Totarol

Last updated
Totarol [1]
Totarol.svg
Names
IUPAC name
14-(Propan-2-yl)podocarpa-8,11,13-trien-13-ol
Systematic IUPAC name
(4bS,8aS)-4b,8,8-Trimethyl-1-(propan-2-yl)-4b,5,6,7,8,8a,9,10-octahydrophenanthren-2-ol
Other names
(4bS)-trans-8,8-Trimethyl-4b,5,6,7,8,8a,9,10-octahydro-1-isopropylphenanthren-2-ol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.151.658 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 622-932-2
PubChem CID
UNII
  • InChI=1S/C20H30O/c1-13(2)18-14-7-10-17-19(3,4)11-6-12-20(17,5)15(14)8-9-16(18)21/h8-9,13,17,21H,6-7,10-12H2,1-5H3/t17-, X mark.svgN
  • InChI=1/C20H30O/c1-13(2)18-14-7-10-17-19(3,4)11-6-12-20(17,5)15(14)8-9-16(18)21/h8-9,13,17,21H,6-7,10-12H2,1-5H3/t17-,20+/m0/s1
    Key: ZRVDANDJSTYELM-FXAWDEMLBD
  • CC(C)C1=C(C=CC2=C1CC[C@@H]3[C@@]2(CCCC3(C)C)C)O
Properties
C20H30O
Molar mass 286.459 g·mol−1
Melting point 128 to 132 °C (262 to 270 °F; 401 to 405 K)
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H315, H319, H335
P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)
New Zealand scientist Sir Thomas Hill Easterfield was the first person to discover totarol. Photo 1920. Thomas Hill Easterfield 1920.jpg
New Zealand scientist Sir Thomas Hill Easterfield was the first person to discover totarol. Photo 1920.

Totarol is a naturally produced diterpene that is bioactive as totarol. It was first isolated by McDowell and Easterfield from the heartwood of Podocarpus totara , a conifer tree found in New Zealand. [2] Podocarpus totara was investigated for unique molecules due to the tree's increased resistance to rotting. [2] Recent studies have confirmed totarol's unique antimicrobial and therapeutic properties. Consequently, totarol is a candidate for a new source of drugs and has been the goal of numerous syntheses.

Contents

Discovery

Totarol was discovered in 1910 [3] by New Zealand scientist Sir Thomas Hill Easterfield. [4] While investigating the properties of Miro , Kahikatea, Rimu, Matai and Totara, Easterfield detected a "crystalline bloom" on totara boards a few hours after leaving the planing machine. After extraction of totarol from Podocarpus totara, Easterfield observed no other compound had been cited in chemical literature before with this formula. Easterfield and his colleague J.C McDowell proposed the name “totarol” in a follow-up paper in 1915, [5] as the crystalline substance was believed to possess a tertiary alcohol group. In 1937 Short and Stromberg continued investigations, publishing Totarol Part 1. [2] In 1951 Short and Wang became the first to identify the chemical structure of totarol with their paper Totarol Part 2. [6]

Occurrence

Although totarol was first isolated in Podocarpus totara , totarol has also been identified in numerous other species of Podocarpaceae and Cupressaceae, with the majority found in the genus Podocarpus of the family Podocarpaceae and the subfamily Cupressoideae of the family Cupressaceae. [7] Outside Podocarpus and Cupressoideae, totarol is rarely found in the plant kingdom. [8] However, totarol has recently been isolated in Rosmarinus officinalis (rosemary). [9] The gymnosperms that contain totarol are distributed worldwide but are concentrated in North America, the far-south regions of South America, East Asia and East Africa. [10]

Biological activity

Antimicrobial activity

Totarol motivates research in drug discovery due to its ability to inhibit numerous microorganisms. Totarol exhibits antimicrobial properties in numerous species including gram-positive bacteria, acid-fast bacteria, nematodes, parasitic protozoans, crustaceous foulers (Table 1). In addition to inhibiting microorganisms by itself, totarol exhibits inhibitory synergy with currently used antimicrobial drugs: totarol potentiates isonicotinic acid hydrazide against various Mycobacteria.; [11] methicillin against Mycobacterium tuberculosis and Staphylococcus aureus ; [12] and anacardic acid [13] and erythromycin [14] against Staphylococcus aureus. In nature, totarol is a key player in gymnosperm's defense against harmful microbes: gymnosperms that produce totarol are resistant to rotting.

