Natural Products & Phytochemicals

Hydroxytyrosol is a naturally occurring polyphenol with remarkable antioxidant activity. Its precursor oleuropein is present in olive fruits but also in all parts of the olive tree. While oleuropein has several known biological activities, the activity of hydroxytyrosol may be even greater. Therefore, obtaining as much as possible hydroxytyrosol, rather than oleuropein, from the plant is desirable.

The agricultural waste produced from annual pruning of olive trees is normally disposed of by burning. However, these leaves and small branches also contain oleuropein. Here there is an opportunity to extract a high-value product from what is generally thought to be a waste material.

Recently, researchers have attempted to develop and optimize just such a process. Enzymatic reactions were developed to convert the original oleuropein into the desired hydroxytyrosol. Enzymes with varied characteristics such as molecular size, isoelectric point, and hydrophobic domains, were tested.

With a two-step reaction strategy, first the glucosidic bond was broken, followed by hydrolysis of the aglycon. They found that the first step alone required 7 days, at low concentration, and the second step did not work as expected, but seemed to also require enzyme action. The outcome was only 5% transformation.

They also examined a one-step reaction scheme using a different type of enzyme, and this process allowed for a higher concentration and obtained 30% transformation in 12 days. This process was much more effective than the two-step strategy.

However, with only 30% transformation, it may be possible to further optimize the process to obtain even better yield of hydroxytyrosol. On the whole, using a waste material to create a valuable product is bound to be a worthwhile endeaver.

Garcia-Molina G, Peters E, Palmeri R, et al. Enzymatic synthesis of hydroxytyrosol from oleuropein for valorization of an agricultural waste. Bioengineered. 2024 Dec;15(1):2396647. PMID: 39235136

Betulinic acid is a natural product found in several plant sources including white birch bark. Interestingly, this molecule has several biological activities, notably antioxidant properties. Studies indicate that the antioxidant activity of this molecule is mediated through the Nrf2/Keap1 signaling pathway, which defends against oxidative stress.

Oxidative stress is one of the major causes of in vitro oocyte maturation defects. Therefore, optimizing the in vitro conditions will lead to more successful outcomes. Undeniably, this is an important step in the process of assisted reproductive technology.

Recently, a study looked at the impact of betulinic acid on the maturation of porcine oocytes. First, the cumulus-oocyte complexes (COCs) were extracted from porcine ovaries. The the COCs were allowed to mature in vitro in the presence or absence of various concentrations of betulinic acid. Next, the matured oocytes were parthenogenetically activated, followed by incubation for 6 days.

As it turns out, the COCs treated with betulinic acid showed enhanced meiotic progression leading to more successful outcomes. Anaylsis indicates that the treatment regulated antioxidant genes, thereby reducing the intracellular oxidative stress level.

Now that these positive in vitro results have been observed, it will be necessary to further evaluate for any long-term effects on the embryonic development. This research is important for the improvement of in vitro maturation systems.

Additionally, related compounds are also available from LKT Labs:

Betulin

Betulin-3-Acetate

Kim MJ, Kang HG, Jeon SB, et al. The antioxidant betulinic acid enhances porcine oocyte maturation through Nrf2/Keap1 signaling pathway modulation. PLoS One. 2024 Oct 10;19(10):e0311819. PMID: 39388445

Inflammatory bowel disease is a group of inflammatory conditions that usually occurs as either Crohn’s disease or ulcerative colitis. In Crohn’s disease, any part of the digestive tract may be involved, most commonly the small or large intestine. In contrast, ulcerative colitis involves only the large intestine. The exact causes of these diseases are unknown. One thing that is clear is that, over time, the gut microbiome is disrupted.

A New Strategy:

One possible way to combat these diseases may be to boost the microbiome back to its normal function. A recent study was performed to attempt just that. Researchers used a mouse model of immune-modulated Crohn’s disease. The mice were fed a diet including raw broccoli sprouts, which contains the anti-inflammatory compound sulforaphane. Sulforaphane in its purified chemical form has previously been shown to protect mice and their gut from ulcerative colitis.

After 7 days, the mice were inoculated with Heliobacter hepaticus, which induced the symptoms of Crohn’s disease. The broccoli sprout diet was then continued for another 2 weeks.

Evaluation:

A healthy gut microbiome must consist of a large diversity of families in the bacterial community. The populations of the good bacteria must be able to thrive over common gut pathogens. The gut microbiome has a changing microbial community early in life and begins to stabilize around adolescence. Therefore, the study included 2 sets of mice of different ages, one group was very young and at post-weaning, the other group was at adolescence. The dietary intervention was found to be much more beneficial for the very young group.

Treatment for inflammatory bowel disease requires consideration of so very many factors. Further research will be needed to confirm whether or not the benefits to the very young group would carry on into adulthood. If so, this will be a good step in learning how to manipulate the gut microbiome to ensure continued good health.

