Highly efficient production of functional substances from synthetic compounds and secondary metabolites by mammal and microbial biotransformation

We report herein a highly efficient production of several functional substances from synthetic aromatic compounds and plant secondary metabolites such as chalcones, mono- and sesquiterpenoids by microorganisms and rabbit. The microbial biotransformation was accomplished by four black fungi, Aspergillus niger, A. sojae, A. usami and A. cellulosae in rotatory growth cultures (120 rpm, Czapek-peptone medium at 30 °C for 3-10 days). In the case of biotransformation by mammals, each terpenoid and aromatic compound was orally administered to rabbits, and their collected urines were enzymatically treated to give each metabolite. Aspergillus niger cultured for 10 days in the presence of chalcone (1) (10 g / 200 mL medium) gave dihydrochalcone (2) in 95% isolated yield. The other Aspergillus strains converted chalcone to dihydrochalcone quantitatively. The substrate amount could be scaled up to 25 g / 200 mL medium. 4-Hydroxy- (3) and 4’-hydroxychalcones (4) incubated with the same Aspergillus afforded 4-hydroxydihydro- (5) and 3,4-dihydroxydihydrochalcones (6), and 4’-hydroxydihydro- (7) and 3’,4’-dihydroxydihydrochalcone (8), in good yield, respectively. Thus, Aspergillus strains introduced a hydroxy group directly onto the already substituted benzene ring and very easily reduced the α,β-unsaturated double bond. 1,1-Diphenylmethane (9), 1,3-diphenylacetone (10), 1,3-diphenylpropane (11), bibenzyl (12), (E and Z)-stilbenes (13, 14) and phenylcyclohexane (15), grifolin (16), 6-shogaol (17), 6-gingerol (18), capsaicin (19), and dihydrocapsaicin (20) were also treated by Aspergillus strains to give the direct benzene ring hydroxylated products and ω-hydroxylation products, as well as epoxides, oxo- and hydroxyketo derivatives. (-)-α-Pinene (21) and β-caryophyllene (22) were converted by rabbits to trans-verbenol (23), an insect larvae pheromone, and 14-hydroxy-β-caryophyllene oxide (24), a constituent of mushrooms, in very high yield. Nootkatone (25), contributor to the grapefruit aroma, was obtained almost quantitatively from valencene (26), by a Mucor strain biotransformation. The metabolites of sesquiterpenoids, (+)- and (-)-cyclocolorenones (27, 28), (+)- and (-)-cuparenes (29, 30) and bisbibenzyls from liverworts, as well as the direct biotransformation of the corresponding essential oils are also reported. The presented methods are a cheap and hazard reduced eco-friendly alternative to classical organic synthesis while still reaching the high yields of the metabolites

Фитохемикалије из бриофита: структура и биолошке активности

Little attention has been paid to the bryophytes as sources for human diet despite the presence of 23,000 species in the world. Some mosses contain Vitamin B1, tocopherols, prostaglandin-like highly unsaturated fatty acids and phenolic compounds. On the other hand, liverworts contain enantiomeric mono-, sesqui- and diterpenoids similar to those found in vascular plants. Additionally, they possess bibenzyls, bis-bibenzyls and polyketides, many of them showing various bioactivity, such as antimicrobial, antiviral, anti-inf­lam­matory, cytotoxicity against cancer cell lines, muscle relaxing, antioxidant and others. In this paper, the structures of phytochemicals from bryophytes and their biological activities are discussed.На бриофите као изворе за људску исхрану се обраћа мала пажња иако их има преко 23000 врста. Неке маховине садрже витамин Б1, токофероле, простагландинима слична једињења, вишеструко незасићене масне киселине и фенолна једињења. С друге стране, јетрењаче садрже моно-, сескви- и дитерпеноиде енентиомерне онима пронађеним у васкуларним биљкама. Поред њих, оне садрже и бибензиле, бис-бибензиле и поликетиде, од којих многи показују антимикробну, антивирусну, анти-инфламаторну, цитотоксичну на ћелије рака, миорекласантску, антиоксидативну и друге. У овом раду су продискутоване структуре и биолошка активност фитохемикалија из јетрењача.Part of the theme issue honoring Professor Emeritus Slobodan Milosavljevićs 80th birthday

Bryophyte volatiles: chemical diversity, chemotaxonomic significance and biological activity