Table 1. Antibacterial activity of totarol against microorganisms

MicroorganismMIC (μg/ml)IC50(μg/ml)
Artemia salina [15]
-
1
Bacterium ammoniagenes [13]
0.78
-
Bacillus subtilis [13]
1.56
-
Caenorhabditis elegans [15]
-
80
Enterococcus faecalis [16]
2
-
Klebsiella pneumoniae [16]
>32
-
Mycobacterium aurum [17]
2
7.5
Mycobacterium fortuitum [17]
4
7.5
Mycobacterium phlei [17]
4
7.5
Mycobacterium smegmatis [17]
2
7.5
Mycobacterium tuberculosis H37Rv [17]
21.1
7.5
Leishmania donovani [13]
-
3.5
Proprionibacterium acnes [18]
3.9
-
Staphylococcus aureus ATCC 12598 [18]
1.56
-
Staphylococcus aureus ATCC 33591 [18]
0.78
-
Staphylococcus aureus ATCC 11632 [18]
0.78
-
Streptococcus mutans [13]
0.78
-
Streptococcus pneumoniae [16]
2
-

Mechanism of antimicrobial inhibition

Although totarol exhibits antimicrobial properties, the mode of action is unclear and various methods of inhibitory action have been proposed. In Staphylococcus aureus strains resistant to penicillin via creation of penicillin binding protein 2’ (PBP2’), totarol may inhibit the synthesis of PBP2’. [12] Totarol may inhibit effluxing Staphylococcus aureus strains through inhibition of MsrA, although it is unclear if MsrA is an efflux pump. [14] Totarol may also gain its antibacterial properties by inhibiting bacterial respiratory transport [19] but this is very unlikely because totarol is also effective against anaerobic organisms. [20] Recently totarol was also hypothesized to inhibit gram-positive and acid-fast bacteria via inhibition of FtsZ protein, which forms the Z-ring, a polymer necessary for efficient bacterial cell cytokinesis. [21]

Totarol may also function by disrupting the structural integrity of the phospholipid bilayer of bacteria by weakening Van der Waals interactions with its phenolic group, [22] [23] [24] which also results in bacterial cells unable to synthesize ATP. [25] Motivation for totarol functioning via disruption of membrane structure is due to its high phospholipid/water partition coefficient. [23] However, totarol's partitioning capability was only observed at concentrations 10 to 100 fold higher than required for antibacterial activity. [25] Thus it is unlikely that totarol is an uncoupler of bacterial respiration at the low levels observed in antimicrobial studies.

Traditional use

The use of Podocarpus totara extract in Maori medicines for treatment of fevers, asthma, coughs, cholera, distemper, chest complaints and venereal disease dates back to over 100 years. [26] The timber of Podocarpus totara is renowned for its resilience against rotting, which made it valuable to Maori for housing, waka (canoes), fencing, pā stockades, drinking vessels, shovels and carvings in chiefs houses. Totara bark [27] [28] was used to cover kelp bags containing preserved muttonbirds [29] known as pōhā. The totara tree was accorded divine status by Maori based on its immense size and its use in making waka employed on long, dangerous voyages. [30] Carved totara can be viewed as a representation of ancestry and historical and mythological events. The totara can also be seen to represent a connection between the past and the present, the secular and the spiritual. It has a strong link to Maori creation stories as it reaches down to Papatūānuku (Mother Earth) and up towards Ranginui (Sky Father). The roots in the symbolism of the totara mark out a genealogical reference point which Maori believe ties them to the natural world, the whenua (land) and their ancestral rohe (territory). [31] In Maori tradition totara is the first born child of Tāne-Mahuta and the forest godess Mumuwhango and is considered a noble tree. [32] According to tradition, felling a totara wasn't possible without seeking permission from Tāne-Mahuta. This involved performing specific rituals and chanting karakia (invocation). [33] European settlers of New Zealand used the wood for wharf piles, bridges, railway sleepers, telegraph poles, lighthouses, mining equipment, fence posts and foundation blocks. The durability stems from the anti-bacterial activity of totarol. Houses, churches, grave markers, and even cobbles and kerbs were made of totara; strips of the bark were used as a roofing material. [34] The presence of totarol means totara wood resists decay and insect attack in the heart timber. [35] Totarol has been found in organic matter in the embankments of a neolithic site in Northern Sweden. Scientists have suggested that totarol from Cupressaceae resin at the site was used for its antibacterial and antifungal properties to preserve meat, as well as for its ability to repel insects. [36] Despite totarol's antimicrobial potential, its commercial use is currently limited to cosmetic purposes. For totarol to be used clinically, its mode of action needs to be clearly defined.

Biochemical properties

Totarol decreases the plasma levels of estrogens [37] and can also effectively reduce pathogenic hepatic cells in vitro . [38] Totarol's anti-cancer activity is hypothesized to be due to the natural product's ability to form an o-quinone methide in vivo. [39] Totarol also prevents cells from undergoing oxidative stress in vitro by acting as a hydrogen donor to peroxy radicals or reacting with other peroxy radicals to terminate undesirable radical reactions. [19]

Biosynthesis

Totarol is a precursor to the formation of nagilactones [40] that possess antifungal properties not possessed by totarol. [19] [41] Consequently, gymnosperms that produce totarol and nagilactones are able to defend themselves against bacteria and fungi.

Scheme 1. The initially proposed biosynthetic route of totarol. Totarol scheme 1.svg
Scheme 1. The initially proposed biosynthetic route of totarol.

