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Bioactive acetylenic metabolites.

ARTICLE INFO

Keywords:

Acetylenic metabolits

Polyacetylenes

Polyynes

Antitumor

Antifungal

Antibacterial

Fatty alcohols

Acids

Cyclohexanoids

Carotenoids

Plants

Fungi

ABSTRACT

This article focuses on anticancer, and other biological activities of acetylenic metabolites obtained from plants and fungi. Acetylenic compounds belong to a class of molecules containing triple bond(s). Naturally occurring acetylenics are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, and immunosuppressive properties. There are of great interest for medicine, pharmacology, medicinal chemistry, and pharmaceutical industries. This review presents structures and describes cytotoxic activities of more than 100 acetylenic metabolites, including fatty alcohols, ketones, and acids, acetylenic cyclohexanoids, spiroketal enol ethers, and carotenoids isolated from fungi and plants.

[c] 2013 Elsevier GmbH. All rights reserved.

Introduction

Acetylenic metabolites display important biological activities, namely antitumor, antibacterial, antimicrobial, antifungal, phototoxic, and other chemical and medicinal properties (Dembitsky 2006; Dembitsky and Levitsky 2006; Dembitsky et al. 2006; Carballeira 2008; Minto and Blacklock 2008; Siddiq and Dembitsky 2008; Bador and Paris 1990).

Plants have been used worldwide for treatment of various human ailments since antiquity. Their use is still quite prevalent in developing countries in the form of traditional/folkloric medicine (Bero et al. 2009; Fabricant and Farnsworth 2001; Nirmal et al. 2012). Intensive chemical and pharmacological studies during the last five decades have led in many cases to validation of traditional claims and facilitated identification of the traditional medicinal plants and of their active principles (Minto and Blacklock 2008; Siddiq and Dembitsky 2008). More than 1000 acetylenic metabolites have been isolated and identified from plant and animal species (Christensen and Jakobsen 2008; Minto and Blacklock 2008; Siddiq and Dembitsky 2008).

Thousands of herbal and traditional compounds are being screened worldwide to validate their use as anti-cancer, antifunal drugs, but terrestrial acetylenic compounds comprise an especially interesting group of the anticancer, antibacterial and antifungal agents (Dembitsky 2006; Dembitsky and Levitsky 2006; Siddiq and Dembitsky 2008). Their structure and biological activities, modes of action, and future prospects are discussed.

Fungal acetylenic metabolites

Fungi species produce many different acetylenic metabolites, but only some of them show cytotoxic, antitumor, antifungal, antibacterial and/or related activities (Siddiq and Dembitsky 2008; Dembitsky 2003; Dembitsky and Levitsky 2006; McAfee and Taylor 1999; Reisch et al. 1967; Stickings and Raistrick 1956; Jones 1966; Herbst 1960; Anchel 1952).

Repandiol (1, Fig. 1), a cytotoxic diepoxide, (2R,3R,8R,9R)-4,6-decadiyne-2,3:8,9-diepoxy-1,10-diol, was isolated from the mushrooms Hydnum repandum and H. repandum var. album (Takahashi et al. 1992; Nozoe et al. 1993). Repandiol demonstrated pronounced cytotoxic effects against various tumor cells. It was found to form interstrand cross-links of DNA, linking deoxyguanosines on opposite strands primarily within the 5'-GNC and 5'-GNNC sequences preferred by diepoxyoctane. However, repandiol was a significantly less efficient cross-linker than diepoxyalkanes (diepoxyoctane and diepoxybutane) (Millard et al. 2004).

Two antibiotics, biformin (or polyacetylenic 9-carbon glycol, 2) and bioforminic acid (3) were obtained from fungus Polyporus biformis (syn: Trichaptum biforme, Basidiomycetes) grown on a modified Czapek-Dox liquid medium (Robbins et al. 1947; Anchel and Cohen 1954). Both compounds showed antibacterial activity Bacillus subtilis, Bacillus subtilis, and Photobacterium fischeri and Pseudomonas aeruginosa (Kavanagh 1947). Same compound, trans-2,3-epoxydeca-4,6,8-triyn-l-ol, has been isolated from the culture filtrate of the fungus Tramtes pubescens (Dagne et al. 1994). It showed antifungal activity against Aspergillus niger and Aspergillus ochraceus.

Two glutamyl-peptides, [gamma]-gluta myl-L-2-aminohex-4-ynoic acid (4) and [gamma]-L-glutamyl-L-erythro-2-amino-3-hydroxyhex-4-ynoic acid (5), were isolated from the fruit bodies of Tricholomopsis rutilans (Niimura and Hatanaka 1977; Okishi 1977; Hatanaka et al. 1973). Derivatives of these amino acids showed antiviral, anticholesterol and anticancer activities (Patel 2001; Sung et al. 1969; Takada et al. 1991; Whitehead 1999).

Mycomycin (6) isolated in 1950 by Jenkins (Jenkins 1950), is used not only as a therapeutic agent for tuberculosis (King 1950; Chain 1958; Beer 1955), but for treatment of late-stage inoperable primary hepatocellular carcinoma (Du and Hu 1997; Veljkovic and Lalovic 1978). More recently, antibiotic 07F275 (also known as mycomycin, 6), is produced by submerged fermentation of fungal culture LL-07F275, and belonging to the allenic polyacetylene family (Schlingmann et al. 1995).

Acetylenic metabolites named drosophilin C (7), and D (8) have been isolated from fungus culture of Drosophila subatrata (now classified as Psathyrella subatrata) (Jones et al. 1960; Kavanagh et al. 1952; Ahmed et al. 1977). These compounds showed antibacterial, antimicrobial and antifungal activities, and they inhibited bacteriophage growth (Anchel 1953, 1954; Asheshov et al. 1954; Kavanagh et al. 1952).