Bryophytes are spore-forming plants, which occupy a position in the plant kingdom in between algae and pteridophytes. These are divided into three classes, mosses, liverworts, and hornworts [1]. Phytochemistry of bryophytes has been neglected for a long time because they are morphologically very small and it is difficult to collect a sufficient amount of plant material for study. The second problem is proper identification of plant material, which is especially challenging, because of their small size, their often microscopic or chemical distinguishing features [1-3]. Among the bryophytes, the chemical constituents of the Marchantiophyta and their biological activity have been studied in the most detail. Liverworts are characterized by the presence of oil bodies, unique organelles in which terpenoids and aromatic compounds are accumulated. Many of these compounds have unprecedented structures, and some, including the pinguisane-type sesquiterpenoids and sacculatane-type diterpenoids, have not been found in any other plants, fungi or marine organisms. A characteristic structural phenomenon of liverwort constituents is that most sesqui- and diterpenoids are enantiomers of those found in higher plants [1-3]. Constituents occurring in liverworts exhibit interesting biological activities, such as antibacterial, antifungal, cytotoxic, insect repellent, as well as some enzyme inhibitory and apoptosis-inducing activities [1,4]. The second very important direction of research concerning liverwort chemistry is the chromatographic fingerprinting of the volatiles present in these spore-forming plants, which can be used for identification and authentication of herbal samples, as well as for chemotaxonomic studies [2,3]. This lecture will cover the structures and biological activity of volatiles present in bryophytes, as well as chemotaxonomic studies. This lecture will also look at where bryophyte pharmacognosy may be directed in the future

Management of Diabetic Bacterial Foot Infections with Organic Extracts of Liverwort Marchantia debilis from Cameroon

Diabetic bacterial foot infections (DBFIs) are limb-threatening complications in patients with diabetes mellitus, accounting for 50% of diabetes related lower limb amputations in developing countries, representing approximately 20 percent of all diabetes-related hospital admissions with significant healthcare-related costs involved. The widespread problem of bacterial resistance to most commonly used antibiotics places a huge economic burden on the healthcare system, with both increased morbidity and mortality among diabetic patients with foot infections. In this study, the antibacterial activity of organic extracts of the fresh liverwort Marchantia debilis from the North West Region of Cameroon is reported. An exit pool system, where patients presenting with DBFIs consented to be involved in the use of phytomedicines, after long term treatment of ulcers with antibiotics and not yielding significant long term benefit, presented themselves at the Phytobiotechnology Research clinic (PRF). Continuous culture of swabs from foot and toe wounds from 30 infected patients on nutrient agar and MacConkey agars in triplicate as well as Gram stain microscopy, revealed the presence of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis and Bacillus species. Light petroleum and methanol extracts of the whole bryophyte plants at 100% concentration were tested. In vitro inhibition of the tested bacterial isolates from the diabetic foot ulcers by M debilis was observed only with the light petroleum extract. No inhibition by the extracts was observed for the Pseudomonas aeruginosa isolate. The light petroleum extract of M debilis was formulated into a petroleum oil based cream named BryoCream (TM). This was administered to 20 of the patients with 90% cure rate in a three week time period. The main nonpolar components were determined by GCMS as lepidozene and beta-barbatene, and by NMR. as stigmasterol and beta-sitosterol. In conclusion, nonpolar extracts from bryophytes from Cameroon could, potentially, be used to treat diabetic bacterial foot infections

Bis-bibenzyls from the Cameroon Liverwort Marchantia debilis

Liverworts are rich sources of terpenoids and aromatic compounds among which bis-bibenzyls are well known for their wide spectrum of biological activities. This is the first report of chemical analysis of the African liverwort Marchantia debilis Goebel. From the methanol extract marchantinquinone-l'-methyl ether was newly isolated together with three known bis-bibenzyls, marchantin C, marchantinquinone and perrottetin E. The presence of bis-bibenzyls with a quinone moiety is noted for the first time in the Marchantia genus

Supplementary data for article: Novakovic, M.; Bukvicki, D.; Andjelkovic, B.; Ilic-Tomic, T.; Veljic, M.; Tesevic, V.; Asakawa, Y. Cytotoxic Activity of Riccardin and Perrottetin Derivatives from the Liverwort Lunularia Cruciata. Journal of Natural Products 2019, 82 (4), 694–701. https://doi.org/10.1021/acs.jnatprod.8b00390

Supporting information for: [https://doi.org/10.1021/acs.jnatprod.8b00390]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3096

Kaempulchraols PT: diterpenoids from the Kaempferia pulchra rhizomes collected in Myanmar