The biosynthesis of totarol was difficult to determine. The main reason for the challenge in determining how the secondary metabolite is produced is because totarol does not follow the isoprene rule: the isopropyl group of totarol is in the “wrong” place [9] at C14. Initially, it was hypothesized that totarol and the “normal” diterpene ferruginol, also found in Podocarpaceae, were derived by a precursor 2 that would be dehydrated and have its isopropyl group migrate to produce totarol 1 and ferruginol 3 (Scheme 1). [42] This hypothesis was motivated by the well known santonin-desmotroposantonin rearrangement of steroid dienones into aromatic compounds. It is now accepted that totarol is synthesized biologically from ferruginol. [9] Geranyl geranyl pyrophosphate 4 undergoes typical diterpene cyclization to form (−)-abietadiene 5, which is oxidized to form ferruginol 3, which proceeds through a spiro intermediate to form totarol (Scheme 2).

Scheme 2. The currently accepted biosynthetic route of totarol Totarol scheme 2.svg
Scheme 2. The currently accepted biosynthetic route of totarol

Synthesis

Scheme 3. The first total synthesis of (+-)-totarol Totarol scheme 3.svg
Scheme 3. The first total synthesis of (±)-totarol

Totarol has been the subject of numerous syntheses. The first total synthesis of totarol (Scheme 3) [43] utilized 6 and the alkyne 7 to yield 8 which was converted to the corresponding ketone 9 via hydrogenation followed by cyclization with polyphosphoric acid. 9 was subsequently converted to 10 and another ketone that were inseparable by chromatography. The synthesis was finalized by treatment with N-Bromosuccinimide followed by debromination to yield (±)-totarol. The main downfall of this synthesis was that in multiple steps, complete conversion of reactant to products was not observed and undesirable side products were often not separable by chromatography. However, since this was the first total synthesis of (±)-totarol, it is notable.

Total enantioselective synthesis

Scheme 4. The first total enantioselective synthesis of totarol Totarol scheme 4.svg
Scheme 4. The first total enantioselective synthesis of totarol

The first total enantioselective synthesis of totarol was achieved in 1979 (Scheme 4). [44] The key step in the synthesis is the formation of 13 via a Wittig reaction between 11 and 12. This same cyclization can also be achieved via a Friedel-Crafts alkylation and cyclization. [45] Subsequent hydrogenation of 13 followed by intramolecular cyclization with aluminium chloride forms the B ring and totarylmethyl ether which is demethylated by boron tribromide to yield totarol.

Scheme 5. The total synthesis of (+) totarol from zamoranic acid. Totarol scheme 5.svg
Scheme 5. The total synthesis of (+) totarol from zamoranic acid.

A more recent organic synthesis of totarol was achieved by utilizing 14, a lamdane diterpene named zamoranic acid (Scheme 5). [46] The addition of the isopropyl group in the chemical synthesis was achieved with complete stereoselectivity. Acetylation to yield 15 required high temperatures due to the steric hindrance of the isopropyl group. Cis-hydroxylation followed by cleavage with H5IO6 yielded a diol that was acylated in pyridine and oxidized to give 16. The key step in the synthesis was the cyclization of ring C: 16 was treated with SmI2 to yield totarane diastereomers which were separated by column chromatography. The desired diastereomer was treated with p-TsOH in benzene to yield 17. The synthesis was completed by a halogenation-dehydrogenation sequence and subsequent bromination to yield 18 and ring aromatization with elimination via a lithium complex.

Total chemoenzymatic synthesis

Scheme 6. The chemoenzymatic synthesis of totarol. Totarol scheme 6.svg
Scheme 6. The chemoenzymatic synthesis of totarol.

Chemoenzymatic synthesis of totarol has also been achieved with high yield (41.8%) (Scheme 6). [47] A racemic beta-keto ester 19 undergoes lipase-assisted resolution to yield chiral alcohol 20. Treatment of 20 with 10% HCl and p-TsOH gives αβ-unsaturated ketone 21. A Michael addition with the anion obtained from the reaction of methyl 5-methyl-3-oxohexanoate 13 with NaOMe gives a 2:1 diastereomeric mixture of 22 which is hydrolyzed to yield 23 which is brominated and debrominated to yield totarol.

Research

YearSubject
1992Bacteria killer and antibiotic enhancer [48]
1996Anti methicillin-resistant Staphylococcus aureus [49]
1997Antioxidant [50]
1998Diterpene [51]
1999Antibacterial [52]
1999Anti methicillin-resistant Staphylococcus aureus [53]
2000Mosquito insecticide [54]
2001Tuberculosis [55]
2001Cell change [56]
2002Insect repellant [57]
2003Antiplasmodial and cytotoxic [58]
2004Antimalarial [59]
2005Anti inflammatory [60]
2006Anti acne [61]
2007Antifungal [62]
2007Staphyloccocus auereus inhibition [63]
2007Tuberculosis [64]
2015Neurological disorders [65]
2015Bacillus subtilis alteration [66]
2017Ultrasound treatment on whey protein-totarol nanoparticles [67]
2017Surgical site infection [68]
2018Plant defense [69]
2018Food preservative [70]
2019Historical food preservative [36]
2019Antibacterial for dental implants [71]
2020Whey protein based tissue adhesive [72]
2020Mastitis [73]
2021Anticancer [74]
2022Drug delivery destroys microbial biofilm [75]
2022Anti inflammatory [76]
2023Insecticide [77]
2023Influenza A [78]
20243D printed PEEK implants with natural totarol coating [79]
2024Staphylococcus pseudintermedius and Staphylococcus coagulans in dogs and cats [80]
2024Prostate and breast cancer inhibitor [81]

