Naturally occurring bioactive cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes, and plants.
This article focuses on the occurrence and biological activities of cyclobutane-containing (CBC) alkaloids obtained from fungi, fungal endophytes, and plants. Naturally occurring CBC alkaloids are of particular interest because many of these compounds display important biological activities and possess anti-tumour, antibacterial, antimicrobial, antifungal, and immunosuppressive properties. Therefore, these compounds are of great interest in the fields of medicine, pharmacology, medicinal chemistry, and the pharmaceutical industry. Fermentation and production of CBC alkaloids by fungi and/or fungal endophytes is also discussed. This review presents the structures and describes the activities of 98 CBC alkaloids.
Contents Introduction Fungi and fungal endophytes CBC alkaloids Novel plant CBC alkaloids Selected analogues of fungi and plant CBC alkaloids Concluding remarks References
Alkaloids represent an extensive group of nitrogen-containing secondary metabolites that are widely distributed throughout the plant and fungus kingdoms (O'Connor 2012, 2009; Rasmussen et al. 2012).
The fungus kingdom has attracted great attention as a source of bioactive metabolites for the development of drugs for medicine and plant protection (Duarte et al. 2012). Higher fungi, in particular Basidiomycetes with their impressive metabolic diversity, open new avenues for the biotechnological production of many flavour and volatile molecules formerly thought to be plant-typical (Cordoba and Rios 2012), including lipids and fatty acids (Hanus et al. 2008; Rezanka et al. 1999; Sancholle and Losel, 1995; Dembitsky et al. 1991,1993a,b,c,d; Chopra and Khuller 1983; Brennan 1974), peroxidases (Eisenstadt and Bogolitsyn 2010), haloperoxidases (Dembitsky 2003), and other enzymes (Janusz et al. 2013) and unusual natural compounds (Dembitsky et al. 2011; Dembitsky 2006). Mushroom-forming fungi (Agaricomycetes) are a rich source of bioactive secondary metabolites and often cytotoxic secondary metabolites (De Silva et al. 2013; Muszynska et al. 2011), and related compounds are found across the range of endophytic fungal associations with plants. The biosynthetic origin of a cyclobutane ring in a natural product often provokes interesting questions. The secondary metabolites of CBC compounds produced by fungi and fungal endophytes and their biological activities are reviewed in this article. Additional information regarding fungal metabolites is provided in other review articles (Abraham 2001; Dembitsky 2003; Kuklev et al. 2013; Wawrzyn et al. 2012).
Plant alkaloids are an important group of diversely distributed, complex, significant natural products. Naturally occurring plant alkaloids, in particular the alkaloids present in herbal medicines, are being identified for therapeutic uses (Cordell 2013; Frisvad et al. 2004).
Fungi and fungal endophytes CBC alkaloids
Fungi and fungal endophytes produce many different biologically active amides (Bladt et al. 2013; Jung et al. 2013; Wang et al. 2011), alkaloids (Roberts and Lindow 2014; Lai et al. 2013; Fyaz et al. 2009), and mycotoxins (Atanda et al. 2011; Reddy et al. 2010; Dembitsky 2008). For example, ergot alkaloids (EA) are the metabolic products of fungi genera such as Claviceps, Penicillium, Rhizopus, and Aspergillus, as well as higher plants and marine animals. EA are a group of biologically active compounds from a class of indole derivatives. EA possess the properties of bases and have a strong physiological effect, and they were named based on a trivial name of the major producers of these compounds such as mushrooms and cereal parasites belonging to the genus Claviceps (ergot). EA hold an important place in the pharmaceutical industry and are incorporated into various pharmacological directions and modes of action. At present, over 100 medicines contain EA, and they are used both individually and combined in numerous recipes (Flulvova et al. 2013; Panaccione et al. 2012).
Additionally, alkaloids have been discovered in endophytic fungi in plants that exhibit excellent biological properties such as antimicrobial, insecticidal, cytotoxic, and anticancer activities (Chandra 2012; Wang et al. 2011; Kharwaret al. 2011).
Tricyclic sesquiterpenoid brasilamides A-D (1-4) have been isolated from cultures of the plant endophytic fungus Paraconiothyrium brasiliense. Isolated metabolites (2-4) show modest inhibitory effects on HIV-1 replication in C8166 cells, and compounds (1 and 2) possess an unprecedented 4-oxatricyclo-[184.108.40.206 (2,7)]nonane skeleton (Liu et al. 2010). A tricyclic sesquiterpene amide, pinthunamide (5), was isolated from the fungus Ampulliferina sp. (Kimura et al. 1989).
Two plant growth regulators named ampullicin (6) and isoampullicin (7) were isolated from a culture filtrate of Ampulliferina-like fungus sp. No. 27 obtained from a dead pine tree (Pinus thunbergii). Compounds (6) and (7) possess a [gamma]-lactam ring that rarely exists in natural metabolites. At doses of 300 and 30 [micro]g/L, both (6) and (7) accelerated the root growth of lettuce seedlings by 200% over the control (Kimura et al. 1990). Dihydroampullicin (8) was isolated from Ampulliferina-like fungus sp. No. 27, and this fungus accelerated the root growth of lettuce (Kimura et al. 1993).
Tripartilactam (9), a structurally unprecedented cyclobutane-bearing tricyclic lactam metabolite, was discovered from Streptomyces sp. isolated from a brood ball of the dung beetle, Copris tripartitus. Tripartilactam was evaluated as a [Na.sup.+]/[K.sup.+] ATPase inhibitor ([IC.sub.50] = 16.6 [micro]g/ml) (Park et al. 2012). compound within 24 h was 50.86 mg/1 against P. redivivus, 47.1 mg/1 against Meloidogyne incognita, and 167.7 mg/1 against B. xylophilus (Liu et al. 2009).
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Phoma exigua var. exigua, a fungal pathogen isolated from Cirsium arvense and Sonchus arvensis, is proposed to be a biocontrol agent of noxious perennial weeds and produces different phytotoxic metabolites with potential herbicidal activity in liquid and solid cultures. Four cytochalasins, termed phomachalasins A-D (11-14), were isolated and characterised as three closely related 26- oxa and one new cytochalasan. The absence of both phytotoxic and antimicrobial activities shown by phomachalasins A-D is most likely due to the strong modification of both functionalities and the conformational freedom of the macrocyclic ring caused by its junction with the bulky and quite rigid new bicycle, namely bicycle[3.2.0]heptene. All of the isolated phomachalasins demonstrated phytotoxic and antimicrobial activities (Evidente et al. 2011).
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Tremorgenic mycotoxins are fungal secondary metabolites that have a specific effect on the central nervous system. Most tremorgenic mycotoxins are synthesized by common saprophytic moulds of the genera Penicillium and Aspergillus. However, the presence of a GABA-like conformation within their active nucleus and the limited torsional flexibility of this moiety suggest that tremorgenic mycotoxins are partial agonists of [gamma]-aminobutyric acid (GABA) (Selala et al. 1989). Mycotoxins, named penitrems A-F (15-21), have been isolated from the mycelium of Penicillium crustosum. All penitrems show convulsive and insecticidal activities against the hemipteran Oncopeltus fasciatus and the dipteran Ceratitis capitata (Gonzalez et al. 2003).
Penicillium crustosum is commonly used for producing penitrem A (15), and P. cyclopium (Hosoe et al. 1990; Hou et al. 1971; Pitt 1979), Penicillium verrucosum var. cyclopium (Pitt 1979), P. palitans (Hou et al. 1971; Pitt 1979) and Penicillium puberulum (Hou et al. 1971) have also been reported as producing penitrem A. These isolates, however, were later shown to be variants of P. crustosum. Penitrem A has also been isolated from Penicillium lanoso-coeruleum (Wells and Cole 1977) and Penicillium janczewskii (Mantle and Penn 1989) and penitrem B (16) has been isolated from Aspergillus sulphureus (Laakso et al. 1992).
A number of toxinogenic fungal species, particularly producers of tremorgenic mycotoxins (penitrem A (15), fumitremorgen B, paxilline, verrucosidin, and verruculogen), have been isolated from traditional fermented meats. Tremorgenic mycotoxins are a group of fungal metabolites known to act on the central nervous system, causing sustained tremors, convulsions, and death in animals. However, the mode of action of these mycotoxins has not been elucidated in detail, and their genotoxic capacity has hardly been investigated and reported (Sabater-Vilar et al. 2003).