Two bioactive polyynes, 10-hydroxyundeca-2,4,6,8-tetraynamide (9) and 3,4,13-trihydroxy-tetradeca-5,7,9,11-tetraynoic acid-[gamma]-lactone (10) were isolated from cultures of the fungus Mycena viridimarginata. Compound (9) was highly active against Gram-positive and Gram-negative bacteria, yeasts, filamentous fungi, and Ehrlich ascites carcinoma. The second compound (10) had similar but less pronounced biological activities (Baeuerle et al. 1982: Jente et al. 1985).

Two anticancer acetylene compounds of the falcarinol (panaxynol, 11) and falcarindiol (12) were described for Ginseng root/rhizome drugs from the plants Panax notoginseng, Panax ginseng and Panax quinquefolium (Ng 2006). The content of some polyacetylenes in P. ginseng is quite high. Thus panaxydol, falcarinol (11) and panaxytriol are present in red ginseng powder at concentrations of 297, 250, and 32011gig, respectively. The antitumor alcohols panaxydol and falcarinol (11), from a powder of the root of Panax ginseng inhibited the growth of various kinds of cultured tumor cell lines (Poplawski et al. 1980; Saita et al. 1993; Kitagawa et al. 1987; Ahn and Kim 1988; Matsunaga et al. 1990). Falcarinol (11) and panaxytriol inhibited the synthesis of DNA, RNA and protein in lymphoid leukemia L-1210 cells incubated with the drugs for 4-16h. Falcarinol showed anti-inflammatory activity, a marginal effect on cyclooxygenase activities ([IC.sub.50] values > 100 [micro]M), inhibited 5-lipoxygenase ([IC.sub.50], 2 [micro]M), two isoforms of 12-lipoxygenase (leukocyte-type, 1 [micro]M platelettype, 67 [micro]M) and 15-lipoxygenase (4 [micro]M) (Kim et al. 1988; Otsuka et al. 1981; Alanko et al. 1994).

Falcarindiol (12) has been shown to have anti-inflammation (Metzger et al. 2008; Zschocke et al. 1997), antibacterial (Deng et al. 2005; Stavri and Gibbons 2005), and anticancer (Sun at al. 2010) activities, as well as protective effects against hepatotoxicity. A recent investigation of Jin et al. (2012) shows that falcarindiol kills cancer cells through inducing excessive endoplasmic reticulum (ER) stress, which leads to apoptosis. Furthermore, falcarindiol inhibits tumor growth in a xenograft tumor model and exhibits strong synergistic killing of cancer cells with 5-fluorouracil, an approved cancer chemotherapeutic drug. Also, falcarindiol induced ER stress and apoptosis is correlated with the accumulation of ubiquitinated proteins, suggesting that falcarindiol functions at least in part by interfering with proteasome function, leading to the accumulation of unfolded protein and induction of endoplasmic reticulum stress. Consistent with this, inhibition of protein synthesis by cycloheximide significantly decreases the accumulation of ubiquitinated proteins and blocks falcarindiol induced endoplasmic reticulum stress and cell death. Taken together, this investigation shows that falcarindiol is a potential new anticancer agent that exerts its activity through inducing ER stress and apoptosis.

Among the plants listed in Table 1, the falcarinol and falcarindiol-proclucing fungus associated with Panax ginseng was identified as a Paecilomyces spp. (Xu et al. 2010). The ether extract (oil) of the cultured fungus produced more than 35 compounds, including falcarinol as one active antitumoral and antifungal compound. A comparative analysis of the ether extract of the host plant Panax ginseng showed the presence of more than 50 compounds that also included, apart from falcarindiol and falcarinol. Xu et al. (2010) observed that falcarinol was present in the ether extract of ginseng in a concentration of 2.87%, whereas in the ether extract of Paecilomyces spp., only 1.38% falcarinol was detected. This could provide some evidence that the Paecilomyces spp. produces similar or the same metabolites as the host Ginseng. In Table 1, nine further occurrences of falcarinol (11) and falcarindiol (12) are listed. With the one exception of Fructus Foeniculi, all others were detected exclusively in the roots or rhizomes of these plants.

Table 1

Traditional Chinese medicine--drugs containing
anticancer agents, falcarinol and falcarindiol.

Species           Drug             Chinese name  References

Angelica          Radix Angelicae  Baizhi        Wang et al.
dahurica          Dahuricae                      (2010), Choi et
                                                 al. (2005),
                                                 Lechner et al.
                                                 (2004)

Angelica          Radix Angelicae  Duhuo         Liu et al.
pubescens         Pubescentis                    (1998)

Angelica          Radix Angelicae  Danggui       Deng et al.
sinensis          Sinensis                       (2008, 2006),
                                                 Chen et al.
                                                 (2006), Wang et
                                                 al. (2005)

Daucus carota     Fructus          Nanheshi      Roman et al.
                  Carotae                        (2011), Rai et
                                                 al. (2011),
                                                 Rawson et al.
                                                 (2011),
                                                 Kjellenberg et
                                                 al. (2010),
                                                 Soltoft et al.
                                                 (2010), Schmiech
                                                 et al. (2009,
                                                 2008), Purup et
                                                 al. (2009),
                                                 Metzger et al.
                                                 (2008),
                                                 Christensen and
                                                 Kreutzmann
                                                 (2007), t5:6
                                                 Baranska et al.
                                                 (2005), Zidorn
                                                 et al. (2005),
                                                 Czepa and Hofmann
                                                 (2003, 2004)

