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6-protoilludene and 7-protoilludene
editIntroduction
edit 6-protoilludene | |
 7-protoilludene |
 Armillaria gallica |
In the chemical industry, natural products are still attracting more and more attention, as they lead an important role in human society with their frequent use in health care and other significant industries. Among of millions of natural compounds, protoilludane is one of them. Protoilludanes are a class of sesquiterpenes characterized by their unique structure, namely 5,6,4-rings. They were typically derived from fungal sources, which is the main source with responsible for over 96% of all the isolated products, moreover they are known for their ecological roles in fungal defense and potential applications in pharmacology and agriculture. 6- and 7-protoilludene have attracted scientific interest due to their antimicrobial, antifungal and cytotoxic properties. Studies have shown that these sesquiterpenes can inhibit growth in various fungal and antibacterial pathogens, additionally their cytotoxic effects against several cancer cell lines highlight their potential for anticancer drug development. The exploration of 6- and 7-protoilludene continued to expand our understanding of the synthesis process, molecular activities, mechanistic analysis, also chemical diversity and biological significance of protoilludane sesquiterpenes. The most important total syntheses for these molecules are Takeshita´s synthesis for 7- Protoilludene.[1] and Furukawa´s synthesis for 6-Protoilludene[2].
Structure
editProtoilludanes are sesquiterpenes with a 5/6/4 framework. Sesquiterpenes belong to the terpenes, which are overall the largest and most diverse group among the natural substance classes with almost 30.000 known different structures[3], where protoilludane sesquiterpenes have 180 derivatives[4]. 2 In more precise terms, protoilludane is a member of the tricyclic sesquiterpenes class, which have the formula C15H24 and is also known as C15 sesquiterpenes.
6- and 7-protoilludenes are two constitutional isomers studied in this paper. Both have the same number and type of atoms with the same structure, except for the existing double bound between different carbon atoms. In 6-protoilludene, the double bond is found between the sixth and seventh carbons (C6-C7), and in the 7-protoilludene, it is located between the seventh and eighth carbons (C7-C8)[4]. The respective numbers in their names are due to the position of said double bonds. The number of the lowest numbered carbon is added to their name, so that they can differ. This small difference is something that has a natural impact in many aspects, from how these molecules are synthesized to how they are used.
Biosynthesis
edit Biosynthesis pathway of 6-protoilludene and 7-protoilludene |
Sesquiterpenes, specifically protoilludane related sesquiterpenes, are found in Basidiomycota fungi, which has 30.000 known species and is a subdivision of the Dicarya. A The species called Armillaria gallica is mostly used in the synthesis of protoilludane-derivates in various studies[4]. The purpose of the studies about protoilludenes directly was to understand the following synthesis pathway of related molecules. The synthesis of varioussesquiterpenes starts with Farnesyl pyrophosphate (C15H28O7P2)[5]. Most of the terpenes and terpenoids are thought to arise through farnesyl pyrophosphate, which makes it a very important intermediate. Another key intermediate results from the enzymatic cyclization of farnesyl pyrophosphate[6]. The enzyme named alpha-humulene-synthase catalyzes the reaction, which has humulene and diphosphate as products[7]. In addition to that, scientists synthetically produced an enzyme system from sage[8], which has the same purpose with alpha-humulene-synthase. After humulene is produced the synthesis continues till the stable molecules 6- and 7-protoilludene are produced.
Interestingly, by the biosynthesis of a protoilludane-derivate, again, protoilludene is formed from farnesyl pyrophosphate, but since there is another biosynthetic enzyme called 6- protoilludene synthase (Mld5) used in this process, only 6-protoilludene is formed although there was intact 7-protoilludene in the molecule[4]. 7-protoilludene is there produced through an enzyme called Mld7[4]. This enzyme is catalyzing oxidation triggered double bound isomerization, which is the way here to change 6-protoilludene rest to 7- protoilludene rest.