Extraction

Totarol is extracted by supercritical extraction. The process uses high pressure carbon dioxide under specific temperature, pressure and gas flow conditions to extract totarol from powdered totara wood. Totarol can be extracted from dead wood, negating the need to cut down live trees. Although totarol can be extracted from other Podocarpus, some trees in the cypress family (cypress, juniper, thuja) and from rosemary, it is most abundant in Podocarpus totara. [82]

Products

Products for sale containing totarol include toothpastes, tooth tablets, mouthwash, toners, cleansers, moisturisers, face masks, concealers, blemish control, anti-acne, pimple patches, face cream, eye cream, sun screen, deodorants, face mists, facial wash, anti-wrinkle, restorative serum, renew cream, scar removal serum, dandruff control, scalp treatment, shampoo bar, pet skin cream, hand wash, hand cream, pressed powder makeup, mascara, rescue cream, skin whitener, lip tint, pregnancy body oil, mouth freshener, sore throat relief, cold and flu nasal spray. [83]

Other uses

Totarol may also be used as an indicator for the quality of juniper berry based spirits. Juniper berries that contain diterpenoids including totarol are used for the aromatization and production of some gins. Consequently, totarol can aid in the characterization of different types of gin or commercial brands, vouching for the authenticity and quality of the product. [84]

Totarol has been found on the posterior tibia of Frieseomelitta silvestrii languida, a species of stingless bees from Brazil. Frieseomelitta silvestrii languida collect resin to create a protective barrier around the opening of their nest to ward off insects from settling near the nest's entrance. [85] The presence of totarol can aid in the determination of this bee species.