Foeniculum        Fructus          Xiaohuixiang  Zidorn et al.
vulgare           Foeniculi                      (2005)

Glehnia           Radix Glehniae   Beishashen    Satoh et al.
littoralis                                       (1996)

Ligusticum        Rhizoma          Chuanxiong    Chang et al.
chuanxiong        Chuanxiong                     (2007)

Notopterygium     Rhizoma et       Qianghuo      Kou et al.
forbesii/incisum  Radix                          (2010), Ohnuma
                  Notopterygii                   et al. (2009), Ma
                                                 et al. (2008),
                                                 Zschocke et al.
                                                 (1997)

Panax ginseng     Radix et         Renslien      Washida and
                  Rhizoma                        Kitanaka (2003),
                  Ginseng                        Liu et al.(2007),
                                                 Xu et al.(2010)

Panax             Radix et         Sanqi         Rao et al.
notoginseng       Rhizoma                        (1997)
                  Notoginseng

Panax             Radix Panacis    Xiyangshen    Wang et al.
quinquefolium     Quinquefolii                   (2000)

Saposhnikovia     Radix            Fangfeng      Wang et al.
divaricata        Saposhnikoviae                 (2000)


A novel chlorinated benzoquinone antibiotic, mycenon (13), was isolated from the culture broth of a basidiomycete, Mycelia sp. and shown to inhibit isocitrate lyase (EC 4.1.3.1) (Hautzel et al. 1990).

Up to 60 species of fungi in the Botryosphaeriaceae family, genera Calophora, Cryptovalsa, Cylindrocarpon, Diatrype, Diatrypella, Eutypa, Eutypella, Fomitiporella, Fomitiporia, Inocutis, Phaeoacremonium and Phaeomoniella have been isolated from decline-affected grapevines all around the World. The main grapevine trunk diseases of mature vines are Eutypa dieback, the esca complex and cankers caused by the Botryospheriaceae, while in young vines the main diseases are Petri and black foot diseases. So far the toxins of only a small number of these decline fungi have been studied (Andolfi et al. 2011). Biologically active natural acetylenic compounds (14-18 and 32-34) were found in grapevine and tomato leaves which produced by pathogen Eutypa lata and Eutypa dieback (Renoud et al., 1989; Molyneux et al. 2002; Defrancq et al. 1992). Acetylenic phenols (14-17, Fig. 2) isolated from the grapevine fungal pathogen Eutypa lata showed inhibited growth of the yeast Saccharomyces cerevisiae (Kim et al. 2004). Several phytotoxic alkynylbenzenes (18-21,24-26) including sterehirsutinol (22), sterehirsutinal (23) have been isolated from Phaeoacremonium chlamydosporum (Tabacchi et al. 2000). Fungus Stereum hirsutum is a one of several fungi involved in a grapevine disease called esca. From the culture medium of this fungus four alkynylbenzenes (30 and 31), sterehirsutinol (22), and sterehirsutinal (23), were isolated and characterized by spectral means. Sterehirsutinal showed callus growth inhibition (Dubin et al. 2000). Two acetylenic compounds, sterehirsutinal and sterehirsutinol (22 and 23), isolated from culture medium of the fungus Stereum hirsutum have been synthesized (Fkyerat et al. 1999). The aromatic acetylene derivatives frustu-losin (28) and frustulosinol (29) isolated from the liquid cultures of Stereum frustulosum were active against several bacteria such as S. aureus, Bacillus mycoides, and B. subtilis and also moderately active against Vibrio cholera and V. cholera phage (Nair and Anchel 1975, 1977).

Toxins (14-35), produced by fungal endophytes, are extremely poisonous substances and are effective at very low concentration. Toxins injure host cells by affecting the cell membrane, the cellular transport system, or by inactivating, inhibiting or interrupting enzymatic reactions (Rodriguez et al. 2009). Endophytic fungi are increasingly recognized as sources of novel bioactive compounds and secondary metabolites for biological control. In addition to studying the distribution and ecology of fungal endophytes from medicinal plants, special attention should be given to screening them for potent metabolites. The endophytic fungi are of biotechnological importance as producers of new pharmaceutical compounds, secondary metabolites, agents of biological control and other useful applications can be found by further exploration of endophytes. Therefore, the use of endophytic fungi opens up new areas of biotechnological exploitations, which leads to the necessity of isolation and cultivation of these organisms (Andolfi et al. 2011; Devaraju and Satish 2010).

The [C.sub.10] acetylenic acid, masutakic acid A (36, Fig. 3) was isolated from the fruiting bodies of the fungus Laetiporus sulphureus var, miniatus (Yoshikawa et al. 2001). This acid exhibited cytotoxicity against Kato III cells. 6-Acetylenic acids (37-44) are analogs of natural acids were prepared and exhibited good antifungal activity (Zhu et al. 2012). 6-Nonadecynoic acid (38), a plant-derived acetylenic acid, exhibited strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes (Xu et al. 2012). Another example of an acetylenic compound exhibiting antifungal activity is the 1-hydroxy-2-nonyn-3-one (45) isolated from the fermentation of the polypore Ischnoderma benzoinum (Anke et al. 1982).

