytotoxic activities against five human cancer cell lines (HL-60, SMMC-7721, A549, MCF-7 and SW480) with IC50 values ranging from 11.80 to 19.32 μM. Compounds 2 and 3 exhibited moderate AChE inhibitory activities. A putative biosynthetic pathway for the pyranonaphthoquinones was proposed.

New Pyrano-4H-benzo[g]chromene-5,10-diones with Antiparasitic and Antioxidant Activities.

New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.

Highly Diastereo‐ and Enantioselective Organocatalyzed Michael/Oxa‐Michael Sequence: Asymmetric Synthesis of Pyranonaphthoquinone Derivatives

An efficient asymmetric synthesis of pyranonaphthoquinones via Michael addition and oxo‐Michael cyclization sequence of 2‐hydroxy‐1,4‐naphthoquinone with (E)‐2‐nitroallylic acetates has been developed. The synthetically useful chiral pyranonaphthoquinone derivatives were obtained in moderate to high yields and high enantioselectivities. This approach offers a facile way to prepare chiral pyranonaphthoquinone derivatives with a wide range of functional group tolerance.

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

A series of pyranonaphthoquinone derivatives possessing structural features present in both natural products annulin B and exiguamine A have been shown to exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. One particular analogue, triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. These results have extended the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature.

Cobalt mediated ring contraction reaction of lapachol and initial antibacterial evaluation of naphthoquinones derived from lapachol

The synthesis of 2-hydroxy-2-(3-methylbut-2-enyl)-2H-indene-1,3-dione 3, from lapachol which involves a ring contraction via the Hooker intermediate 1,2-dihydroxy-2-(3-methylbut-2-en-1-yl)-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid 2 is described. Different pyranonaphthoquinone derivatives, obtained in our previous synthetic work, were screened for antimycobacterial (Mycobacterium tuberculosis) activity and against resistant strains of Gram-positive (Bacillus cereus and Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. The results indicated significant activity of all the tested samples against M. tuberculosis and only moderate activity against the Gram-positive and Gram-negative bacteria.

Concise Synthesis of (±)-Rhinacanthin A, Dehydro α-Lapachone, and β-Lapachone, and Pyranonaphthoquinone Derivatives

A concise synthesis of (±)-rhinacanthin A is achieved in two steps by epoxidation of dehydro-α-lapachone, followed by chemoand regioselective reduction. Dehydro-α-lapachone was also synthesized in two steps starting from 4-methoxy-1-naphthol by ethylenediamine diaetate (EDDA)-catalyzed benzopyran formation and a CAN-mediated oxidation reaction. β-Lapachone was synthesized in three steps from 4-methoxy-1-naphthol by benzopyran formation, catalytic hydrogenation, and Jones oxidation. As additional reactions, synthesis of pyranonaphthoquinone derivatives with the pyranokunthone B skeleton has been achieved in a single step from readily available 2-hydroxy-6-methoxy1,4-naphthoquinone and 2-hydroxy-7-methoxy-1,4-naphthoquinone.

Environmentally benign, one-pot synthesis of pyrans by domino Knoevenagel/6π-electrocyclization in water and application to natural products

In water medium, environmentally benign, facile, and efficient synthesis of pyrans was achieved in good yields by the reactions of a variety of cyclic 1,3-dicarbonyls with several α,β-unsaturated aldehydes. The key strategy was a formal [3+3] cycloaddition by domino Knoevenagel/6π- electrocyclization. This methodology was applied to the synthesis of biologically interesting pyranocoumarin, pyranoquinolinone, and pyranonaphthoquinone derivatives along with selected natural and non-natural products.

Pyranonaphthoquinone derivatives of eleutherin, ventiloquinone L, thysanone and nanaomycin A possessing a diverse topoisomerase II inhibition and cytotoxicity spectrum

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.

A Concise Route for the Synthesis of Pyranonaphthoquinone Derivatives.

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The Synthesis and Biological Activity of Pyranonaphthoquinone Derivatives from Streptomyces sp. and Their Related Substances.

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A Concise Route for the Synthesis of Pyranonaphthoquinone Derivatives

An efficient synthesis of pyranonaphthoquinones is achieved by ethylenediamine diacetate-catalyzed reactions of 4-hydroxy-2-quinolones with a variety of α,β-unsaturated aldehydes in moderate yields. This method provides a rapid entry into biologically interesting α-lapachone derivatives with a variety of substituents on the pyran ring.

Synthesis of (±)-pyranonaphthoquinone derivatives, a Cdc25A phosphatase inhibitor

The novel pyranonaphthoquinone 2 , carrying Cdc25A phosphatase inhibitory activity, has been successfully synthesized through tricyclic compound 16 , which was obtained from 15 by using the intramolecular Michael addition. The precursor 9 was derived from 5-bromoveratraldehyde.

Novel mechanism of cellular DNA topoisomerase II inhibition by the pyranonaphthoquinone derivatives alpha-lapachone and beta-lapachone.

The mechanisms of intracellular topoisomerase II inhibition by the pyranonaphthoquinone derivatives alpha-lapachone and beta-lapachone were studied. Cell-based mechanistic studies were designed based on the in vitro mechanisms [17] and primarily involved the use of cultured KB (nasopharyngeal tumor cells) cells and the etoposide-resistant sub-line KB-7d. The KB-7d cells exhibited collateral sensitivity to alpha-lapachone; this supports the possibility of catalytic inhibition of topoisomerase II in the cells. Interestingly, both compounds induced an increase (two- to threefold) in reversible double-stranded DNA breaks in cell lines with a reduced expression of topoisomerase II. However, these drug-induced DNA breaks became irreversible at treatment times greater than 1 h. Studies showed that DNA breaks in KB-7d cells were not caused by endonucleases. Use of antioxidants abolished the appearance of cellular DNA breaks; this suggests involvement of the oxidation-reduction cycle of pyranonaphthoquinones in topoisomerase II inhibition; however, irreversible DNA breaks were not a result of drug-induced oxidative stress. On the basis of the findings, it is proposed that the compounds, on longer incubation with cells, induce abortive dissociation of topoisomerase II from the DNA, leading to an irreversible accumulation of high molecular weight DNA fragments. In addition to establishing topoisomerase II as an intracellular target of alpha-lapachone, the results suggest that both compounds can be classified as neither typical poisons nor as typical catalytic inhibitors of the enzyme. In summary, both compounds are members of a new inhibitor class, and alpha-lapachone, in particular, can be considered a potential lead for the development of drugs to treat multidrug-resistant cell lines with lower expression of topoisomerase II.

Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives—eleutherin, α lapachone, and β lapachone∗

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), β lapachone (compound 2), and its structural isomer, α 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 β 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. α 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.

Synthesis of Isagarin, a New Type of Tetracyclic Naphthoquinone from Pentas longiflora

Isagarin (1) was synthesized in four steps from 1,4-dimethoxynaphthaldehyde (4). The key intermediate 2-(1,2-dihydroxyethyl)-1,4-naphthoquinone (3) was found to react with acylated pyridinium ylides to afford, after spontaneous intramolecular condensation, the desired natural product isagarin (1). Depending on the type of acylated pyridinium ylides, different types of new pyranonaphthoquinone derivatives were obtained.