Penitrem A (15) is a well-recognised tremorgenic mycotoxin produced by several Penicillium spp. However, most natural cases of penitrem A intoxication have been associated with Penicillium crustosum. Another Penicillium sp., Penicillium roqueforti, is used for the production of blue cheese and is found in silage and feeds. Penicillium roqueforti produces a mycotoxin, roquefortine C, which is also produced by P. crustosum. According to obtained results, roquefortine C can serve as a sensitive biomarker for penitrem A intoxication, but the clinical presentation needs to be considered for proper interpretation of its detection in the absence of penitrem A (Tiwaryl et al. 2009).
The fungus, Penicillium nigricans, produced griseofulvin, a biochemical feature consistent with identification of the organism on mor- phological criteria as P. nigricans, one of the first species found to elaborate griseofulvin. While the penitrems and griseofulvin are biosynthetically distinct, the former being indole and isoprene-derived and the latter a polyketide, inclusion of chlorine in the molecule is a characteristic which griseofulvin has in common with several penitrems including the most abundant penitrem A (15). Penicillium nigricans is as ineffectual in submerged culture as other penitrem-producing penicillia when grown in a Czapek Dox yeast extract medium, but the present report demonstrates that it is sensitive to the sporulation-inducing effect of calcium chloride and concomitantly in submerged culture elaborates penitrems A, C and E (15,19, and 17) in significant yield. A strain of Penicillium nigricans, which produces both the anti- fungal antibiotic griseofulvin and tremorgenic penitrem mycotoxins concurrently in static liquid culture, also elaborated both metabolites in submerged culture when stimulated by calcium chloride to sporulate. Maximum yield of penitrems (60 mg/L) occurred within 5 d in a 60 L stirred fermenter, thus constituting the first significant process for penitrem production in submerged culture (Mantle et al. 1984).
Sixty-one isolates of Penicillium crustosum originating from various foodstuffs were screened for penitrem A (15) production by high- PTLC. The highest producers of penitrem A (4 isolates) were grown in various liquid media. Skimmed milk (2%)/potato extract (2%)/sucrose (2%) (SPS) medium supported the highest toxin production and P. crustosum Sp 1552 was selected as the best producer of penitrem A. The isolation and purification of penitrem A was described (El-Banna and Leistner 1988).
Roquefortine and the penitrems were biosynthesised concurrently at an approximately equimolar rate by Penicillium crustosum after growth and sporulation. [14C]mevalonic acid was incorporated (15% efficiency) into the isoprenoid regions of the penitrem and roquefortine molecules to an extent consistent with their 6:1 molar ratio of isoprenoid components. [14C]-penitrem A (15) (specific activity, 3.4 x 102 p, Ci mM/L) and 14C-penitrems B (16), C (19), and E (17) re-administered to young cultures were metabolically interconverted, indicating considerable metabolic flux, though generally directed towards penitrem A as the end product and suggesting a metabolic grid for the penitrem metabolites. Addition of bromide to the medium preferentially favoured the production of bromo-analogues rather than the usual chloropenitrems (Mantle et al. 1983). Also [14C]-paxilline was biosynthetically incorporated into penitrem A (3.1-8.7%), and when calculated to include penitrem E (17) to a greater extent (3.3-17%), in submerged fermentations of Penicillium janczewskiv, concurrent biotransformation of [14C] paxilline to a hydroxy derivative may indicate another intermediate in penitrem biosynthesis (Mantle and Penn 1989).
Penitremones A-C (22-24), which are Penicillium metabolites containing an oxidised penitrem carbon skeleton, provide insight into structure-tremorgenic relationships. The principal metabolite penitremone A (22), produced with penitrem A by a Penicillium sp., is an isomer of penitrem E and is also similarly tremorgenic. The principal metabolite penitremone A (22), produced with penitrem A by a Penicillium sp., is an isomer of penitrem E and is also similarly tremorgenic (Naik et al. 1995).
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The MF-24 and AK-40 strains of Penicillium simplicissimum cause convulsion in silkworms upon oral administration. Two convulsants, penitrem A and 6-bromopeniterm E (25, which has a bromine atom instead of a chlorine atom at C-6 of penitrem A), were also isolated from AK-40 (Hayashi et al. 1993).
The anti-insectan metabolite 10-oxo-ll,33-dihydropenitrem B (26) was isolated from the sclerotia of Aspergillus sulphureus and is related to the penitrems, a known group of tremorgenic fungal metabolites. A known aflavinine analogue, 10,23- dihydro-24,25- dehydroaflavinine, was also isolated from Aspergillus sulphurerus sclerotia (Laakso et al. 1993). The minor metabolites, namely PC-M5 and PC-M6, were isolated along with penitrems A-F from the mycelium of Penicillium crusotsum, which contaminated bread intended for school lunches in Tokyo city. Two indoloditerpenes, PC-M4 (27) and PC-M5, were also isolated from the above fungus. PC- M4 (27) has the same carbon number as the penitrems but a different cyclic ring system. PC-M5, PC-M4, and potentially PC-M5' and PC-M6 may be biosynthetic precursors of penitrems (Yamaguchi et al. 1993).
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Three isolates of Penicillium crustosum cultures led to the isolation and structure elucidation of secopenitrem D (28). Penitrems A-F (15-21) were also present in the isolates analysed. Secopenitrem D lacks the C-16-C-18 ether linkage present in penitrems A-F (Moldes- Anayaet al. 2011).
A prominent analogue of penitrem A (15), pennigritrem (29), has been resolved from the tremorgenic alkaloids of a strain of Penicillium nigricans, which has been shown to involve the terminal diterpenoid isoprene during cyclisation, a unique process among fungal indole-diterpenoids. Consequent conformational changes in the biological active moiety significantly reduce tremorgenicity (Penn et al. 1992).
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Two indole-alkaloid isoprenoids were isolated from extracts of Penicillium crustosum grown on rice, and their chemical structures are related to penitrems. The two compounds, designated thomitrem A (30) and thomitrem E (31), contain an 18(19)-double bond and lack the characteristic penitrem 17(18)-ether linkage (Rundberget and Wilkins 2002).
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More recently, fermentation, isolation and identification of a marine-derived Penidllium species has been reported (Sallam et al. 2013). Bioassay-guided fractionation afforded the indole diterpene alkaloids penitrems A (15), B (16), D (20), E (17), and F (18) as well as paspaline and emnidole SB. Supplementing the fermentation broth of the growing fungus with KBr afforded the new 6-bromopenitrem B (32a) and the known 6-bromopenitrem E (25). These compounds showed good antiproliferative, antimigratory and anti-invasive properties against human breast cancer cells. Penitrem B (16) also showed a good activity profile in the NCI-60 DTP human tumour cell line screen. The nema- tode Caenorhabditis elegans was used to assess the BK channel inhibitory activity and toxicity of select compounds. A pharmacophore model was generated to explain the structural relationships of (15-20, and 25) with respect to their antiproliferative activity against the breast can- cer MCF-7 cells (Sallam et al. 2013). The maxi-k channel blocker named as 6-bromopenitrem D (32b) was also reported (Garcia et al. 2003).
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A cultures of Penidllium crustosum strain 21143, Penidllium cydopium and Penidllium palitans from Auckland area (New Zealand) have been reported as producing several indole-diterpenoids: penitrems (15-20) and as well as janthitrems A-D, lolitrem B, paspalinine, paxilline and terpendole C (Babu 2008).
At present time, we have not found publications, which described of microbial synthesis and/or biosynthesis of CBC alkaloids using industrial fermentation.
Novel plant CBC alkaloids
Some times ago, we reported (Dembitsky 2008; Sergeiko et al. 2008) an occurrence of CBC alkaloids in marine and terrestrial species. In this section of the review, we discuss new alkaloids discovered since 2008 and also alkaloids that are not mentioned in previous publications (Dembitsky 2008; Sergeiko et al. 2008).
