naphthoquinones and xyloidone

Probiotics are currently added to a variety of functional foods to provide health benefits to the host and are commonly used by patients with gastrointestinal complaints or diseases. The therapeutic effects of lapachol continue to inspire studies to obtain derivatives with improved bioactivity and lower unwanted effects. Therefore, the general goal of this study was to show that probiotics are able to convert lapachol and are important to assess the effects of bacterial metabolism on drug performance and toxicity. The microbial transformations of lapachol were carried out by Bifidobacterium sp. and Lactobacillus acidophilus and different metabolites were produced in mixed and isolated cultures. The cytotoxic activities against breast cancer and normal fibroblast cell lines of the isolated metabolites (4α-hydroxy-2,2-dimethyl-5-oxo-2,3,4,4α,5,9β-hexahydroindeno[1,2-β]pyran-9β-carboxilic acid, a new metabolite produced by mixed culture and dehydro-α-lapachone produced by isolated cultures) were assessed and compared with those of lapachol. The new metabolite displayed a lower activity against a breast cancer cell line (IC50 = 532.7 μmol l(-1) ) than lapachol (IC50 = 72.3 μmol l(-1) ), while dehydro-α-lapachone (IC50 = 10.4 μmol l(-1) ) displayed a higher activity than lapachol. The present study is the first to demonstrate that probiotics are capable of converting lapachol into the most effective cytotoxic compound against a breast cancer cell line.. Probiotics have been used in dairy products to promote human health and have the ability to metabolize drugs and other xenobiotics. Naphthoquinones, such as lapachol, are considered privileged scaffolds due to their high propensity to interact with biological targets. The present study is the first to demonstrate that probiotics are capable of converting lapachol into the most effective cytotoxic compound against a breast cancer cell line. The developed approach highlights the importance of probiotics to assess the effects of bacterial metabolism on drug performance and toxicity.

Topics: Antineoplastic Agents; Bifidobacterium; Biotransformation; Cell Line, Tumor; Doxorubicin; Drug Screening Assays, Antitumor; Female; Humans; Indenes; Inhibitory Concentration 50; Lactobacillus acidophilus; Naphthoquinones; Probiotics

Antivascular agents have become a standard of treatment for many malignancies. However, most of them target the VEGF pathway and lead to refractoriness. To improve the diversity of options for antivascular therapy, we applied a high-throughput screen for small molecules targeting cell adhesion. We then assayed the resulting antiadhesion hits in a transgenic zebrafish line with endothelial expression of EGFP (Tg(fli1:EGFP)(y1)) to identify nontoxic molecules with antivascular activity selective to neovasculature. This screen identified dehydro-α-lapachone (DAL), a natural plant product. We found that DAL inhibits vessel regeneration, interferes with vessel anastomosis, and limits plexus formation in zebrafish. Furthermore, DAL induces vascular pruning and growth delay in orthotopic mammary tumors in mice. We show that DAL targets cell adhesion by promoting ubiquitination of the Rho-GTPase Rac1, which is frequently up-regulated in many different cancers.

Topics: Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Cell Adhesion; Cell Line, Tumor; Cells, Cultured; Endothelial Cells; Female; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Mammary Neoplasms, Experimental; Mice; Mice, SCID; Naphthoquinones; Plants, Medicinal; rac1 GTP-Binding Protein; Tabebuia; Zebrafish

Lapachones are pharmaceutically active compounds generating reactive oxygen species. The crystal structure and redox behaviour of the title lapachones, derivates of quinones, were determined by X-ray diffraction and cyclovoltametric measurements. The observed results were compared with beta-lapachone.

Topics: Crystallography, X-Ray; Electrochemistry; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Naphthoquinones

The methanol extract of stems of Catalpa ovata G Don exhibits potent in vivo antifungal activity against Magnaporthe grisea (Hebert) Barr (rice blast) on rice plants, Botrytis cinerea Pers ex Fr (tomato grey mould) and Phytophthora infestans (Mont) de Bary (tomato late blight) on tomato plants, Puccinia recondita Rob ex Desm (wheat leaf rust) on wheat plants and Blumeria graminis (DC) Speer f. sp. hordei Marchal (barley powdery mildew) on barley plants. An antifungal substance was isolated and identified as dehydro-alpha-lapachone from mass and nuclear magnetic resonance spectral data. It completely inhibited the mycelial growth of B. cinerea, Colletotrichum acutatum Simmonds, Colletotrichum gloeosporioides Simmonds, M. grisea and Pythium ultimum Trow over a range of 0.4-33.3 mg litre(-1). It also controlled the development of rice blast, tomato late blight, wheat leaf rust, barley powdery mildew and red pepper anthracnose (Colletotrichum coccodes (Wallr) S Hughes). The chemical was particularly effective in suppressing red pepper anthracnose by 95% at a concentration of 125 mg litre(-1).

Topics: Bignoniaceae; Fungi; Fungicides, Industrial; Microbial Sensitivity Tests; Naphthoquinones; Plant Diseases; Plant Shoots; Plants

A number of lapacho compounds, representing the most common constituents of the inner bark of Tabebuia impetiginosa, together with some synthetic analogues, were evaluated in vitro against the growth of the human keratinocyte cell line HaCaT. With an IC(50) value of 0.7 microM, beta-lapachone (4) displayed activity comparable to that of the antipsoriatic drug anthralin. 2-Acetyl-8-hydroxynaphtho[2,3-b]furan-4,9-dione (7), which was prepared in a four-step synthesis from 2,8-dihydroxy-1, 4-naphthoquinone, was the most potent inhibitor among the known lapacho-derived compounds and inhibited cell growth with an IC(50) value of 0.35 microM. Furthermore, other active constituents of lapacho inhibited keratinocyte growth, with IC(50) values in the range of 0.5-3.0 microM. However, as already observed with anthralin, treatment of HaCaT cells with these potent lapacho compounds also caused remarkable damage to the plasma membrane. This was documented by leakage of lactate dehydrogenase into the culture medium, which significantly exceeded that of the vehicle control. Because of their potent activity against the growth of human keratinocytes, some lapacho-derived compounds appear to be promising as effective antipsoriatic agents.

Topics: Administration, Topical; Anthralin; Anti-Inflammatory Agents; Cell Division; Cell Line; Humans; Keratinocytes; Keratolytic Agents; L-Lactate Dehydrogenase; Naphthoquinones; Psoriasis; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

Several xiloidone analogues were prepared, in a one step reaction, by the alkylation of lawsone with aldehydes obtained from natural essential oil sources. By Pd/C hydrogenation of these xyloidone derivatives, alpha-lapachone analogues were obtained in high yield. beta-lapachone isomers were prepared from the alpha-derivatives by treatment with sulphuric acid.

Topics: Alkylation; Chemical Phenomena; Chemistry; Hydrogenation; In Vitro Techniques; Isomerism; Naphthoquinones; Trypanosoma cruzi