Biological Effects
editAccording to a lot of research, it has shown that the protoilludane class of natural products contain a characteristic annulated of 5/6/4-ring structure, in which this structure possesses a diverse range of bioactivities, such as antimicrobial, antifungal and cytotoxic properties. A total of 180 protoilludane natural products have been isolated from fungi (an abundant source of drug discovery), plants and other marine sources. Even though biological effects of 6-protoilludene and 7-protoilludene may not be well-documented and quite scarce, it is reasonable to predict that they could exhibit similar activities to other protoilludane sesquiterpenes, that is why we will be focusing on other products that are closely related to 6- and 7-protoilludene instead.
Antifungal
editStarting with 5-epi-Armillol, one of the oxidation products that has a similar core structure as 6-protoilludene and has been isolated from Laurilia sulcate. This genus belongs to the phylum Basidiomycota, which is one of the largest phyla of higher fungi. 5-epi-Armillol has been reported to exhibit antifungal activity against Cladosporium cucumerinum[9]. This fungus is known for causing scabs and disease in cucumbers and other cucurbit plants. The experiment was performed by using bioautography, in which pure metabolites were loaded onto TLC plates and were then sprayed with a conidial suspension of the tested fungi. The result that indicated inhibition of fungal growth was shown as white spots on a gray-black background on TLC plates, which 5-epi-Armillol has demonstrated antifungal activity against Cladosporium cucumerinum at its concentration as low as 50 µg[9].
Antimicrobial
editAnother related molecule of 6-protoilludene is Armillyl orsenllinate, which has been isolated from Armillaria mellea[10][11]. The test was performed to prove the antimicrobial effect by using overlay bioautography and agar dilution. By overlay Bioautography, the compounds were deposited on silica gel plates, which were developed with CHCL3- MeOH and 8 inoculated with microorganisms[11]. Activity was visualized by spraying with methythiazoyl tetrazolium chloride. The result, as the presence of clear inhibition zones on the TLC plate indicated that Armillyl orsenlinate exhibit significant antimicrobial effect against Bacillus subtilis at the lowest concentration at 0.5 µg per disc[11]. Bacillus subtilis is a bacterium that is commonly found in soil and the gastrointestinal tract of humans, even though Bacillus subtilis is considered non-pathogenic and is classified as Biosafety level 1, it can cause opportunistic infections in immunocompromised individuals, such as those with weakened immune systems[12]
Cytotoxic
editMelleolides are one of the 2,3-protoilludene, that have been isolated from Armillaria mellea, which means they contain a 7-protoilludene in the molecules. There are many types and structures of melleolides, most of them have been proved to exhibit cytotoxic activities against several human cancer cell lines.[11][13][14][15]. Melleolides F, J and N are some examples. The Cytotoxicity was measured by determining the CC50, GI50 and IC50 (Inhibitory concentration 50). Melleolides F and J were proved to contain cytotoxic against MFC-7 (breast adenocarcinomacell) at IC50 8.3 µM and H460 (lung cancer) at 5.1 µM, where melleolide J has it at IC50 4.4 µM against MCF-7 and 5.7 µM against H460. For melleolide N, other than two cancer cell that have been mentioned before, it also exibit cytotoxic against CEM (leukemia) with 5.4 µM and against HT29 (colon cancer) at 7.1 µM[11][13][14][15]
Other biological Effects
editThere are still a lot of other effects other than the three main effects that have already been mentioned, for example, as a plant growth promoter.[16]. Repraesentin A is one of the molecules that has been proofed through an experiment to contain this effect, specifically to a lettuce. Repraesentin A is closely related to 6-protoilludene and was isolated from the mushroom Lactarius reprasentaneus[16]. The experiment was carried out by starting with lettuce seeds that were germinated on wet filter paper for 30 hours at the 23°C, which then were placed on filter paper in Petri dishes, to which a methanol solution of the test compound was added. Methanol was removed under reduced pressure, and Hoagland-Aron medium was added. The elongation of the radicle was measured after seedlings were grown in an illuminated chamber for 72 hours. Showed promotion activity of Repraesentin A was of 136% at a concentration of 67 ppm and maximum of 143% at 33 ppm[16]
Application and Uses
edit |
Even though, there is no clearly stated document that given the evidence that 6-, 7- protoilludene have been used in medical, pharmaceutical or other branches industries, due to other alternative from other molecules or substances, that possibly have a stronger effect, but according to biological effects that they contain, they certainly have the potential application to be developed and use in real life. For example, from Repraesentin A and 5- epi-Arrmillol, which respectively can act as a plant promoter in lettuce and has an antifungal that can occur in crops, these potentials can lead to a more productive process in agriculture industries. Moreover, cytotoxic activity will draw more attention as people nowadays are focusing more about cancer cells than ever.