Flueggedine (33), a highly symmetric [2 + 2] cycloaddition indolizidine alkaloid dimer, was isolated from the twigs and leaves of Flueggea virosa. A plausible biogenetic pathway of (33) was also proposed (Zhao et al. 2013). Flueggea (or Bushweeds, family Phyllanthaceae) is a genus of plants consisting of several much-ramified shrubs to large trees distributed throughout the tropical zones of the Eastern Flemisphere.
Novel quinolinone alkaloids bearing a phenylpropanoid or a coumarin moiety, named melicodenine C (34), D (35), E (36,37), F (38), and G (39), were isolated from the leaves of Melicope denhamii. Quinolinone alkaloids were tested for anti-proliferative activity against DLD-1 human colon cancer cells. Melicodenine G (37) showed the most potent inhibitory activity, causing the induction of apoptosis with an IC50 value of 9.4 p,M (Nakashima et al. 2012).
The carbazole alkaloid bicyclomahanimbine (40) was isolated for the first time from Clausena dunniana. Isolated alkaloids show growth inhibitory activity effects on human fibrosarcoma HT-1080 cells and cell cycle M-phase inhibitory and apoptosis- inducing (MIC 30 p,g/ml) activities on mouse tsFT210 cells. The compound (40) provided the first example of carbazole alkaloids as new cell cycle inhibitors and apoptosis inducers (Cui et al. 2002). The same alkaloid (40) was isolated from the ethanol extract of the leaves of Malayan Murraya koenigii (Kureel et al., 1969; Sim and Teh 2011) and from Murraya euchrestifolia (Wu et al. 1995). The curry tree Murraya koenigii (family Rutaceae) is native to India and Sri Lanka, and its leaves are used in many dishes in India and neighbouring countries. The leaves of M. koenigii are also used in ayurvedic medicine and possess anti-diabetic properties. Murrayafoline M (41), a carbazole alkaloid, together with other alkaloids, was isolated from the leaves and root bark of Murraya euchrestifolia (Wu et al. 1998). Most of the isolated carbazole alkaloids show potent inhibitory activity on rabbit platelet aggregation induced by arachidonic acid (100 p.M), collagen (10p,g/ml), and PAF (2ng/ml). Two carbazole alkaloids named karapinamine C (also known as bicyclomahanimbine) (40) and karapinamine D (42) have been obtained from the Et20 extract of dried Murraya koenigii leaves. Karapinamine C (40) inhibited melanin formation in B16 melanoma 4A5 cells with an IC50 of 3.0 p.M (Yoshikawa 2013).
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A natural pentacyclic compound, kingianin A (43), was isolated as a racemic mixture from Endiandra kingiana (Lauraceae) bark (Leverrier et al. 2010). An in vitro biological screening of Malaysian plants allowed the selection of several species with a significant binding affinity for the anti-apoptotic protein Bcl-xL. The investigation of Endiandra kingiana led to the isolation of a series of CCM polyketides named kingianin A (43) and other kingianins (44-52) that possess a pentacyclic carbon skeleton described for the first time in nature. The levorotatory enantiomers showed a more potent binding affinity for Bcl-xL with the Ki ranging from 1.0 to 12 p,M (Leverrier et al. 2011). These compounds are biogenetically closely related to endiandric acids, which were previously isolated from the Endiandra and Beilschmieda genera. The biological study indicated that the ([+ or -])-enantiomers of kingianins 1< and L have the most potent binding affinity for the protein Bcl-xL with a Ki in the 1 M range. These results show that the presence of two acidic side chains or one acidic and one N- ethylacetamide side chain and their spatial position are essential to reach a significant binding affinity for Bcl-xL.
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A bis-[beta]-carboline alkaloid, quassidine A (53), was isolated from the stems of Picrasma quassioides (in Chinese--ku shu, and/or in Japanese--nigaki). This compound is known as "Bitterwood" and is native to Himalaya, China, Taiwan, and Japan. The bark is used as a bitter flavouring and antibacterial agent. Quassidine A is the first reported bis-[beta]-carboline alkaloid possessing a novel cyclobutane moiety. A possible biogenetic pathway for these alkaloids was proposed. All of the compounds were evaluated for anti- inflammatory activity, and only quassidine A (53) showed weak activity (Jiao et al. 2010). 1,2-Dihydro-cyclobuta[b]quinoline-8-carboxylic acid (54) was detected in the ether extract of Securidaca longipedunculata roots (family Polygalaceae, known as the violet tree in some parts of Africa) (Costa et al. 1992). The roots and bark are extremely poisonous and are taken orally either as a powder or as infusions for treating chest complaints, headache, inflammation, abortion, ritual suicide, tuberculosis, infertility problems, venereal diseases, and constipation.
The methanol extract of Centaurea schischkinii seeds (syn. Psephellus schischkinii, family Asteraceae) afforded a novel indole alkaloid, named schischkiniin (55), together with four lignans, arctiin, arctigenin, three flavonoids, astragalin, afzelin, and apigenin. Arctigenin exhibited promising in vitro anticancer activity ([IC.sub.50] = 7 [micro]M), while schischkiniin showed moderate anticancer activity ([IC.sub.50] = 76 [micro]M) (Shoeb et al. 2005).
An antineoplastic agent (56) demonstrated inhibitory activity against many tumour cells and has been isolated from the traditional Chinese medicine Incarvillea delavayi (family Bignoniaceae) (Zhang et al. 2008). The alkaloid (56) is an active ingredient of drug carriers and is used to treat chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, and other diseases (Zhang et al. 2011).
The production of phytoalexins by Thellungiella halophila exposed to UV radiation and NaCl was reported (Pedras et al. 2009). Two CCM phytoalexins named biswasalexins A1 (57) and A2 (58) resulted from the head-to-tail photodimerisation of wasalexin A. Biswasalexins A1 and A2 may protect the plant from fungal attack and UV radiation (Pedras et al. 2009).
Fourteen alkaloids were isolated from the blue-green algae Hapalosiphon welwitschii (Stigonemataceae) as minor constituents viz. a novel spiro oxindole, welwitindolinone A isonitrile (59), five tetracyclic oxindoles, and eight biogenetically related fischerindoles and hapalindoles. Isonitrile alkaloids showed the fungicidal activity of H. welwitschii. The biogenesis of these alkaloids was previously discussed (Stratmann et al. 1994).
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A dimeric Lythraceae alkaloid with a cyclobutane ring, sarusubine A (59), has been isolated from the leaves of Lagerstroemia subcostata (Watanabe et al. 2007). This shrub is a deciduous tree that is native to China, Taiwan, Japan, and the Philippines.
Two alkaloids (60 and 61) have been obtained from the water-ethanol extract of raw materials from Abrus cantortiensis and Abrus mollis (family Fabaceae) (Yuan and Lin 2013). Abrus is a genus of flowering plants and is found only in the Tribe Abreae. The entire A. Cantortiensis plant was reported to be primarily used for the treatment of acute and chronic hepatitis, jaundice, and mastitis.
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A tropane alkaloid with a 2-methyl-4-phenylcyclobutane 1,2,3-tricarboxylic acid ester as the central structure was first isolated from the aerial sections of Schizanthus grahamii more than 20 years ago and was named grahamine (Hartmann et al. 1990). More recently, a series of new alkaloids, named grahamines A-E (62-66, respectively), were isolated from an endemic Chilean plant, S. grahamii (Butterfly flower, family Solanaceae), which is known to contain tropane alkaloids (Cretton et al. 2011).
Tropane alkaloids constitute one of the distinctive groups of secondary metabolites of the Solanaceae, and many plants containing these alkaloids have been utilised for their medicinal, hallucinogenic, and poisonous properties. Tropane alkaloids showed pharmacological effects on mydriatica, spasmolytica, analgetica, and sedativa (Grynkiewicz and Gadzikowska 2008).
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Bisalkaloids such as dipiperamides A-C (67-71) were isolated from the white pepper (Piper nigrum) along with piperine and piperylin. Dipiperamides A-C inhibit cytochrome P 450 (CYP) 3A4 activity (Tsukamoto et al. 2002a,b). Dipiperamides D (70) and E (71) were isolated as inhibitors of a drug-metabolising enzyme cytochrome P 450 (CYP) 3A4 from the white pepper Piper nigrum. These dipiperamides (D and E) showed potent CYP3A4 inhibition, with [IC.sub.50] values of 0.79 and 0.12 [micro]M, respectively (Tsukamoto et al. 2002a,b).