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References

  1. ↑ "(4bS)-trans-8,8-Trimethyl-4b,5,6,7,8,8a,9,10-octahydro-1-isopropylphenanthren-2-ol". Sigma-Aldrich .
  2. 1 2 3 Short WF, Stromberg H (1937). "116. Totarol. Part I.". Journal of the Chemical Society (Resumed): 516–520. doi:10.1039/JR9370000516.
  3. ↑ Bendall JG, Cambie RC (1995). "Totarol: a Non-Conventional Diterpenoid". Australian Journal of Chemistry. 48 (5): 883. doi:10.1071/ch9950883. ISSN   0004-9425.
  4. ↑ Easterfield TH (1910). "Studies on the chemistry of the New Zealand flora. Part IV.—The chemistry of the Podocarpi". Transactions and Proceedings of the New Zealand Institute. 43: 53–55.
  5. ↑ Easterfield TH, Mcdowell JC (1915). "The chemistry of Podocarpus totara and Podocarpus spicatus". Transactions of the New Zealand Institute. 48: 518–520.
  6. ↑ Short WF, Wang H (1951). "662. Totarol. Part II". Journal of the Chemical Society (Resumed): 2979–2987. doi:10.1039/jr9510002979. ISSN   0368-1769.
  7. ↑ Sharp H, Latif Z, Bartholomew B, Bright C, Jones CD, Sarker SD, et al. (February 2001). "Totarol, totaradiol and ferruginol: three diterpenes from Thuja plicata (Cupressaceae)". Biochemical Systematics and Ecology. 29 (2): 215–217. Bibcode:2001BioSE..29..215S. doi:10.1016/s0305-1978(00)00047-8. PMID   11106853.
  8. ↑ Le Métayer P, Schaeffer P, Adam P, Albrecht P, Roussé S, Duringer P (June 2008). "An unprecedented condensation pathway leading to the formation of phenolic C40 bis-diterpenoids in sediments from the Lower Oligocene of the Rhine Rift Valley". Organic Geochemistry. 39 (6): 658–675. Bibcode:2008OrGeo..39..658L. doi:10.1016/j.orggeochem.2008.02.020.
  9. 1 2 3 Bendall JG, Cambie RC (1995). "Totarol: A non-conventional diterpenoid". Australian Journal of Chemistry. 48 (5): 883–917. doi:10.1071/CH9950883.
  10. ↑ Farjon A (2001). World Checklist and Bibliography of Conifers (2nd ed.). Kew: Royal Botanic Gardens. p. 212.
  11. ↑ Mossa JS, El-Feraly FS, Muhammad I (November 2004). "Antimycobacterial constituents from Juniperus procera, Ferula communis and Plumbago zeylanica and their in vitro synergistic activity with isonicotinic acid hydrazide". Phytotherapy Research. 18 (11): 934–7. doi:10.1002/ptr.1420. PMID   15597311. S2CID   33772478.
  12. 1 2 Gibbons S (January 2005). "Plants as a source of bacterial resistance modulators and anti-infective agents". Phytochemistry Reviews. 4 (1): 63–78. Bibcode:2005PChRv...4...63G. doi:10.1007/s11101-005-2494-9. S2CID   24225316.
  13. 1 2 3 4 5 Kubo I, Muroi H, Himejima M (October 1992). "Antibacterial activity of totarol and its potentiation". Journal of Natural Products. 55 (10): 1436–40. doi:10.1021/np50088a008. PMID   1453180.
  14. 1 2 Smith EC, Kaatz GW, Seo SM, Wareham N, Williamson EM, Gibbons S (December 2007). "The phenolic diterpene totarol inhibits multidrug efflux pump activity in Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 51 (12): 4480–3. doi:10.1128/AAC.00216-07. PMC   2168009 . PMID   17664318.
  15. 1 2 Samoylenko V, Dunbar DC, Gafur MA, Khan SI, Ross SA, Mossa JS, et al. (December 2008). "Antiparasitic, nematicidal and antifouling constituents from Juniperus berries". Phytotherapy Research. 22 (12): 1570–1576. doi:10.1002/ptr.2460. PMID   19067375. S2CID   10379153.
  16. 1 2 3 Evans GB, Furneaux RH, Gravestock MB, Lynch GP, Scott GK (September 1999). "The synthesis and antibacterial activity of totarol derivatives. Part 1: modifications of ring-C and pro-drugs". Bioorganic & Medicinal Chemistry. 7 (9): 1953–1964. doi:10.1016/s0968-0896(99)00162-5. PMID   10530944.
  17. 1 2 3 4 5 Gordien AY, Gray AI, Franzblau SG, Seidel V (December 2009). "Antimycobacterial terpenoids from Juniperus communis L. (Cuppressaceae)". Journal of Ethnopharmacology. 126 (3): 500–5. doi:10.1016/j.jep.2009.09.007. PMID   19755141.
  18. 1 2 3 4 Muroi H, Kubo I (April 1996). "Antibacterial activity of anacardic acid and totarol, alone and in combination with methicillin, against methicillin-resistant Staphylococcus aureus". The Journal of Applied Bacteriology. 80 (4): 387–94. doi:10.1111/j.1365-2672.1996.tb03233.x. PMID   8849640.
  19. 1 2 3 Haraguchi H, Ishikawa H, Sakai S, Ying BP, Kubo I (June 1996). "Inhibition of lipid peroxidation by diterpenoid from Podocarpus nagi". Experientia. 52 (6): 573–6. doi:10.1007/BF01969731. PMID   8698092. S2CID   31273106.
  20. ↑ Shapiro S, Guggenheim B (August 1998). "Inhibition of oral bacteria by phenolic compounds. Part 1. QSAR analysis using molecular connectivity". Quantitative Structure-Activity Relationships. 17 (4): 327–337. doi:10.1002/(SICI)1521-3838(199808)17:04<327::AID-QSAR327>3.0.CO;2-O.
  21. ↑ Jaiswal R, Beuria TK, Mohan R, Mahajan SK, Panda D (April 2007). "Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ". Biochemistry. 46 (14): 4211–20. doi:10.1021/bi602573e. PMID   17348691.