References
edit- ^ Takeshita, Hitoshi; Kouno, Isao; Iino, Mitsuaki; Iwabuchi, Hisakatsu; Nomura, Danji (1980). "Synthetic Photochemistry. XIX. The Synthesis of Protoilludanes by Photocycloadditions, Protoillud-7-ene and Several Oxygenated Derivatives". Bulletin of the Chemical Society of Japan. 53 (12): 3641–3647. doi:10.1246/bcsj.53.3641. Retrieved 2024-07-17.
- ^ Nozoe, Shigeo; Kobayashi, Hisayoshi; Urano, Shiro; Furukawa, Jun (January 1977). "Isolation of Δ6-protoilludene and the related alcohols". Tetrahedron Letters. 18 (16): 1381–1384. doi:10.1016/S0040-4039(01)93049-7.
- ^ Dingermann, Theo (2006-12-14). "Naturstoffchemie – Mikrobielle, pflanzliche und tierische Naturstoffe. Von P. Nuhn, unter Mitarbeit von L. Wessjohann". Pharmazie in unserer Zeit. 36 (1): 71. doi:10.1002/pauz.200690166. ISSN 0048-3664.
- ^ a b c d e Fukaya, Mitsunori; Nagamine, Shota; Ozaki, Taro; Liu, Yaping; Ozeki, Miina; Matsuyama, Taro; Miyamoto, Kazunori; Kawagishi, Hirokazu; Uchiyama, Masanobu; Oikawa, Hideaki; Minami, Atsushi (2023-10-26). "Total Biosynthesis of Melleolides from Basidiomycota Fungi: Mechanistic Analysis of the Multifunctional GMC Oxidase Mld7". Angewandte Chemie International Edition. 62 (44): e202308881. doi:10.1002/anie.202308881. ISSN 1433-7851. PMID 37534412.
- ^ Abraham, Wolf-Rainer (2001). "Bioactive Sesquiterpenes Produced by Fungi are they Useful for Humans as Well". Current Medicinal Chemistry. 8 (6): 583–606. doi:10.2174/0929867013373147. PMID 11281843.
- ^ Nozoe, Shigeo; Kobayashi, Hisayoshi; Urano, Shiro; Furukawa, Jun (1977-01-01). "Isolation of Δ6-protoilludene and the related alcohols". Tetrahedron Letters. 18 (16): 1381–1384. doi:10.1016/S0040-4039(01)93049-7. ISSN 0040-4039.
- ^ Yu, Fengnian; Okamto, Sho; Nakasone, Kaoru; Adachi, Kyoko; Matsuda, Satoru; Harada, Hisashi; Misawa, Norihiko; Utsumi, Ryutaro (2008-02-14). "Molecular cloning and functional characterization of α-humulene synthase, a possible key enzyme of zerumbone biosynthesis in shampoo ginger (Zingiber zerumbet Smith)". Planta. 227 (6): 1291–1299. Bibcode:2008Plant.227.1291Y. doi:10.1007/s00425-008-0700-x. ISSN 0032-0935. PMID 18273640.
- ^ Croteau, Rodney; Gundy, Afaf (1984-09-01). "Cyclization of farnesyl pyrophosphate to the sesquiterpene olefins humulene and caryophyllene by an enzyme system from sage (Salvia officinalis)". Archives of Biochemistry and Biophysics. 233 (2): 838–841. doi:10.1016/0003-9861(84)90513-7. ISSN 0003-9861. PMID 6486812.