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Pipercyclobutanamides A (72), C (73) and G (74) have been isolated from Piper nigrum leaves (Subehan et al. 2006). The isolated alkaloids were tested for their inhibition on human liver microsomal dextromethorphan O-demethylation activity, a selective marker for CYP2D6, and pipercyclobutanamide A (72) showed the most potent inhibition with an [IC.sub.50] value of 0.34 [micro]M. The result demonstrated the potential of drug-alkamide interactions on concomitant consumption of white pepper with the drugs being metabolised by the human liver microsomal cytochrome P450 2D6.
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Selected analogues of fungi and plant CBC alkaloids
The anti-tumour agent mitindomide (75) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II. Furthermore, mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells (Hasinoff et al. 1997). The photochemical reaction between benzene and maleic anhydride or benzene and maleimide produced mitindomide, which showed pronounced activity (e.g., PS T/C 201 at 50mg/kg) against several of the U.S. National Cancer Institute's key experimental tumour systems (Pettit et al. 1983). CBC alkaloids as analogues of natural rapamycin (76) were prepared and used as immunosuppressive, anti-inflammatory, anti-fungal, anti-proliferative, and anti-tumour agents (Nelson and Schiehser 1995).
Tetramic acid analogues such as (77) and (78) were prepared for use in antibacterial pharmaceutical compounds with activity against Gram-positive bacteria. Furthermore, these compounds are iron chelators. The prepared tetramic acid analogues (77 and 78) were evaluated for antibacterial activity against bacterial pathogens such as Mycobacterium tuberculosis H37 Rv, Bacillus anthracis Sterne 34F2, Bacillus subtilis ATCC 23857, Streptococcus pneumoniae DAW30EC, Enterococcus faecalis ATCC 33186, methicillin-resistant Staphylococcus aureus (MRSA) ATCC 33591, methicillin-sensitive Staphylococcus aureus (MSSA) 8325 ATCC 35556, Propionibacterium acnes ATCC 6919, and Streptococcus pyogenes ATCC 700294 by assessing the activity against biofilms and for cytotoxicity using the Vero monkey kidney cell line (ATCC, CCL-81) (Lee et al. 2009). A mycobacterial inhibitor (79) was prepared and showed a MIC value of [less than or equal to] 20 [micro]g/ml against single- and multiple-drug-resistant strains of Mycobacterium tuberculosis (Balganesh et al. 1999). A pyrrolidin-2-one derivative (80) was synthesized and used for the treatment of glaucoma and/or elevated intraocular pressure (Old et al. 2008). A synthetic compound (81) showed activity against bacteria and yeasts such as Bacillus megaterium, B. subtilis, Enterococcus faecalis, Serratia marcescens, Enterobacter aerogenes, Mycobacterium smegmatis, Proteus vulgaris, and Pseudomonas aeruginosa (Ahmedzade et al. 2003).
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Ergot alkaloids are a large complex family of mycotoxins and have a long history associated with agricultural problems and human diseases. As a result, developing an effective detection procedure is of substantial importance for alkaloids produced by the fungal endophyte Neotyphodium coenophialum and/or fungi of the genus Claviceps (Belesky and Bacon 2009; Cross 2003).
Ergot alkaloids produced by the parasitic fungus Claviceps, which parasitises on cereals, include three major groups: clavine alkaloids, dlysergic acid (82) and its derivatives, and ergopeptines. These alkaloids are important substances for the pharmaceutical industry where they are used for the production of anti-migraine drugs, uterotonics, prolactin inhibitors, anti-Parkinson's disease agents, and others (Wallwey and Li 2011). The production of ergot alkaloids is based either on traditional field cultivation of ergot-infected rye or on submerged cultures of the fungus in industrial fermentation plants. These alkaloids are isolated from the dried sclerotium of the fungus Claviceps purpurea (Hypocreaceae) (Flieger et al. 1997; Van Dongen and De Groot 1995). Notably, the semi-synthetic lysergic acid (82) diethylamide, named LSD (83), was initially developed for the treatment of various psychiatric disorders; however, due to its hallucinogenic effects, it remains an illegal drug. Approximately 75 years ago, Albert Hofmann began synthesising LSD, an analogue of the ergot alkaloids, which led to a revolution in the pharmaceutical industry, inspiring researchers to understand how the structure of a molecule is recognised and how this recognition triggers a physiological response as well as a revolution in the social identity crisis of America and Europe during the 1960s (Craig and Kauffman 2006; Jay 2013).
Three semi-natural alkaloids, named N-cyclobutyl-lysergamide (84), N-cyclobutyl-iso-lysergamide (85), and N-cyclobutyl- 9,10-dihydro-D-lysergamide (86), were obtained from natural alkaloids isolated from C. purpurea (Semonsky and Zikan 1959; Hladovec and Votava 1958; Macek and Vanecek 1962).
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Alkaloid morphine produced by plants is widely used as a medicine. Although it remains uncertain when morphine (87) was first used or discovered, the date can be narrowed to approximately 4000 BC. Morphine was used to relieve anxiety and pain, and the first recorded use of opium for medical purposes was in 200 BC. In 1803, Serturner, a German pharmacist, identified and isolated the primary ingredient of opium, morphine, from Papaver somniferum. He named this alkaloid Morphia after Morpheus, the Greek god of dreams (Bogusz 2000; Holzgrabe 2005; Ghosh et al. 1982; Stork 1960). Pain is a common and key clinical problem, which can cause stress responses and has important effects on the therapy, operations, and the prognosis of patients; therefore, the control of pain is very important in the clinic. Among the many analgesia drugs, butorphanol (88) has displayed predominance in a series of animal tests and clinic searches. Butorphanol (88) is a synthetically derived opiate. As a nasal spray, butorphanol (88) was approved for release in 1991 and was subsequently promoted as a safe treatment for migraines. Subsequently, numerous reports have highlighted problems with butorphanol similar to any narcotic, especially dependence-addiction and major psychological disturbances. Opioid dependence that specifically mediates through the popioid receptor remains a major concern of opioid analgesics. Drugs that interact with K-opioid receptors are increasingly used as an alternative to p-agonist analgesics. Several studies have reported that the chronic administration of K-opioid agonists such as U-50488H, U-69,593, and butorphanol also results in the development of physical dependence/withdrawal. In addition, the ability of a highly selective K-opioid antagonist, nor-binaltorphimine, given systemically or spinally, on withdrawal behaviours in opioid-dependent animals further demonstrates that both supra-spinal and spinal sites of K-opioid receptors play an important role in opioid dependence/withdrawal (Commiskey et al. 2005).
Opiate analgesics provide effective pain relief and are widely used to control mild to severe pain. The well-known side effects of the mu-agonist opioids, including pruritis, nausea/emesis, constipation, urinary retention, respiratory depression, excessive sedation, and the development of tolerance and dependence, are occasionally problematic. Several carbamate analogues (89-91) were synthesized from butorphanol and/or Ievorphanol and evaluated in vitro for their binding affinity to the [mu], [delta], and [kappa] opioid receptors. Ph carbamate derivatives showed the highest binding affinity for the [kappa] receptor ([K.sub.i] = 0.046 and 0.051 nM) and for the p receptor ([K.sub.i] = 0.11 and 0.12 nM). Compound (88) showed the highest p. selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [[sup.35]S] GTP[gamma]S binding mediated by the [kappa] opioid receptor illustrated that all of these ligands were [kappa] agonists. At the [mu] receptor, compound (90) was an agonist, while compound (91) was a [mu] agonist/antagonist (Peng et al. 2007).
The opioid agonist-antagonist nalbuphine (92) in opioid analgesia was prepared. Used as the sole opioid analgesic, it can satisfactorily relieve mild to moderate pain with a low incidence of the common opioid side effects. With care, nalbuphine (92) can be used concurrently with the more commonly employed mu-opioid agonists (e.g., morphine, hydromorphone, and fentanyl), yielding analgesia while simultaneously decreasing the incidence and severity of mu-agonist side effects (Gunion et al. 2004).