Unusual 18-bromo-9-hydroxy-12,13-trans-epoxy-(10E,15Z)-octadeca-10,15-diene-17-ynoic acid methyl ester (46) was isolated from N-fixing lichen Leptogium saturninum and Peltigera canina (Rezanka and Dembitsky 1999). Leptogium saturninum (order Peltigerales) displayed strong activity of multi-copper oxidases (e.g. tyrosinase) as well as heme-containing peroxidases (Liers et al. 2011; Dembitsky 2003). Peltigera sp., a cyanolichen containing Nostoc as cyanobiont, produced arginase and arginine (Diaz et al. 2009; Dembitsky and Rezanka 2005), also produced of phycobiliprotein pigments (Czeczuga et al. 2011), and displayed laccase activity (Laufer et al. 2006). Both lichen species contains unusual lipids and fatty acids (Dembitsky 1992, 1996: Dembitsky et al. 1991, 1993).

Two acetylenic acids (47 and 48) were isolated from the edible mushroom Chanterelle (Cantharellus cibarius) (Hong et al. 2012). Isolated acids specifically activated peroxisome proliferator-activated receptor (PPAR)--[gamma] with an [EC.sub.50] value of 1.88 [micro]M as measured by a reporter gene assay.

Tricholomenyns A (49) and B (50) were isolated from the fruiting bodies of the poisonous Tricholoma acerbum (also known as Bitter Knight or Gerippter Ritterling) (Garlaschelli et al. 1995). Tri-cholomenyns C (51) and D (52, Fig.4) were isolated from the fruiting bodies of T. acerbum and other species of the genus Tricholoma, are the first naturally occurring dimeric dienyne geranyl cyclo-hexenones (Garlaschelli et al. 1996). T. acerbum (genus Tricholoma) is a fairly large genus of mycorrhizal gilled mushrooms. The tri-cholomenyns efficiently inhibit mitosis of T-lymphocyte cultures and are potent as anticancer agents.

(-)-Harveynone (53, Fig. 5) also known as (-)-PT toxin is naturally occurring anti-cancer agent was isolated from the tea gray blight fungi, Pestalotiopsis longiseta and Pestalotiopsis theae (Kamikubo and Ogasawara 1998). Harveynone from Curvularia harveyi (a hyphomycete (mold) fungus, IFO 30129) at 3.2-12.5 [micro] g/ml inhibited cell division of sea urchin egg (Kawazu et al. 1991), and inhibited spindle formation (a microtubule-related function) in sea urchin (Kobayashi et al. 1989). Harveynone from Camellia sasanqua leaves showed antibacterial activity (Nagata 1990).

Asperpentyn (54) produced by culture of Aspergillus duricaulis (Muehlenfeld and Achenbach 1988), and also isolated from the mangrove-derived fungus Pestalotiopsis sp. PSU-MA69, displayed weak antifungal activity against Candida albicans and Cryptococcus neoformans (Klaiklay et al. 2012).

Antibiotic oxirapentyn (55) was produced by the fungus Beauveria feline. It displayed antibacterial activity against Staphylococcus aureus, but was only weakly active against Streptococcus faecalis. The [LD.sub.50] (i.p. in mice) of (55) was 6.25 mg/kg (Takahashi et al. 1983). Three highly oxygenated chromene derivatives, oxi-rapentyns B (56), C (57) and D (58) were isolated from the lipophilic extract of marine-derived fungus Isaria felina KMM 4639 (Smetanina et al. 2012). The oxirapentyns (56, 57 and 58) were assayed for their cytotoxic activities against T-47D, SK-Mel-5 and SK-Mel-28 cell lines and CD-I murine splenocytes. Oxirapentyn A (55) exhibited weak cytotoxicity against T-47D. SK-Mel-5 and SK-Mel-28 cell lines with [IC.sub.50] values of 25, 19 and 17 [micro]M, respectively. Oxirapentyns A (55) and D (58) were not cytotoxic toward CD-I mouse splenocytes (IC.sub.50] = 120 [micro]M and 140 [micro]M, respectively). The inhibitory activities of compounds (55, 56 and 58) against Staphylococcus aureus ATCC 21027, Bacillus subtilis ATCC 10702, Escherichia coli ATCC 15034, Pseudomonas aeruginosa ATCC 27853 and Candida albicans KMM 453 were also reported. Oxirapentyns A (55) and D (58) showed weak growth inhibition against S. aureus and B. subtilis with MICs of 140 [micro]M and 150 [micro]M, respectively (Smetanina et al. 2012).

Acetylenic epoxy cyclohexanoids (59-69, Fig. 6) were isolated from the basidiomycete Hexagonia speciosa (family Polyporaceae) which was collected in the tropical and subtropical zones of China, such as the Hainan and Yunnan Provinces. Five human cancer cell lines, human myeloid leukemia HL-60, hepatocellular carcinoma SMMC-7721, lung cancer A-549, breast cancer MCF-7, and colon cancer SW480 cells, were used in the cytotoxic assay. Speciosin B (60) showed significant inhibitory activity against the five cell lines with I [C.cub.50] values of 0.23 [micro]M (HL-60), 0.70 [micro]M (SMMC-7721), 3.30 [micro]M (A-549), 2.85 [micro]M (MCF-7), and 2.95 [micro]M (SW480). The other compounds were inactive ([IC.sub.50] values >40 [micro]M) (Jiang et al. 2011, 2009). The metabolite (69) showed activity against phy-topathogens and plant growth promoting activity, properties that are also expressed in vivo by the ectotrophic fungus (Kim et al. 2006).