- ^ a b Arnone, Alberto; Nasini, Gianluca; Assante, Gemma; Eijk, Gijsbertus W. Van (1992-06-01). "Three sesquiterpenes produced by the fungus Laurilia sulcata". Phytochemistry. 31 (6): 2047–2050. Bibcode:1992PChem..31.2047A. doi:10.1016/0031-9422(92)80360-Q. ISSN 0031-9422.
- ^ Cremin, Peadar; Guiry, Patrick J.; Wolfender, Jean-Luc; Hostettmann, Kurt; Donnelly, Dervilla M. X. (2000-01-01). "A liquid chromatography–thermospray ionisation–mass spectrometry guided isolation of a new sesquiterpene aryl ester from Armillaria novae-zelandiae". Journal of the Chemical Society, Perkin Transactions 1 (15): 2325–2329. doi:10.1039/B001980L. ISSN 1364-5463.
- ^ a b c d e Donnelly, Dervilla; Sanada, Shuichi; O'Reilly, Joseph; Polonky, Judith; Prangé, Thierry; Pascard, Claudine (1982-01-01). "Isolation and structure (X-ray analysis) of the orsellinate of armillol, a new antibacterial metabolite from Armillaria mellea". Journal of the Chemical Society, Chemical Communications (2): 135–137. doi:10.1039/C39820000135. ISSN 0022-4936.
- ^ Iqbal, Sajid; Begum, Farida; Rabaan, Ali A.; Aljeldah, Mohammed; Al Shammari, Basim R.; Alawfi, Abdulsalam; Alshengeti, Amer; Sulaiman, Tarek; Khan, Alam (January 2023). "Classification and Multifaceted Potential of Secondary Metabolites Produced by Bacillus subtilis Group: A Comprehensive Review". Molecules. 28 (3): 927. doi:10.3390/molecules28030927. ISSN 1420-3049. PMC 9919246. PMID 36770594.
- ^ a b Bohnert, Markus; Nützmann, Hans-Wilhelm; Schroeckh, Volker; Horn, Fabian; Dahse, Hans-Martin; Brakhage, Axel A.; Hoffmeister, Dirk (2014-09-01). "Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure–activity relationships". Phytochemistry. 105: 101–108. Bibcode:2014PChem.105..101B. doi:10.1016/j.phytochem.2014.05.009. ISSN 0031-9422. PMID 24906293.
- ^ a b Chen, Chien-Chih; Kuo, Yueh-Hsiung; Cheng, Jing-Jy; Sung, Ping-Jyun; Ni, Ching-Li; Chen, Chin-Chu; Shen, Chien-Chang (June 2015). "Three New Sesquiterpene Aryl Esters from the Mycelium of Armillaria mellea". Molecules. 20 (6): 9994–10003. doi:10.3390/molecules20069994. ISSN 1420-3049. PMC 6272629. PMID 26035099.
- ^ a b Li, Zhijin; Wang, Yunchao; Jiang, Bin; Li, Wenliang; Zheng, Lihua; Yang, Xiaoguang; Bao, Yongli; Sun, Luguo; Huang, Yanxin; Li, Yuxin (2016-05-26). "Structure, cytotoxic activity and mechanism of protoilludane sesquiterpene aryl esters from the mycelium of Armillaria mellea". Journal of Ethnopharmacology. 184: 119–127. doi:10.1016/j.jep.2016.02.044. ISSN 0378-8741. PMID 26952552.
- ^ a b c HIROTA, Mitsuru; SHIMIZU, Yuji; KAMO, Tsunashi; MAKABE, Hidefumi; SHIBATA, Hisao (January 2003). "New Plant Growth Promoters, Repraesentins A, B and C, fromLactarius repraesentaneus". Bioscience, Biotechnology, and Biochemistry. 67 (7): 1597–1600. doi:10.1271/bbb.67.1597. ISSN 0916-8451. PMID 12913310.