Xorphanol mesylate (93) is a new mixed agonist-antagonist from the morphinan class of analgesics. Based on animal experiments, the physical dependence liability of xorphanol is predicted to be of low order in man. Conceptually, xorphanol is of interest because in vitro experiments have revealed anti-naloxone properties and resistance to antagonism by opioid antagonists. At the practical level, xorphanol is a well-tolerated, orally active analgesic that provides effective pain relief (Howes et al. 1985).
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Novel tricyclic spiro-oxathiine naphthoquinone derivatives such as (93) were prepared and were therapeutically useful in inducing cell death and/or inhibiting cancer proliferation or precancerous cells. This naphthoquinone derivative is an analogue of [beta]-lapachone, a naphthoquinone derived from lapachol isolated from Tabebuia avellanedae (Bignoniaceae), and showed anti-proliferative activity against a number of cancer cell lines such as DLD-1 and HT-29 human colon carcinoma (Ashwell et al. 2007).
Compound (94) is a synthetic analogue of the natural proteasome inhibitor salinosporamide A from the marine bacterium Salinispora tropica and is a promising drug candidate for the treatment of multiple myeloma and mantle cell lymphoma. One of the engineered compounds is equipotent to salinosporamide A in the inhibition of the chymotrypsin-like activity of the proteasome, yet it exhibits superior activity in the cell-based HCT-116 assay (Nett et al. 2009).
The 2-substituted oleanolic acid derivative (95) was prepared and showed anti-tumour activity against leukaemia at the [IC.sub.50] value of 0.52 [micro]g/ml (Xu et al. 2013).
Novel anti-parasitic compounds including 5-, 6-, and 7-member N heterocyclic rings (96, 97, and 98, respectively) were synthesised and used to kill parasites including blood flukes, cestodes, cysticercus, Clonorchis sinensis, lung flukes, and Fasciolopsis buski in humans or animals (Yang et al. 2011).
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The F-substituted E-ring camptothecin analogue (99) exhibited an [IC.sub.50] value of 0.309 [micro]g/ml against lung tumours (Zhang et al. 2013). The synthetic protease inhibitor (100) was effective against the HIV-1 virus 184 V mutant (Almerico et al. 2006).
Novel oligosquaramide-based macrocycle (101) as an anticancer agent was prepared and exhibited significant anti- proliferative activity against the NCI-60 human tumour cell line panel, with [IC.sub.50] values ranging from 1 to 10 [micro]M, and was also an effective inhibitor of several important kinases such as ABL1, CDK4, CHK1, PKC, c-MET, FGFR, and others (Villalonga et al. 2012).
CBC alkaloids comprise a rare group of natural products. They are primarily present in plant and fungi species and have also been detected in several marine invertebrates. Little information is known about the biological activities of these metabolites. Nevertheless, reported activities for these isolated compounds have shown strong anticancer, antibacterial, antiviral, and other activities. The widest spectra of pharmacological activities are exhibited by isolated alkaloids and/or their synthesised derivatives. CBC alkaloids have been shown to be promising candidates for the development of new drugs used for the treatment of several diseases. Therefore, synthetic methodologies have been investigated in recent years as a growing field of interest for chemists, biologists, and pharmacologists.
Abraham, W.R., 2001. Bioactive sesquiterpenes produced by fungi: are they useful for humans as well? Curr. Med. Chem. 8, 583-606.
Ahmedzade, M., Cukurovali, A., Koparir, M., 2003. Synthesis and antimicrobial activity of some of new 1,1,3- trisubstituted cyclobutane-containing thiazoles, succinimide and phthalimide derivatives. J. Chem. Soc. Pak. 25, 51-55.
Almerico, A.M., Tutone, M., Lauria, A.. Diana, P., Barraja, P., Montalbano, A., Cirrincione, G., Dattolo, G., 2006. A multivariate analysis of HIV-1 protease inhibitors and resistance induced by mutation. J. Chem. Inform. Model. 46, 168-179.
Ashwell, M., Tandon, M., Lapierre, J.-M., Ali, S., Vensel., D., Li, C.J., 2007. Novel lapachone compounds and methods of use thereof. Patent: WO 2007139569 A1, PCT/US2006/032660.
Atanda, S.A., Pessu, P.O., Agoda, S., Isong, I.U., Adekalu, O.A., Echendu, M.A., Falade, T.C., 2011. Fungi and mycotoxins in stored foods. Afr. J. Microbiol. Res. 5, 4373-4382.
Babu, J.V., 2008. Bioactive chemicals of importance in endophyte--Infected Grasses. (PhD Thesis), Waikato University, New Zealand.
Balganesh, M., Ethiraj, K., Ganguly, B., Janakiraman, R., Kaur, P., Kajipala, R., Nandan, S., Murugappan, R.P., Ramachandran, N., Venkataraman, B., 1999. Preparation of pyrroline-2,5-diones and pyrrolidine-2,5-diones as mycobacterial Inhibitors. WO 9965483 A1, 40 pp., PCT Int. Appl.
Belesky, D.P., Bacon, C.W., 2009. Tall fescue and associated mutualistic toxic fungal endophytes in agroecosystems. Toxin Rev. 28, 102-117.
Bladt, T.T., Frisvad, J.C., Knudsen, P.B., 2013. Anticancer and antifungal compounds from Aspergillus. Penicillium and other filamentous fungi. Molecules 18, 11338-11376.
Bogusz, M.J., 2000. Opiate agonists. In: Bogusz, M.J. (Ed.), Forensic Science (Handbook of Analytical Separations), vol. 2. Elsevier Science, Amsterdam, pp. 3-65.
Brennan, P.J., 1974. The lipids of fungi. Prog. Chem. Fats Other Lipids 14, 49-89.
Chandra, S., 2012. Endophytic fungi: novel sources of anticancer lead molecules. Appl. Microbiol. Biotechnol. 95, 47- 59.
Chopra, A., Khuller, G.K., 1983. Lipids of pathogenic fungi. Prog. Lipid Res. 22, 189-220.
Commiskey, S., Fan, L.-W., Ho, I.K., Rockhold, R.W., 2005. Butorphanol: effects of a prototypical agonist-antagonist analgesic on K-opioid receptors. J. Pharmacol. Sci. (Tokyo, Japan) 98, 109-116.
Cordell, G.A., 2013. Fifty years of alkaloid biosynthesis in phytochemistry. Phytochemistry 91, 29-51.
Cordoba, K.A.M., Rios, A.H., 2012. Biotechnological applications and potential uses of the mushroom Tramestes versicolor. Mycol. Res. 105, 1514-1518.
Costa, C., Bertazzo, A., Biasiolo, M., Allegri, G., Curcuruto, O., Traldi, P., 1992. Gas chromatographic/mass spectrometric investigation of the volatile main components from roots of Securidaca longipedunculata. Org. Mass Spectrom. 27, 255-257.
Craig, G.W., Kauffman, G.B., 2006. Albert Hofmann: life and work. Sojourn of a chemist of nature. Chem. Educator 11, 427-437.
Cretton, S., Bartholomeusz, T.A., Humam, M., Marcourt, L., Allenbach, Y., Jeannerat, D., Munoz, O., Christen, P., 2011. Grahamines A-E, cyclobutane-centered tropane alkaloids from the aerial parts of Schizanthus grahamii. J. Nat. Prod. 74, 2388-2394.
Cross, D.L., 2003. Ergot alkaloid toxicity. Mycology Series 19, 475-494.
Cui, C.-B., Yan, S.-Y., Cai, B., Yao, X.-S., 2002. Carbazole alkaloids as new cell cycle inhibitor and apoptosis inducers from Clausena dunniana Levi. J. Asian Nat. Prod. Res. 4, 233-241.
Dembitsky, V.M., 2003. Oxidation, epoxidation and sulfoxidation reactions catalyzed by haloperoxidases. Tetrahedron 59, 4701-4720.
Dembitsky, V.M., 2006. Natural neo acids and neo alkanes: their analogues and derivatives. Lipids 41, 309-340.