Junghuhnia nitida (family Meruliaceae) is a corticioid fungus that breaks down wood deciduous trunks by a white rot (Kirk et al. 2008). It was found that nitidon (70, Fig. 7), a highly oxidized pyranone derivative is produced by the fungus. The compound was isolated and its biological activities were evaluated (Gehrt et al. 1998). A nitidon isomer--compound (71) exhibited antibiotic and cytotoxic activities and induced morphological and physiological differentiation of tumor cells at nanomolar concentrations (Gehrt et al. 1998). The first total synthesis of naturally occurring (-)-nitidon (70) and its enantiomer (71) was reported. Both enantiomers of nitidon were found to exhibit significant cytotoxic activity against human cancer cell lines in vitro (Bellina et al. 2004).

Aporpinone B (72) and 1 '-acetylaporpinone B (73) with an unusual skeleton containing an acetylene unit were isolated from the culture of the wood inhabiting fungus Aporpium caryae (Basicl-iomycete). Compounds (72) and (73) showed weak to moderate antibacterial activity against Bacillus subtilis, Staphylococcus aureus and Escherichia coli (Levy et al. 2003).

Acetylenic metabolites from plant origin

Many anticancer acetylenic compounds have been isolated from the genus Panax. P. ginseng roots have long been used as a medicinal herb in oriental countries. Extracts from the ginseng roots exhibited significant antitumor activities. Thus, the ethyl acetate fraction extracted from Korean ginseng root inhibited the growth of murine leukemia L5178Y cells and murine Sarcoma 180 cells in vitro (Yun et al. 1980a); petroleum ether extracts of Panax ginseng roots showed inhibitory activity against three human renal cell carcinoma (RCC) cell lines, A498, Caki-1, and CURC II (Sohn et al. 1998); the petroleum ether extract from Korean ginseng roots inhibited the growth of murine leukemia L5178Y cells and murine Sarcoma 180 cells in vitro, and also inhibited DNA, RNA, and protein synthesis in the latter cell (Yun et al. 1980b): the extract of the roots of Panax notoginseng exhibited a significant anti-tumor-promoting activity on two stage carcinogenesis of mouse skin tumors (Oh et al. 1999); water extracts of the roots Pfaffia paniculata (Brazilian ginseng) showed cytotoxic effects on the Ehrlich tumor in its ascitic form in mice (Matsuzaki et al. 2003); and the American ginseng root extract demonstrated an effect on proliferation of breast cancer cell lines MCF-7, T-47D, and BT-20 (Duda et al. 1996). Other cytotoxic activities of the ginseng root extracts have also been observed and reported (Park et al. 2009; Lu et al. 2009; Wong et al. 2010).

Thus panaxydol (74. Fig. 8) is present in red ginseng powder at concentrations of 297 [micro] g/g. The Antitumor alcohols panaxy-dol and panaxynol, from a powder of the root of Panax ginseng inhibited the growth of various kinds of cultured tumor cell lines (Ahn and Kim 1988; Kitagawa et al. 1987; Matsunaga et al. 1990; Poplawski et al. 1980; Saita et al. 1993). The alpha-cyclodextrin complexes of (74) inhibited growth of various kinds of cultured cell lines in a concentration-dependent fashion. Their inhibitory activity was much stronger against malignant cells than against normal cells. ATPase activities of cells from Sarcoma 180 and rat liver were slightly inhibited by panaxydol (74). Panaxydol (74), panaxynol (falcarinol) and panaxytriol inhibited the synthesis of DNA, RNA and protein in lymphoid leukemia L-1210 cells incubated with the drugs for 4-16 h (Alanko et al. 1994; Kim et al. 1988; Otsuka et al. 1981).

Tetradeca-13-ene-1,3-diyne-6,7-epoxide (panaxyne epoxide 75) revealed cytotoxic activity against L1210 cells (Kim et al. 1989a). The content of some polyacetylenes in P. ginseng is quite high. A series of other polyacetylene compounds of ginseng origin, including chlorine-containing chloropanaxydiol (76) and panaxydol (74) were tested for cytotoxic activities in different cell and tissue cultures (Fujimoto and Sato 1988; Fujiki et al. 1987; Fujimoto et al. 1989). Chloropanaxydiol showed inhibitory activity against leukemia cells (L-1210) in tissue culture, and exhibited fungicidal properties. The heptadeca-1-ene-4,6-diyne-3,9-diol 10-acetate (10-acetyl panaxytriol from Korean ginseng roots) showed strong cytotoxic activity against L-1210 cells (E[D.sub.50] = 1.2 [micro] g/ml) (Kim et al. 1989b). Of the active compounds, panaxydol (74) was found to be most efficient (I[C.sub.50] DT cells: 0.65 [micro]M, 3T3 cells: 1.3 [micro]M, L-1210 cells: 0.19 [micro]M). Panaxynol (74) and 9,10-epoxy-16-hydroxy-octadeca-17-ene-12,14-diyne-1 -al (92, Fig. 9) (from Foeniculi fructus, bitter fennel) as well as a naxydol, pa naxynol ( from Pan ax ginseng) inhibited the growth of a human gastric adenocarcinoma cell line, MK-1 cells, in a dose-dependent manner (Saita et al. 1995; Lee et al. 2000; Setzer et al. 2000).

Acetylenic compounds (82-85, Fig. 8) from the root of P. ginseng were tested for their cytotoxic activities on murine and human malignant cells (DT. NIH/3T3, L-1210, HeLa, T24 and MCF7 cells) in vitro (Hirakura et al. 2000). Most of them showed more potent cytotoxicity than 5-fluorouracil (5-FU) and cisplatin (CDDP). Cytotoxic polyacetylenes, PQ-2 (79), and PQ-3 (80), from Panax quinquefolium exhibited strong cytotoxic activities against leukemia cells (L-1210) in tissue culture (Fujimoto et al. 1991).