  22. ↑ Micol V, Mateo CR, Shapiro S, Aranda FJ, Villalaín J (April 2001). "Effects of (+)-totarol, a diterpenoid antibacterial agent, on phospholipid model membranes". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1511 (2): 281–90. doi: 10.1016/s0005-2736(01)00284-x . PMID   11286971.
  23. 1 2 Mateo CR, Prieto M, Micol V, Shapiro S, Villalaín J (December 2000). "A fluorescence study of the interaction and location of (+)-totarol, a diterpenoid bioactive molecule, in model membranes". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1509 (1–2): 167–175. doi:10.1016/s0005-2736(00)00291-1. PMID   11118528.
  24. ↑ Bernabeu A, Shapiro S, Villalaín J (October 2002). "A MAS-NMR study of the location of (+)-totarol, a diterpenoid bioactive molecule, in phospholipid model membranes". Chemistry and Physics of Lipids. 119 (1–2): 33–9. doi:10.1016/s0009-3084(02)00050-6. PMID   12270671.
  25. 1 2 Evans GB, Furneaux RH, Gainsford GJ, Murphy MP (July 2000). "The synthesis and antibacterial activity of totarol derivatives. Part 3: Modification of ring-B". Bioorganic & Medicinal Chemistry. 8 (7): 1663–75. doi:10.1016/s0968-0896(00)00096-1. PMID   10976514.
  26. ↑ Abdillahi HS, Stafford GI, Finnie JF, Van Staden J (January 2010). "Ethnobotany, phytochemistry and pharmacology of Podocarpus sensu latissimo (sl)". South African Journal of Botany. 76 (1): 1–24. doi: 10.1016/j.sajb.2009.09.002 . S2CID   85271055.
  27. ↑ "Pōhā, airtight storage containers. Science Learning Hub, Pokapū Akoranga Pūtaiao".
  28. ↑ "Pōhā Tītī - Te Papa New Zealand".
  29. ↑ "Podocarpus Totara". Landcare Research. July 1, 2020.
  30. ↑ Simpson P (2017). Totara: A Natural and Cultural History. University of Auckland Press.
  31. ↑ Connor H (2021). "Ko te Rākau Hei Tohu Mō te Rangahau Me te Tuhi Whakapapa: Tree Symbolism as a Method for Researching and Writing Genealogy". School of Māori and Indigenous Studies, Faculty of Education and Social Work, University of Auckland. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  32. ↑ Neich R (2001). "Carved Histories: Rotorua Ngati Tarawhai Woodcarving". Google Scholar.
  33. ↑ Irwin J (1984). An Introduction to Māori Religion. Bedford Park - Australian Association for the Study of Religions.
  34. ↑ Gilchrist S (July 24, 2017). "Children of Tane". Otago Daily Times.
  35. ↑ Duncan CR (2004-01-01). "Fire protection of New Zealand's traditional Maori buildings" (PDF).
  36. 1 2 Kaal J, Linderholm J, Martínez Cortizas A. "Fire, meat and totarol: organic matter in the embankments of the Neolithic site Bastuloken (North Sweden)" (PDF). Analytical Pyrolysis Letters. 7: 1–16.
  37. ↑ Minami T, Iwamoto M, Ohtsu H, Ohishi H, Tanaka R, Yoshitake A (August 2002). "Aromatase inhibitory activities of standishinal and the diterpenoids from the bark of Thuja standishii". Planta Medica. 68 (8): 742–5. doi:10.1055/s-2002-33787. PMID   12221600. S2CID   26017116.
  38. ↑ Lee MK, Yang H, Yoon JS, Jeong EJ, Kim DY, Ha NR, et al. (July 2008). "Antifibrotic activity of diterpenes from Biota orientalis leaves on hepatic stellate cells". Archives of Pharmacal Research. 31 (7): 866–71. doi:10.1007/s12272-001-1239-9. PMID   18704328. S2CID   22860187.
  39. ↑ Van De Water RW, Pettus TR (July 2002). "o-Quinone methides: intermediates underdeveloped and underutilized in organic synthesis". Tetrahedron. 58 (27): 5367–5406. doi:10.1016/S0040-4020(02)00496-9.
  40. ↑ Bailly C (2020-12-01). "Anticancer Activities and Mechanism of Action of Nagilactones, a Group of Terpenoid Lactones Isolated from Podocarpus Species". Natural Products and Bioprospecting. 10 (6): 367–375. doi: 10.1007/s13659-020-00268-8 . ISSN   2192-2195. PMC   7648843 . PMID   33034879.
  41. ↑ Kubo I, Muroi H, Kubo A (December 1993). "Antibacterial activity of long-chain alcohols against Streptococcus mutans". Journal of Agricultural and Food Chemistry. 41 (12): 2447–2450. doi:10.1021/jf00036a045.
  42. ↑ Short WF, Wang H (1951). "662. Totarol. Part II". Journal of the Chemical Society (Resumed): 2979–2987. doi:10.1039/JR9510002979.
  43. ↑ Barltrop JA, Rogers NA (1958). "520. Experiments on the synthesis of diterpenes. Part I. A total synthesis of (±)-totarol". Journal of the Chemical Society (Resumed): 2566–2572. doi:10.1039/JR9580002566.
  44. ↑ Matsumoto T, Suetsugu A (May 1979). "The Total Synthesis of (+)-Totarol and (+)-Podototarin". Bulletin of the Chemical Society of Japan. 52 (5): 1450–1453. doi:10.1246/bcsj.52.1450.
  45. ↑ Das S, Sukanta B, Debabrata M (January 1992). "Stereocontrolled total synthesis of (±)-totaryl methyl ether and (±)-semperviryl methyl ether". Tetrahedron. 48 (41): 9101–9110. doi:10.1016/S0040-4020(01)82004-4.
  46. ↑ Marcos IS, Cubillo MA, Moro RF, Dıez D, Basabe P, Sanz F, et al. (December 2003). "Synthesis of (+)-totarol". Tetrahedron Letters. 44 (49): 8831–8835. doi:10.1016/j.tetlet.2003.09.193.