Dembitsky, V.M., 2008. Bioactive a cyclobutane-containing alkaloids. Journal of Natural Medicines (Tokyo) 62, 1-33.
Dembitsky, V.M., Bychek, I.A., Shustov, M.V., Rozentsvet, O.A., 1991. Phospholipid and fatty acid composition of some lichen species. Phytochemistry 30, 837-839.
Dembitsky, V.M., Rezanka, T., Shubina, E.E., 1993a. Chemical constituents of some higher fungi. 2. Fatty acid composition of ascomycetes. Cryptogamic Botany 3, 378-381.
Dembitsky, V.M., Rezanka, T., Shubina, E.E., 1993b. Chemical composition of fatty acids from some fungi. Cryptogamic Botany 3, 382-386.
Dembitsky, V.M., Rezanka, T., Shubina, E.E., 1993c. Chemical constituents of some higher fungi. 1. Fatty acid and phospholipid compositions of Basidiomycetes. Cryptogamic Botany 3, 373-377.
Dembitsky, V.M., Rezanka, T., Shubina, E.E., 1993d. Unusual hydroxy fatty acids from some fungi. Phytochemistry 34, 1057-1059.
Dembitsky, V.M., Quntar, A., Srebnik, M., 2011. Natural and synthetic small boron-containing molecules as potential inhibitors of bacterial and fungal quorum sensing. Chem. Rev. 111, 209-237.
Van Dongen, P.W.J., De Groot, A.N.J.A., 1995. History of ergot alkaloids from ergotism to ergometrine. Eur. J. Obstet. Gynaecol. Reprod. Biol. 60, 109-116.
De Silva, D.D., Rapior, S., Sudarman, E., Stadler, M., Xu, J., Alias, S.A., Hyde, K.D., 2013. Bioactive metabolites from macrofungi: ethnopharmacology, biological activities and chemistry. Fungal Diversity 62, 1-40.
Duarte, G.C., Moreira, L.R.S., Jaramillo, P.M.D., Filho, E.X.F., 2012. Biomass-derived inhibitors of Holocellulases. BioEnergy Res. 5, 768-777.
Eisenstadt, M.A., Bogolitsyn, K.G., 2010. Peroxidase oxidation of lignin and its model compounds. Russ. J. Bioorg. Chem. 36, 802-815.
El-Banna, A.A., Leistner, L., 1988. Production of penitrem A by Penicillium crustosum isolated from foodstuffs. Int. J. Food Microbiol. 7, 9-17.
Evidente, A., Andolfi, A., Cimmino, A., 2011. Relationships between the stereochemistry and biological activity of fungal phytotoxins. Chirality 23, 674-693.
Flieger, M., Wurst, M., Shelby, R., 1997. Ergot alkaloids-sources, structures and analytical methods. Folia Microbiol. 42, 3-30.
Frisvad. J. C., Smedsgaard, J., Larsen, T.O., Samson, R.A., 2004. Mycotoxins, drugs and other extrolites produced by species in Penicillium subgenus Penicillium. Studies Mycol. 49, 201-241.
Fyaz, I.F.M., Levitsky, D.O., Dembitsky, V.M., 2009, Aziridine alkaloids as potential therapeutic agents, Eur. J. Med. Chem. 44, 3373-3387.
Garcia, M.L., Goetz, M.A., Kaczorowski, G.J., McManus, O.B., Monaghan, R.L., Strohl, W.R., Tkacz, J.S., 2003. Novel maxi-k channel blockers, methods of use and process for making the same. US Patent: 20050239787 A1.
Ghosh, A.C., Lavoie, R.L., Herlihy, P., Howes, J.F., Razdan, R.K., 1982. 14-Alkoxy dihydrocodeinones, dihydromorphinones, and morphinanones--a new class of narcotic analgesics. NIDA Res. Monogr. 41, 105-111.
Gonzalez, M.C., Lull, C., Moya, P., Ayala, L, Primo, J., Primo Yufera, E., 2003. Insecticidal activity of penitrems, including penitrem G, a new member of the family isolated from Penicillium crustosum. J. Agrie. Food Chem. 51, 2156-2160.
Grynkiewicz, G., Gadzikowska, M., 2008. Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. Pharmacol. Rep. 60, 439-463.
Gunion, M.W., Marchionne, A.M., Anderson, C.T.M., 2004. Use of the mixed agonist-antagonist nalbuphine in opioid based analgesia. Acute Pain 6, 29-39.
Hanus, L.O., Shkrob, L, Dembitsky, V.M., 2008. Lipids and fatty acids of wild edible mushrooms of the genus Boletus. J. Food Lipids 15, 370-383.
Hasinoff, B.B., Creighton, A.M., Kozlowska, H., Thampatty, P., Allan, W.P., Yalowich, J.C., 1997. Mitindomide is a catalytic inhibitor of DNA Topoisomerase II that acts at the bisdioxopiperazine binding site. Mol. Pharmacol. 52, 839-845.
Hayashi, H., Asabu, Y., Mukaihara, M., Murao, S., Nakayama, M., Arai, M., Clardy, J., 1993. Convulsive substances produced by fungi. Symp. Chem. Nat. Prod. 35, 670-677.
Hladovec, J., Votava, Z., 1958. The effect of ergot alkaloids, their partial synthetic derivatives and serotonin on blood clotting. Chekhoslov Fiziologia 7, 553-558.
Hosoe, T., Nozawa, K., Udagawa, S., Nakajima, S., Kawai, K., 1990. Structures of new indoloditerpenes, possible biosynthetic precursors of the tremorgenic mycotoxins, penitrems, from Penicillium crustosum. Chem. Pharm. Bull. 38, 3473-3475.
Hou, C.T., Ciegler, A., Hesseltine, C.W., 1971. Tremorgenic toxins from Penicillia. III. Tremortin production by Penicillium species on various agricultural commodities. Appl. Microbiol. 21, 1101-1103.
Hulvova, H., Galuszka, P., Frebortova, J., Frebort, L., 2013. Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids. Biotechnol. Adv. 31, 79-89.
Janusz, G., Kucharzyk, K.H., Pawlik, A., Staszczak, M., Paszczynski, A.J., 2013. Fungal lacease, manganese peroxidase and lignin peroxidase: gene expression and regulation. Enzyme Microb. Technol. 52, 1-12.
Jay, M., 2013. Drug discovery: synthesized dreams. Nature (London, UK) 497, 435-436.
Jiao, W.-H., Gao, H., Li, C.-Y., Zhao, F., Jiang, R.-W., Wang, Y., Zhou, G.-X., Yao, X.-S., Quassidines, A.-D., 2010. bis-[beta]-carboline alkaloids from the stems of Picrasma quassioides. J. Nat. Prod. 73, 167-171.
Hartmann, R., San-Martin, A., Munoz, O., Breitmaier, E., 1990. Grahamine, an unusual tropane alkaloid from Schizanthus grahamii. Angew. Chem. 102, 441-443.
Holzgrabe, U., 2005. 200 years of morphine. New developments from research. Pharmaz Z (Germany) 150, 32-38.
Howes, J.F., Villarreal, J.E., Harris, L.S., Essigmann, E.M., Cowan, A., 1985. Xorphanol. Drug Alcohol Depend. 14, 373- 380.
Kharwar, R.N., Mishra, A., Gond, S.K., 2011. Anticancer compounds derived from fungal endophytes: their importance and future challenges. Nat. Prod. Rep. 28, 1208-1228.
Kureel, S.P., Kapil, R.S., Popli, S.P., 1969. Terpenoid alkaloids from Murraya koenigii Spreng. II. The constitution of cyclomahanimbine, bicyclomahanibine, and mahanimbidine. Tetrahedron Lett. 44, 3857-3862, 1969.
Kimura. Y., Hiromitsu, M., Takashi, H., 1989. Pinthunamide, a new tricyclic sesquiterpene amide produced by a fungus, Ampullifernia sp. Tetrahedron Lett. 30.1267-1270.
Kimura, Y., Nakajima, H., Hamasaki, T., Matsumoto, Y., Tseunda, A., 1990. Ampullicin and isoampullicin, a new metabolites from Ampullifera--like fungus sp. No 27. Agrie. Biol. Chem. 54, 813-814.