Anticancer agents panaquinquecol 4 (PQ-4) (81), panaquinquecol 5 PQ-5 (86), and panaquinquecol 6 (PQ-6) (87) were isolated from roots extracts of P. quinquefolium as active ingredients, and had I [C.sub,50] values of 0.5, 10, and 0.5 [micro] /mlrespectively against murine leukemia L1210 (Fujimoto 1994). [C.sub.17] -polyacetylenes PQ-4 (81) and PQ-6 (87) and a [C.shp.14] -polyacetylene PQ-5 (86, Fig. 8) were isolated from dried roots of P. quinquefolium (Fujimoto et al. 1992). The cytotoxic activity of C17-poly-acetylenes (81) and (87) against leukemia cells (L-1210) was about 20 times higher than that of the C14-polyacetylene (86).

Panaxydol, heptadeca-1,8-diene-4,6-diyne-3,10-diol, and 8-methoxy-panaxydol (89, Fig. 9) from Acanthopanax senticosus roots seem to induce various pro-apoptosis mechanisms in animal cells (Bae et al. 2003; Kustrak 1993; Kwak et al. 2003; Nishibe 1995; Smith and Boon 1999; Zhang et al. 2002; Zhang 2005). Com-pound (89) was preferably used in treating leukemia. Anticancer agent (90) which inhibited L-1210, Ehrlich, and HeLa cell lines with I [C.sub.50] of 0.2, 1.3, and 2.1 [micro] /ml, respectively, has been isolated from Japanese ginseng (Fujihashi et al. 1991). [C.sub.17]-and [C.sub.14]-polyacetylenes (91) and (88, PQ-8 Fig. 8), from the dried roots of P. quinquefolium, showed strong cytotoxic activity (I [C.sub.50] = 0.1 and 0.5 [micro] g/ml, respectively) against leukemia cells (L-1210) in tissue culture (Fujimoto et al. 1994).

A polyacetylenic diepoxide compound gummiferol (93) was isolated from the leaves of Adenia gummifera (Passifloraceae) by KB cytotoxicity-guided fractionation. It exhibited cytotoxic actions on KB cell lines and a broad cytotoxic spectrum against another ten human cancer cell lines (Table 2) (Fullas et al. 1995). This medicinal plant Adenia gummifera is used to improve animal health in Tanzania.

Table 2 Cytotoxicity of gummiferol (93) isolated from Adenia ummifera.

Cell line  E [D.sub.50] ([micro] g/ml)

BCA-1                              0.2
HT-1080                            0.1
LUC-1                              0.9
MEL-2                              1.3
COL-1                              0.6
KB                                 0.3
KB-V--                             0.4
KB-V+                              0.3
P-388                             0.03
A-431                              0.5
LNCaP                              0.2
ZR-75-1                            0.2
U-373                             0.05

Key to cell lines used: BO, human breast cancer; HT-1080,
human fibrosarcoma; LUC-1, human lung cancer; MEL-2,
human melanoma; COL-1, human colon cancer; KB, human
oral epidermoid carcinoma; KB-V+, multidrug-resistant
KB assessed in the presence of vinblastine (1 pg/ml):
KB-V--, multidrug-resistant KB assessed in the absence
of vinblastine; P-388, murine lynphoid neoplasm; A-431,
human epidermoid carcinoma; LNCaP, hormone dependent
human prostate cancer; ZR-75-1, hormone dependent human
breast cancer; U-373, human glioblastoma.


A set of polyacetylenic compounds isolated from roots of Gym-nasrer koraiensis (Cornpositae) included the gymnasterkoreaynes A to F were separated by bioassay-guided fractionation using the L1210 tumor cell line as a model for cytotoxicity (Jung et al. 2002). Of the compounds isolated, gymnasterkoreaynes B (94, Fig. 9) exhibited significant cytotoxicity against L-1210 tumor cells with E [D.sub.50] values of 0.12-3.3 [micro] g/ml. In addition, gymnasterkoreaynes A-F showed considerable antiproliferative activity against various cancer cells, inhibition of NO production and inhibition of ACAT (Bae and Jung 1999).

Sweet wormwood, Artemisia annua (qinhao) has traditionally been used in Chinese medicine. Extracts of A. annua showed activities against HeLa cancer cells (I[C.sub.50] 54.1 [micro]/m1), and and antipro-liferative effects on four cancer (AGS, HeLa, HT-29 and MCF-7) cell line. A. annua contain the strong anticancer metabolite artemisinin (human hepatocellular carcinoma cell lines HepG2 and SMMC-7721) (Weathers et al. 2011; Rabe et al. 2011; Zhai et al. 2010), as well as a highly unstable polyacetylene named annuadiepoxide (95, Fig. 10) (Matins and Hartmann 1992).

Polyacetylenic phytoalexin (96) obtained from roots of Arctium lappa (Takasugi et al. 1987), isolated from Ptilostemon diacanthum and P. afer (Bohlmann and Ziesche 1980), and roots, green parts, and flower heads of Centaurea scabiosa (Andersen et al. 1977).

Fifteen acetylenic compounds, including (97) have been isolated and characterized from the flower heads of Chrysanthemum leucanthemum (Wrang and Lam 1975). The water extract of Chrysanthemum indicum has been shown to possess anti-inflammatory and anticancer activities, and the methylene chloride fraction of C. indicum exhibited strong cytotoxic activity as compared with the other fractions and clearly suppressed constitutive STAT3 activation against both DU145 and U266 cells, but not MDA-MB-231 cells (Kim et al. 2013). Chrysanthemum tea could be obtained from dried flowers. Chrysanthemum tea has many purported medicinal uses, including an aid in recovery from influenza, acne and as a "cooling" herb. In traditional Chinese medicine, chrysanthemum tea is also said to clear the liver and the eyes. In western herbal medicine, Chrysanthemum tea is drunk or used as a compress to treat circulatory disorders such as atherosclerosis and varicose veins. Chrysanthemum tea was first drunk during the Song Dynasty (960-1279) (Campbell 1995).