The isolation of the oily fraction obtained from the CHCl3-soluble extract of the rhizomes of Kaempferia pulchra (Zingiberaceae) afforded five new isopimarane diterpenoids, kaempulchraols P−T (1−5), along with two known analogues. The structures were elucidated using spectroscopic techniques, including 2D NMR spectroscopy

Kaempulchraols IO: new isopimarane diterpenoids from Kaempferia pulchra rhizomes collected in Myanmar and their antiproliferative activity

The isolation of the CHCl3 soluble extract of Kaempferia pulchra rhizomes afforded seven new isopimarane diterpenoids, kaempulchraols I−O, together with one known analogue. The structures of these compounds were elucidated using 1D and 2D NMR and X-ray diffraction analyses. The antiproliferative activity of the isolated compounds was evaluated against a panel of five human cancer cell lines. Kaempulchraol L exhibited weak antiproliferative activity against PANC-1 and PSN-1 cells with IC50 values of 39.9 and 22.6 μM, respectively

Chemo- and biocatalytic esterification of marchantin A and cytotoxic activity of ester derivatives

Chemical and biocatalytic synthesis of seven previously undescribed marchantin A ester derivatives has been presented. Chemical synthesis afforded three peresterified bisbibenzyl products (TE1-TE3), while enzymatic method, using lipase, produced regioselective monoester derivatives (ME1-ME4). The antiproliferative activities of all prepared derivatives of marchantin A were tested on MRC-5 healthy human lung fibroblast, A549 human lung cancer, and MDA-MB-231 human breast cancer cell lines. All tested esters were less cytotoxic in comparison to marchantin A, but they also exhibited lower cytotoxicity against healthy cells. Monoesters displayed higher cytotoxic activities than the corresponding peresterified products, presumably due to the presence of free catechol group. Monohexanoyl ester ME3 displayed the same IC50 like marchantin A against MDA-MB-231 cells, but the selectivity was higher. In this way, regioselective enzymatic monoesterification enhanced selectivity of marchantin A. ME3 was also the most active among all derivatives against lung cancer cells A549 with the slightly lower activity and selectivity in comparison to marchantin A.Related to published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1367]This is the peer reviewed version of the paper: Novaković, M., Simić, S., Koracak, L., Zlatović, M., Ilić-Tomić, T., Asakawa, Y., Nikodinović-Runić, J., & Opsenica, I. (2020). Chemo- and biocatalytic esterification of marchantin A and cytotoxic activity of ester derivatives. Fitoterapia, 142.[ https://doi.org/10.1016/j.fitote.2020.104520

Management of Diabetic Bacterial Foot Infections with Organic Extracts of Liverwort Marchantia debilis from Cameroon

Diabetic bacterial foot infections (DBFIs) are limb-threatening complications in patients with diabetes mellitus, accounting for 50% of diabetes related lower limb amputations in developing countries, representing approximately 20 percent of all diabetes-related hospital admissions with significant healthcare-related costs involved. The widespread problem of bacterial resistance to most commonly used antibiotics places a huge economic burden on the healthcare system, with both increased morbidity and mortality among diabetic patients with foot infections. In this study, the antibacterial activity of organic extracts of the fresh liverwort Marchantia debilis from the North West Region of Cameroon is reported. An exit pool system, where patients presenting with DBFIs consented to be involved in the use of phytomedicines, after long term treatment of ulcers with antibiotics and not yielding significant long term benefit, presented themselves at the Phytobiotechnology Research clinic (PRF). Continuous culture of swabs from foot and toe wounds from 30 infected patients on nutrient agar and MacConkey agars in triplicate as well as Gram stain microscopy, revealed the presence of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis and Bacillus species. Light petroleum and methanol extracts of the whole bryophyte plants at 100% concentration were tested. In vitro inhibition of the tested bacterial isolates from the diabetic foot ulcers by M debilis was observed only with the light petroleum extract. No inhibition by the extracts was observed for the Pseudomonas aeruginosa isolate. The light petroleum extract of M debilis was formulated into a petroleum oil based cream named BryoCream (TM). This was administered to 20 of the patients with 90% cure rate in a three week time period. The main nonpolar components were determined by GCMS as lepidozene and beta-barbatene, and by NMR. as stigmasterol and beta-sitosterol. In conclusion, nonpolar extracts from bryophytes from Cameroon could, potentially, be used to treat diabetic bacterial foot infections