Kimura, Y., Matsumoto. T., Nakajima, H., Hamasaki, T., Matsuda, Y., 1993. Dihydroampullicin, a new plant growth regulators produced by the Ampulliferina-Uke fungus sp No 27. Biosci. Biotechnol. Blochem. 57, 687-688.
Kuklev, D.V., Domb, A.J., Dembitsky, V.M., 2013. Bioactive acetylenic metabolites. Phytomedicine 20, 1145-1159.
Laakso, J., Gloer, J.B., Wicklow, D.T., Dowd, P.F., 1992. Sulpinines A-C and secopenitrem B: new antiinsectan metabolites from the sclerotia of Aspergillus sulphureus. J. Org. Chem. 57, 2066-2071.
Laakso, J.A., Gloer, J.B., Wicklow, D.T., Dowd, P.F., 1993. A new penitrem analog with antiinsectan activity from the sclerotia of Aspergillus sulphureus. J. Agrie. Food Chem. 41, 973-975.
Lee, F.-P., Chen, Y.-C, Chen, J.-J., Tsai, I.-L., Chen, I.-S., 2009. Cyclobutanoid amides from Piper arborescens. Helv. Chim. Acta 87, 463-468.
Leverrier, A., Awang, K., Gueritte, F., Litaudon, M., 2011. Pentacyclic poiyketides from Endiandra kingiana as inhibitors of the Bcl-xL/Bak interaction. Phytochemistry 72, 1443-1452.
Leverrier, A., Dau, M.E.T.H., Retailleau, P., Awang, K., Gueritte, F., Litaudon, M., Kingianin, A., 2010. A new natural pentacyclic compound from Endiandra kingiana. Org. Lett. 12, 3638-3641.
Liu, L, Gao, H., Chen, X., Cai, X., Yang, L, Yao, X., Che, Y., Brasilamides, A.-D., 2010. Sesquiterpenoids from the Plant Endophytic Fungus Paraconiothyrium brasiliense. Eur. J. Org. Chem. 17, 3302-3306.
Liu, Y.J., Zhai, C.Y., Liu, Y., Zhang, K.Q., 2009. Nematicidal activity of Paecitomyces spp. and isolation of a novel active compound. J. Microbiol. 47, 248-252.
Macek, K., Vanecek, S., 1962. Ergot alkaloids. XXIV. Paper chromatography of lysergic acid cycloalkamides and N-methy- lergolinyl-N 0 -cycloalkylureas. Pharmazie 17, 442-444.
Mantle, P.G., Laws, L, Tan, M.J., Tizard, M., 1984. A novel process for the production of Penitrem mycotoxins by submerged fermentation of Penicillium nigricuns. J. Gen. Microbiol. 130, 1293-1298.
Mantle, P.G., Penn. J., 1989. A role for paxilline in the biosynthesis of indole-diterpenoid penitrem mycotoxins. J. Chem. Soc., Perkin Trans. 1, 1539-1540.
Mantle, P.G., Perera, K.P., Maishman, N.J., Mundy, G.R., 1983. Biosynthesis of penitrems and roquefortine by Penicillium crustosum. Appl. Environ. Microbiol. 45, 1486-1490.
Moldes-Anaya, A., Rundberget, T., Uhlig, S., Rise, F., Wilkins, A.L., 2011. Isolation and structure elucidation of secopenitrem D, an indole alkaloid from Penicillium crustosum Thom. Toxicon 57, 259-265.
Muszynska, B., Maslanka, A., Ekiert, H., Sulkowska-Ziaja, K., 2011. Analysis of indole compounds in Armillaria mellea fruiting bodies. Acta Pol. Pharm. 68, 93-97.
Naik, J.T., Mantle, P.G., Sheppard, R.N., Waight, E.S., Penitremones, A.-C., 1995. Penicillium metabolites containing an oxidized penitrem carbon skeleton giving insight into structure-tremorgenic relationships. J. Chem. Soc., Perkin Trans. 1 (9), 1121 -1125.
Nakashima, K.-L., Oyama, M., Ito, T., Akao, Y., Witono, J.R., Darnaedi, D., Tanaka, T., Murata, J., Iinuma, M., 2012a. Novel quinolinone alkaloids bearing a lignoid moiety and related constituents in the leaves of Melicope denhamii. Tetrahedron 68, 2421-2428.
Nakashima, K., Oyama, M., Ito, T., Witono, J.R., Darnaedi, D., Tanaka, T., Murata, J., Iinuma, M., 2012b. Novel zierane- and guaiane-type sesquiterpenes from the root of Melicope denhamii. Chem. Biodiversity 9, 2195-2202.
Nelson, F.C., Schiehser, G.A., 1995. Immunosuppressant hindered esters of rapamycin. 16 pp., US Patent: 5385908 A.
Nett, M., Gulder, T.A.M., Kale, A.J., Hughes, C.C., Moore, B.S., 2009. Function-oriented biosynthesis of [beta]-lactone proteasome inhibitors in Salinispora tropica. J. Med. Chem. 52, 6163-6167.
O'Connor, S.E., 2012. Alkaloids. Nat. Prod. Chem. Biol., 209-237.
O'Connor, S.E., 2009. Alkaloid biosynthesis. In: Begley, T.P. (Ed.), Wiley Encyclopedia of Chemical Biology, vol. 1, pp. 17-33.
Panaccione, D.G., Ryan, K.L., Schardl, C.L., Florea, S., 2012. Analysis and modification of ergot alkaloid profiles in fungi. Methods Enzymol. 515, 267-290.
Park, S.H., Moon, K., Bang, H.S., Kim, S.H., Kim, D.G., Oh, K.B., Shin, J., Oh, D.C., 2012. Tripartilactam, a cyclobutane-bearing tricyclic lactam from a Streptomyces sp. in a dung beetle's brood ball. Org. Lett. 14, 1258-1261.
Penn, J., Biddle, J.R., Mantle, P.G., Bilton, J.N., Sheppard. R.N., 1992. Pennigritrem, a naturally-occurring penitrem A analog with novel cydization in the diterpenoid moiety. J. Chem. Soc., Perkin Trans. 11, 23-26.
Reddy, K.R.N., Salleh, B., Saad, B., Abbas, H.K., Abel, C.A., Shier, W.T., 2010. An overview of mycotoxin contamination in foods and its implications for human health. Toxin Rev. 29, 3-26.
Pedras, M.S.C., Zheng, Q.-A., Schatte, G., Adio, A.M., 2009. Photochemical dimerization of wasalexins in UV-irradiated Thellungiella halophila and in vitro generates unique cruciferous phytoalexins. Phytochemistry 70, 2010-2016.
Peng, X., Knapp, B.I., Bidlack, J.M., Neumeyer, J.L., 2007. High-affinity carbamate analogues of morphinan at opioid receptors. Bioorg. Med. Chem. Lett. 17, 1508-1511.
Pettit, G.R., Pauli, K.D., Herald, C.L., Herald, D.L., Riden, J.R., 1983. Antineoplastic agents. 90. The structure of the benzene-maleimide photosynthetic product (mitindomide). Can. J. Chem. 61, 2291-2294.
Pitt, J.L., 1979. Penicillium crustosum and P. simplicissimum, the correct names for two common species producing tremorgenic mycotoxins. Mycologia 71, 1166-1177.
Rasmussen, S., Parsons, A.J., Jones, C.S., 2012. Metabolomics of forage plants: a review. Ann. Bot. (Oxford, UK) 110, 1281-1290.
Rezanka, T., Rozentsvet, O.A., Dembitsky, V.M., 1999. Characterization of the hydroxy fatty acid content of Basidiomycotina. Folia Microbiolgia 44, 635-641.
Roberts, E., Lindow, S., 2014. Loline alkaloid production by fungal endophytes of Fescue species select for particular epiphytic bacterial microfiora. ISME J. 8, 359-368.
Rundberget, T., Wilkins, A.L., 2002. Thomitrems A and E, two indole-alkaloid isoprenoids from Penicillium crustosum Thom. Phytochemistry 61, 979-985.