Tree ponticaepoxide (98-100) were isolated from roots of Achillea ptarmica (Kuropka et al. 1991), and from Anthemicleae family: Artemisia pontica, A. senjavinensis, A. manshuria, A. ludoviciana, Chrysanthemum tchihatchewii, C serotinum, C. uliginosum, C. myconis, Anthem is tenuifolia, A. nobills, A. cota, Achillea ageratifolia, A. aspienifolia, A. atrata, A. clavennae, A. clusiana, A. clypeolata, A. compacta, A. conescens, A. distans, A. impatiens, A. ligustica, A. millefolium, A. pectinata, A. ptarmica, A. santolina, A. serbica, A. setacea, A. sibirica, A. sudetica, A. sulphurea, A. tanacetifolia, A. taygetea, A. umbdlata and A. vandasii (Bohlmann et al. 1962).

Bioactive acetylenic compounds (101-105, Fig. 11) have been isolated from leaves and/or roots of some plants. Thus, ivorenolide A (101), a novel 18-membered macrolide featuring conjugated acetylenic bonds and five chiral centers, was isolated from Khaya ivorensis. Aqueous extracts from the Kh. ivorensis stern-bark of the showed antiplasmodial activity. The structure of (101) was fully determined by spectroscopic analysis, single-crystal X-ray diffraction, and bioinspired total synthesis. Both compound (101) and its synthetic enantiomer (102) showed potent and selective immunosuppressive activity (Zhang et al. 2012). Phytotoxic polyacetylene (103) was isolated from roots of Russian knapweed (Acroptilon repens, Asteraceae). It showed phytotoxic activity against Arabidopsis thaliana seedlings (Quintana et al. 2008). Water and ethanol extracts of A. repens contained polyphenols and acetylenic compounds.The extracts had a strong reducing power and superoxide/hydroxyl radical-scavenging effect, and the capacity of ethanol extract was more effective than that of water extract; both of the extracts had a reducing lipid peroxidation rate above 47%. The extracts also had strong capacity of sodium nitrite scavenging and nitrosamine synthesis disconnection. Water extract presented a 60.4% of scavenging rate for sodium nitrite while ethanol extract presented 86.5% for the rate of nitrosamine synthesis disconnection. It is inferred that ethanol extract of A. repens could be used both as an antioxidant and anticancer agent, which has many effects such as eliminating free radicals in organism, reducing lipid peroxidation, delaying aging and preventing cardiovascular diseases and cancer (Tursun et al. 2010).

Foeniculacin (aromatic acetylenic epoxide, 104) was detected in stem extract of endemic to the Canary Islands, Argyranthemum foeniculaceum (Gonzalez et al. 1987). Extracts from Argyranthemum adauctum, A. foeniculaceum and A. frutescens showed antimicrobial activity against Gram-positive and Gram-negative and cytotoxic activity against HeLa and Hep-2 cell lines (Gonzalez et al. 1997).

Water and ethanol extracts of crushing leaves of Oplopanax elatus (0. horridus, or 0. japonicus) showed antitumor effect against human lung, pancreas and stomach neoplasms (Dou et al. 2010). Polyacetylene, oploxynes A (105) falcarindiol were isolated from the stem of Oplopanax elatus. It inhibited the formation of nitric oxide (NO, [IC.sub.50] = 1.98 [micro]M) and prostaglandin E (2) (PGE2, I [C.sub.50] = 3.08 [micro]M) in lipopolysaccharide (LPS)-induced murine macrophage RAW 267.7 cells (Yang et al. 2010). Synthetic compounds displayed potent cytotoxicity against neuroblastoma and prostate cancer cell lines (Yadav et al. 2011). Acetylenic spiroketal enol ethers (106 and 107) are inhibitors of HL-60 cells (Table 3) and were isolated from the leaves of Artemisia lactiflora (Compositae, Thailand) (Nakamura et al. 1998; Murakami and Ohigashi 1999; Ohigashi et al. 1998). Compounds (107, 109, and 110) were evaluated for their ability to inhibit 12-lipoxygenase; (109) and (110) showed moderate activity at 30 [micro]g/ml. Compound (108) was tested on a series of colorectal and breast cancer cell lines and its [IC.sub.50] values ranged from 5.8 to 37.6[micro]g/ml. The inhibitory effects of a diacetylenic spiroketal enol ether epoxide (AL-1 (108) from white mugwort, Asteraceae; Artemisia lactiflora) on a variety of tumor promoter-induced biological responses such as oxidative stress as well as tumor promotion in ICR mouse skin were reported (Nakamura et al. 1999). AL-1 (108) strongly inhibited tumor promoter-induced Epstein-Barr virus activation in Raji cells ([IC.sub.50] 0.5[micro]M), the effect was comparable to or even stronger than that of curcumin, a well-known antioxidative chemopreventer from turmeric (Table 3, Fig. 12). The cytotoxic compound lactiflo-rasyne (111) containing a Spiro system has been isolated from the flowers and leaves of Artemisia lactiflora (Xu et al. 1986; Fang et al. 1984; Nakamura et al. 1999).

Table 3 Inhibitory effects of some polyacetylenes on
TPA-Induced [0.sup.-2]-generation'.