  47. ↑ Miyake T, Kigoshi H, Akita H (December 2007). "Chemoenzymatic synthesis of (+)-totarol,(+)-podototarin,(+)-sempervirol, and (+)-jolkinolides E and D.". Tetrahedron: Asymmetry. 18 (24): 2915–2922. doi:10.1016/j.tetasy.2007.11.024.
  48. ↑ Kubo I, Muroi H, Himejima M (October 1992). "Antibacterial activity of totarol and its potentiation". Journal of Natural Products. 55 (10): 1436–1440. doi:10.1021/np50088a008. PMID   1453180.
  49. ↑ Muroi H, Kubo I (April 1996). "Antibacterial activity of anacardic acid and totarol, alone and in combination with methicillin, against methicillin-resistant Staphylococcus aureus". The Journal of Applied Bacteriology. 80 (4): 387–394. doi:10.1111/j.1365-2672.1996.tb03233.x. PMID   8849640.
  50. ↑ Haraguchi H, Ishikawa H, Kubo I (1997-06-01). "Antioxidative Action of Diterpenoids from Podocarpus nagi". Planta Medica. 63 (3): 213–215. doi:10.1055/s-2006-957655. ISSN   0032-0943. PMID   9225601. S2CID   260248488.
  51. ↑ Nicolson K (1998). Antibacterial properties of diterpenes and their derivatives: a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Microbiology at Massey University (Thesis thesis). Massey University.
  52. ↑ Evans GB, Furneaux RH, Gravestock MB, Lynch GP, Scott GK (September 1999). "The synthesis and antibacterial activity of totarol derivatives. Part 1: modifications of ring-C and pro-drugs". Bioorganic & Medicinal Chemistry. 7 (9): 1953–1964. doi:10.1016/S0968-0896(99)00162-5. PMID   10530944.
  53. ↑ Nicolson K, Evans G, O'Toole PW (1999-10-01). "Potentiation of methicillin activity against methicillin-resistant Staphylococcus aureus by diterpenes". FEMS Microbiology Letters. 179 (2): 233–239. doi: 10.1111/j.1574-6968.1999.tb08733.x . PMID   10518721.
  54. ↑ Lee SE, Park EK, Kim JG (October 2000). "A Mosquito Larvicidal Diterpenoid Isolated from Podocarpus totara D. Don ex Lambert" (PDF). Journal of Entomological Science. 35 (4): 474–477. doi:10.18474/0749-8004-35.4.474. ISSN   0749-8004.
  55. ↑ Gordien AY, Gray AI, Franzblau SG, Seidel V (December 2009). "Antimycobacterial terpenoids from Juniperus communis L. (Cuppressaceae)". Journal of Ethnopharmacology. 126 (3): 500–505. doi:10.1016/j.jep.2009.09.007. PMID   19755141.
  56. ↑ Micol V, Mateo CR, Shapiro S, Aranda FJ, Villalaín J (April 2001). "Effects of (+)-totarol, a diterpenoid antibacterial agent, on phospholipid model membranes". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1511 (2): 281–290. doi: 10.1016/S0005-2736(01)00284-X . PMID   11286971.
  57. ↑ Patricio EF, Cruz-López L, Maile R, Tentschert J, Jones GR, Morgan ED (February 2002). "The propolis of stingless bees: terpenes from the tibia of three Frieseomelitta species". Journal of Insect Physiology. 48 (2): 249–254. doi:10.1016/S0022-1910(01)00170-6. PMID   12770125.
  58. ↑ Clarkson C, Musonda CC, Chibale K, Campbell WE, Smith P (October 2003). "Synthesis of totarol amino alcohol derivatives and their antiplasmodial activity and cytotoxicity". Bioorganic & Medicinal Chemistry. 11 (20): 4417–4422. doi:10.1016/S0968-0896(03)00491-7. PMID   13129578.
  59. ↑ Tacon C (2004). Chemical modification and pharmacological evaluation of the antimalarial natural product totarol (PDF) (Master Thesis thesis). University of Cape Town.
  60. ↑ US6881756B2,Gendimenico, Gerard J.,"Method for treating skin disorders",issued 2005-04-19
  61. ↑ Nixon D, Hobbs D (August 15, 2006). "The use of totarol to treat acne in an adolescent: A case study" (PDF). NZFP. 33 (4): 253–255 – via Essentially New Zealand Ltd.
  62. ↑ Yamaji K, Mori S, Akiyama M, Kato A, Nakashima T (2007-12-05). "The Antifungal Compound Totarol of Thujopsis dolabrata var. hondai Seeds Selects for Fungi on Seedling Root Surfaces". Journal of Chemical Ecology. 33 (12): 2254–2265. Bibcode:2007JCEco..33.2254Y. doi:10.1007/s10886-007-9390-2. ISSN   0098-0331. PMID   18026796. S2CID   20883003.
  63. ↑ Smith EC, Kaatz GW, Seo SM, Wareham N, Williamson EM, Gibbons S (December 2007). "The phenolic diterpene totarol inhibits multidrug efflux pump activity in Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 51 (12): 4480–4483. doi:10.1128/AAC.00216-07. PMC   2168009 . PMID   17664318.
  64. ↑ Jaiswal R, Beuria TK, Mohan R, Mahajan SK, Panda D (April 2007). "Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ". Biochemistry. 46 (14): 4211–4220. doi:10.1021/bi602573e. PMID   17348691.
  65. ↑ Gao Y, Xu X, Chang S, Wang Y, Xu Y, Ran S, et al. (December 2015). "Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction". Toxicology and Applied Pharmacology. 289 (2): 142–154. doi:10.1016/j.taap.2015.10.001. PMID   26440581.