Sabater-Vilar, M., Nijmeijer, S., Fink-Gremmels, J., 2003. Genotoxicity assessment of five tremorgenic mycotoxins (fumitremorgen B, paxilline, penitrem A, verruculogen, and verrucosidin) produced by molds isolated from fermented meats. J. Food Prot. 66, 2123-2129.
Sallam, A.A., Houssen, W.E., Gissendanner, C.R., Orabi, K.Y., Foudah, A.I., El-Sayed, K.A., 2013. Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors. Med. Chem. Commun. 10, 1360-1369.
Sancholle, M., Losel, D.M., 1995. Lipids in fungal biotechnology. In: Kuck (Ed.), The Mycota II Genetics and Biotechnology. Springer, Berlin Heidelberg, New York, pp. 339-367.
Sim, K.-M., Teh, H.-M., 2011. A new carbazole alkaloid from the leaves of Malayan Murraya koenigii. J. Asian Nat. Prod. Res. 13, 972-975.
Shoeb, M., Celik, S., Jaspars, M., Kumarasamy, Y., MacManus, S.M., Nahar, L., Thoo-Lin, P.K., Sarker, S.D., 2005. Isolation, structure elucidation and bioactivity of schischkiniin, a unique indole alkaloid from the seeds of Centaurea schischkinii. Tetrahedron 61, 9001-9006.
Sergeiko, A., Poroikov, V.V., Hanus, L.O., Dembitsky, V.M., 2008. Cyclobutane-containing alkaloids: origin, synthesis, and biological activity. Open Med. Chem. J. 2,26-37.
Selala, M.I., Daelemans, F., Schepens, P.J., 1989. Fungal tremorgens: the mechanism of action of single nitrogen containing toxins-a hypothesis. Drug Chem. Toxicol. 12, 215-237.
Semonsky, M., Zikan, V., 1959. Cycioalkylamides of D-lysergic acid. GB Patent: 816273 19590708, CA 54, 7424.
Stork, G., 1960. Morphine alkaloids. In: Manske, R.H.F. (Ed.), Alkaloids-Chemistry And Physiology, vol. 6. Academic, London, pp. 219-245.
Stratmann, K., Moore, R.E., Bonjouklian, R., Deeter, J.B., Patterson, G.M.L., Shaffer, S., Smith, C.D., Smitka, T.A., 1994. Welwitindolinones, unusual alkaloids from the blue-green algae Hapalosiphon welwitschii and Westiella intricata. Relationship to Fischer indoles and hapalinodoles. J. Am. Chem. Soc. 116, 9935-9942.
Subehan, U.T., Kadota, S., Tezuka, Y., 2006. Alkamides from Piper nigrum L and their inhibitory activity against human liver microsomal cytochrome P450 2D6 (CYP2D6). Planta Med. 72, 527-532.
Tiwaryl, A.K., Puschner, B., Poppenda, R.H., 2009. Using Roquefortine Cas a Biomarker for Penitrem A Intoxication. J. Vet. Diagn. Invest. 21, 237-239.
Tsukamoto, S., Cha, B.-C., Ohta, T., 2002a. Dipiperamides A, B, and C: bisalkaloids from the white pepper Piper nigrum inhibiting CYP3A4 activity. Tetrahedron 58, 1667-1671.
Tsukamoto, S., Tomise, K., Miyakawa, K., Cha, B.-C., Abe, T., Hamada, T., Hirota, H., Ohta, T., 2002b. CYP3A4 inhibitory activity of new bisalkaloids, dipiperamides D and E, and cognates from white pepper. Bioorg. Med. Chem. 10, 2981-2985.
Villalonga, P., Fernandez de Mattos, S., Ramis, G.. Obrador-Hevia, A., Sampedro, A., Rotger, C., Costa, A., 2012. Cyclosquaramides as kinase inhibitors with anticancer activity. ChemMedChem 7, 1472-1480.
Wallwey, C., Li, S.-M., 2011. Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat. Prod. Rep. 28, 496-510.
Wang, L.-W., Zhang, Y.-L., Lin, F.-C., 2011. Natural products with antitumor activity from endophytic fungi. Mini-Rev. Med. Chem. 11, 1056-1074.
Watanabe, K., Kubota. T., Shinzato, T., Ito, J., Mikami, Y., Kobayashi, J., Sarusubine, A., 2007. A new dimeric Lythraceae alkaloid from Lagerstroemia subcostata. Tetrahedron Lett. 48, 7502-7504.
Wawrzyn, G.T., Bloch, S.E., Schmidt-Dannert, C., 2012. Discovery and characterization of terpenoid biosynthetic pathways of fungi. Methods Enzymol. 515, 83-105.
Wells, J.M., Cole, R.J., 1977. Production of penitrem A and of an unidentified toxin by Penicillium lanoso-coeruleum isolated from weevil-damaged pecans. Phytopathology 67, 779-782.
Wu, T.-S., Wang, M.-L., Wu, P.-L., Jong, T.-T., 1995. Two carbazole alkaloids from leaves of Murraya euchrestifolia. Phytochemistry 40, 1817-1819.
Wu, T.-S., Chan, Y.-Y., Liou, M.-J., Lin, F.-W., Shi, L.-S., Chen, K.-T., 1998. Platelet aggregation inhibitor from Murraya euchrestifolia. Phytother. Res. 12, S80-S82.
Xu, R., Rong, F., Lai, H., Xie, F., 2013. 2-Substituted oleanolic acid derivative, method preparing for same, and application thereof. Chinese Patent: Hangzhou Bensheng Pharmaceutical Co. Ltd. WO/2013/079018.
Yamaguchi, T., Nozawa, K., Hosoe, T., Nakajima, S., Kawai, K., 1993. Indoloditerpenes related to tremorgenic mycotoxins, penitrems, from Penicillium crustosum. Phytochemistry 32, 1177-1181.
Yang, Y., Sun, D., Yang, C, Luo, M., Zhang, L, Sun, L., Zhang, W., Gou, Z., Wang, J., Hu, C., 2011. New pyrazine isoquinoline derivative with antiparasitic activity and its preparation. Chinese Patent: CN 2011-10154047, 14 pp., Faming Zhuanli Shenqing.
Yoshikawa, M., 2013. Carbazole alkaloids and skin-lightening compositions. Japanese Patent: JP 2013014530 A, 41 pp. Jpn. Kokai Tokkyo Koho.
Yuan, X., Lin, L., 2013. A compound, its manufacture method and application. Chinese Patent: CN 102898322 A, 20 pp.. Faming Zhuanli Shenqing.
Zhang, W., Shen, Y., Su, J., Liu, R., Li, H., Xu, X., Lu, T., 2008. Preparation and application of Incarvillea delavayi delavatine A as antineoplastic agent. Chinese Patent: CN 2008-10034539.
Zhang, W., Miao, Z., Zhu, L., Sheng, C., Yao, J., Dong, G., Wang, S., Liu, Y., Chen, H., 2013. F-substituted E-ring camptothecin analog useful in treatment of cancer and its preparation. Chinese Patent: CN 103288842 A, 16 pp., Faming Zhuanli Shenqing.
Zhang, W., Yu, Y., Zhang, S., Dai, X., Cao, X., Su, J., Li, J., Shen, Y., Shan, L., 2011. Drug preparation with alkaloid in pineapple flower for the treatment of autoimmune disease and graft rejection. Chinese Patent: CN 102008468 A, 9 pp.. Faming Zhuanli Shenqing.
Zhao, B.-X., Wang, Y., Li, C., Wang, G.-C., Huang, X.-J., Fan, C.-L., Li, Q.-M., Zhu, H.-J., Chen, W.-M., Ye, W.-C., 2013. Flueggedine. A novel axisymmetric indolizidine alkaloid dimer from Flueggea virosa. Tetrahedron Lett. 54, 4708-4711.
Received 21 May 2014
Received in revised form 3 June 2014
Accepted 2 July 2014
Valery M. Dembitsky *
Institute of Drug Discovery, Har-Hotsvim, P.O. Box 45289, Jerusalem 91451, Israel
* Tel.: +972 52 687 7444; fax: +972 52 687 7444.
E-mail address: firstname.lastname@example.org
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|Author:||Dembitsky, Valery M.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Oct 15, 2014|
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