Compounds  10([micro]M)  50 ([micro]M)  100 ([micro]M)  [IC.sub.50]
                                                         ([micro]M)

106                  32             61              80           29

107                  60            >99              NT          7.6

108                  15             51              77           47

109                  NT             55              78           43

112                  29             67              75           28

113                  19             47              60           56

The maximal SD for each experiment was 5% from at
least duplicate tests. NT, not tested.

TPA, 12-0-tetradecanoylphorbol-13-acetate.


Several acetylenic lactones (112-121) showed anti-tumor activity. Two chlorine-containing metabolites, (112 and 113), are inhibitors of HL-60 cells (Table 3, Fig. 12) and were isolated from the leaves of Artemisia lactiflora (Compositae, Thailand) (Murakami and Ohigashi 1999; Ohigashi et al. 1998). Several diacetylenic spiroketal enol ethers known as flosculins A (114), B (115), and C (116), along with five known compounds (117-121) of the same structural class, were isolated from the leaves of Plagius flosculosus. All isolated compounds exhibited significant cytotoxic activity against leukemia cells (Jurkat T and HL-60). Compounds (117-121) induced apoptosis in HL-60 cells with corresponding [IC.sub.50] values ranging from 4 to 6 [micro]M (Casu et al. 2006).

Marine carotenoids pyrrhoxanthin (122, Fig. 13), halocynthiaxanthin and derivatives (123-125) have characteristic structures, commonly possessing a monoacetylenic end group and the epoxide end group of 5,6-epoxy carotenoids. Carotenoids with an acetylenic [beta]-end group accumulated in some invertebrates. In feeding experiments with algal unicultures, fucoxanthin, 19'-hexanoyl-oxyfucoxanthin, cliadinoxanthin, and peridinin were resorbed by the bivalves. Hydrolysis of carotenoid acetates, conversion of allenic to acetylenic end groups, and conversion of 5,6-epoxicles to 5,6-glycols were general metabolic reactions. Fucoxanthin (active ingredient of brown algae) was converted to halocynthiaxanthin. The diacetylenic alloxanthin was a terminal metabolic product. Peridinin (carotenoid found in red, brown and green algae, and dinoflagellates) was converted to peridininol and pyrrhoxanthinol (Partali et al. 1989).

Pyrrhoxanthin (122) was isolated for the first time from the marine dinoflagellate Gyrodinium resplendens (Loeblich and Smith 1968), from the photosynthetic dinoflagellates Amphidinium carterae (2 strains), Glenodinium, Gymnodinium splendens, Gymnodinium nelsoni, and Gyrodinium dorsum (Johansen et al. 1974), the clam Corbicula (Chinese freshwater clam) (Dembitsky and Maoka 2007: Maoka et al. 2005), from two molluscan (Tridacna crocea, a giant clam, and Pteraeolidia ianthina, a nudibranch) and cnidian (Pseudopterogorgia bipinnata, a gorgonian coral) (Skjenstad et al. 1984), corals (Acropora hyacinthus, A. japonica, and A. secale) and the tridacrid clam Tridacna squamosa (Maoka et al. 2011). It does not induce DR5 expression in human colorectal cancer DLD-1 cells, nor sensitize DID-1 to TRAIL-induced apoptosis (Maoka et al. 2011).

Halocynthiaxanthin (123, and derivatives 124 and 125) was isolated from the ascidian Halocynthia roretzi (Matsuno and Ookubo 1981; Matsuno et al. 1984), and found in marine bivalves (e.g. oysters and clams (Hertzberg et al. 1988; Maoka et al. 2010, 2012), suggesting that halocynthiaxanthin is present in marine microalgae. Compound (123) strongly inhibits TPA-induced [0.sub.2]-generation in differentiated HL-60 cells at 25 [micro]M, and LPS/IFN-K-induced inflammation in mouse macrophage RAW 264.7 cells at 50 [micro]M (Maoka et al. 2012). A significant anti-neoplastic effect of the carotenoid (123) was demonstrated on human neuroblastoma GOTO cells where 5 [micro]g/ml induced a complete cell proliferation arrest (Nishino et al. 1992). Carotenoid (123) also induces apoptosis in human leukemia, breast and colon cancer cells, with a concentration-dependent activation of DNA fragmentation, and 30% decrease in Bcl-2 protein expression at 25 [micro]M (Yoshida et al. 2007). Carotenoid (123 ) also stimulated DR5 death receptor expression, in a dose and time-dependent manner in colon cancer cells (Yoshida et al. 2007; Konishi et al. 2006).

Conclusion remarks

Intensive searches for new classes of pharmacologically potent agents produced by algae, plants, invertebrates, and fungi have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingredients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and aquatic derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source.

This limited supply (of fungi metabolites) will be overcome in the near future, as the pharmaceutical industry is increasingly able to produce the most interesting metabolites on an industrial scale using isolated phytofungi strains and modern fermentation processes.

* Corresponding author. Tel.: +972 2 675 8042; fax: +972 2 675 8042.

E-mail address: valeryd@ekmd.huji.ac.il (V.M. Dembitsky).

0944-7113/$--see front matter [c] 2013 Elsevier GmbH. All rights reserved.

http://dx.doi.org/10.1016/j.phymed.2013.06.009

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Dmitry V. Kuklev (a), Abraham J. Domb (b), Valery M. Dembitsky (b), *.

(a) Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor. MI 48109, USA

(b) Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University. P.O. Box 12065.Jerusalem 91120, Israel
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Author:Kuklev, Dmitry V.; Domb, Abraham J.; Dembitsky, Valery M.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9JAPA
Date:Oct 15, 2013
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