  66. ↑ Reddy PJ, Ray S, Sathe GJ, Gajbhiye A, Prasad TS, Rapole S, et al. (January 2015). "A comprehensive proteomic analysis of totarol induced alterations in Bacillus subtilis by multipronged quantitative proteomics". Journal of Proteomics. 114: 247–262. doi:10.1016/j.jprot.2014.10.025. PMID   25464363.
  67. ↑ Ma S, Shi C, Wang C, Guo M (October 2017). "Effects of Ultrasound Treatment on Physiochemical Properties and Antimicrobial Activities of Whey Protein-Totarol Nanoparticles". Journal of Food Protection. 80 (10): 1657–1665. doi: 10.4315/0362-028X.JFP-17-078 . PMID   28876131.
  68. ↑ Reinbold J, Uhde AK, Müller I, Weindl T, Geis-Gerstorfer J, Schlensak C, et al. (September 2017). "Preventing Surgical Site Infections Using a Natural, Biodegradable, Antibacterial Coating on Surgical Sutures". Molecules. 22 (9): 1570. doi: 10.3390/molecules22091570 . PMC   6151728 . PMID   28925959.
  69. ↑ Qazi SS, Lombardo DA, Abou-Zaid MM (October 2018). "A Metabolomic and HPLC-MS/MS Analysis of the Foliar Phenolics, Flavonoids and Coumarins of the Fraxinus Species Resistant and Susceptible to Emerald Ash Borer". Molecules. 23 (11): 2734. doi: 10.3390/molecules23112734 . PMC   6278661 . PMID   30360500.
  70. ↑ Shi C, Che M, Zhang X, Liu Z, Meng R, Bu X, et al. (March 2018). "Antibacterial activity and mode of action of totarol against Staphylococcus aureus in carrot juice". Journal of Food Science and Technology. 55 (3): 924–934. doi:10.1007/s13197-017-3000-2. PMC   5821648 . PMID   29487434.
  71. ↑ Xu Z, Krajewski S, Weindl T, Han X, Kimmerle-Müller E, Schweizer E, et al. (September 25, 2019). "The application of natural antibacterial coating for the surface modification of dental implants and abutments". Clinical Oral Implants Research. 30 (S19): 132. doi: 10.1111/clr.90_13509 . ISSN   0905-7161. S2CID   204052249.
  72. ↑ Hou Y, Zhang X, Wang C, Guo M (2020-04-24). "Formulation and Functional Properties of Whey Protein-Based Tissue Adhesive Using Totarol as an Antimicrobial Agent". Processes. 8 (4): 496. doi: 10.3390/pr8040496 . ISSN   2227-9717.
  73. ↑ Velathanthiri N, Balmer T, Grinberg A (March 2020). Minimum Inhibitory and Bactericidal Concentrations of a Totarol™ formulation against Staphylococcus aureus strains obtained from bovine intramammary infections in New Zealand. Antimicrobials 2020. doi:10.13140/RG.2.2.29327.33449.
  74. ↑ Laamari Y, Oubella A, Bimoussa A, El Mansouri AE, Ketatni EM, Mentre O, et al. (October 2021). "Design, Hemiysnthesis, crystal structure and anticancer activity of 1, 2, 3-triazoles derivatives of totarol" (PDF). Bioorganic Chemistry. 115: 105165. doi:10.1016/j.bioorg.2021.105165. PMID   34298240.
  75. ↑ Shariati A, Chegini Z, Ghaznavi-Rad E, Zare EN, Hosseini SM (2022-06-21). "PLGA-Based Nanoplatforms in Drug Delivery for Inhibition and Destruction of Microbial Biofilm". Frontiers in Cellular and Infection Microbiology. 12: 926363. doi: 10.3389/fcimb.2022.926363 . PMC   9253276 . PMID   35800390.
  76. ↑ Cuevas-Cianca SI, Leal AC, Hernández LR, Arreola ES, Bach H (October 13, 2022). "Antimicrobial, toxicity, and anti-inflammatory activities of Buddleja perfoliata Kunth". Phytomedicine Plus. 2 (4): 100357. doi: 10.1016/j.phyplu.2022.100357 . S2CID   252728375.
  77. ↑ Bosly HA (November 3, 2022). "Larvicidal potential of Thuja orientalis leaves and fruits extracts against Culex pipiens (Diptera: Culicidae)". Journal of King Saud University - Science. 35 (1): 102396. doi: 10.1016/j.jksus.2022.102396 . S2CID   253198996.
  78. ↑ Abdullahi M, Uzairu A, Shallangwa GA, Mamza PA, Ibrahim MT (December 8, 2022). "Computational modelling of some phenolic diterpenoid compounds as anti-influenza A virus agents". Scientific African. 19: e01462. doi: 10.1016/j.sciaf.2022.e01462 . S2CID   253944227.
  79. ↑ Han X, Sharma N, Xu Z, Krajewski S, Li P, Spintzyk S, et al. (22 February 2024). "A balance of biocompatibility and antibacterial capability of 3D printed PEEK implants with natural totarol coating". Dental Materials.
  80. ↑ "Efficacy of totarol against Staphylococcus pseudintermedius and Staphylococcus coagulans in dogs and cats: An in vitro study".
  81. ↑ "1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors".
  82. ↑ "Bioactive Totarol". Totarol.com. July 23, 2023.
  83. ↑ "Products with Totarol". INCIDecoder.
  84. ↑ Vichi S, Aumatell MR, Buxaderas S, López-Tamames E (November 2008). "Assessment of some diterpenoids in commercial distilled gin". Analytica Chimica Acta. 628 (2): 222–9. Bibcode:2008AcAC..628..222V. doi:10.1016/j.aca.2008.09.005. PMID   18929011.
  85. ↑ Patricio EF, Cruz-López L, Maile R, Tentschert J, Jones GR, Morgan ED (February 2002). "The propolis of stingless bees: terpenes from the tibia of three Frieseomelitta species". Journal of Insect Physiology. 48 (2): 249–254. doi:10.1016/s0022-1910(01)00170-6. PMID   12770125.
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