Several forms of Sulforaphane are available at LKT Labs:

R,S-Sulforaphane, Research Grade (≥97%)

R,S-Sulforaphane, High Purity (≥99%)

R-Sulforaphane, Research Grade (≥97%)

R-Sulforaphane, High Purity (≥98%)

S-Sulforaphane (97%)

Holcomb L, Holman J, Hurd M, et al. Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease. mSystems. 2023 Dec 21;8(6):e0068823. doi: 10.1128/msystems.00688-23. PMID: 37942948

Vitamin K2 has several major forms due to slight differences in the side chain of the molecule. The major forms are menaquinone-4 (MK-4), menaquinone-7, menaquinone-8, and menaquinone-9. The major source of this vitamin is the conversion of vitamin K1 present in the diet. The presence of vitamin K directly impacts the synthesis and metabolism of sphingolipids in the brain. The sphingolipids in turn impact a variety of neuronal processes, including aging.

Therefore, the hypothesis was proposed, that vitamin K2 may provide some protection against age-related cognitive deterioration. This hypothesis was put to the test using Sprague-Dawley rats in an animal lab. Twenty rats were divided into two groups: (1) Control- sunflower oil, (2) Test- sunflower oil dosed with vitamin K2 each day. The animal treatments lasted for 17 months, and then the rats were subjected to several behavioral tests. An additional control group (3) of 10 adult rats, not aged, was also subjected to these tests. Finally, the animals were processed and the brain tissues examined.

Behavior Tests

The behavioral tests included an anxiety test, a depressive-like behavior test, and a memory test. These tests did not show any significant differences between the untreated group (3) and the MK-4 treated group (2). However, there were negative differences measured for the control- sunflower oil group (1). This group consistently had the lowest performance.

Tissue Tests

Finally, the brain tissues were collected and examined by PCR, biochemical analysis of oxidative stress, ELISA, and several histopathological and immunohistochemical processes. These tests all showed groups (1) and (3) to have similar results, while group (2) had less desirable results. This evidence all points to vitamin K2 being correlated with good brain health, preventing the signs of aging in the brain.

Vitamin K2 impact on the brain may hold promise for preserving cognitive function and decreasing age-related disorders.

Elkattawy H, Ghoneim F, Eladl M, et al. Vitamin K2 (menaquinone-7) reverses age-related structural and cognitive deterioration in naturally aging rats. Antioxidants (Basel). 2022 Mar 8;11(3):514. doi: 10.3390/antiox11030514. PMID: 35326164

Vitamin K is a class of fat-soluble molecules that are required for blood clotting and calcium binding in the human body. Although acute vitamin K deficiency is rare, there is evidence that subclinical deficiency raises the risk of heart disease and osteoporosis. The menaquinones (vitamin K2) are an especially good dietary source of vitamin K because of their bioavailability and stability. Menaquinones can be found in fermented foods such as natto and dairy.

A team of researchers at the Norwegian University of Life Sciences wanted to enhance the menaquinone content of dairy to increase its functional value. To achieve this goal, they planned to genetically engineer a lactobacterium, Lactococcus lactis, that is involved in making yogurt. L. lactis contains a biosynthetic pathway to produce several menaquinones, especially menaquinone-9. The researchers tried overexpressing the genes in that pathway. Overexpression of some genes (menF, menA) caused L. lactis to produce extra menaquinone-3, instead of the more desirable menaquinone-9. The overexpression of other genes (mvk, llmg_0196) led to increased production of menaquinone-9.

When the engineered L. lactis was used to culture milk, the yogurt had enhanced levels of menaquinone-9. The researchers calculate that moderate intake of such yogurt would help many people get optimal vitamin K in their diet. This encouraging result suggests that engineered bacteria can be used more broadly to enhance nutrition.

Boe C, Holo H. Engineering Lactococcus lactis for increased vitamin K2 production. Front Bioeng Biotechnol. 2020 Mar 18;8:191. PMID: 32258010. doi: 10.3389/fbioe.2020.00191

Gut peptides are hormones secreted by the gut that act on the brain to regulate digestion and appetite. The function of gut peptides is a promising area of research for the treatment of type-2 diabetes and obesity.

Background

In the last ten years, glucagon-like peptide (GLP-1) agonists have reached clinical use to treat type-2 diabetes. This class of drugs can cause side effects such as nausea and vomiting, so the maximum tolerable dose is limited. A combination of gut peptide agonists might allow better patient outcomes at lower doses of each drug.

New Studies Using Combination

Recently, a team of researchers sought to understand the effects of combining a GLP-1 agonist with a cholecystokinin (CCK) agonist. They gave mice a GLP-1 agonist and a CCK agonist by injection and measured the mice’s food intake in the short and the long term. Mice on the GLP-1/CCK1 agonist combination ate less and lost more body weight than mice on either agonist alone. The researchers also tested the effect of the GLP-1/CCK1 agonist combination on mice that had become obese by eating a high-fat diet. The obese mice had a similar but smaller response.

Impact on Brain

The researchers wanted to know what effect the agonist combination had on the mouse brain. They immunostained mouse brains for a marker of brain metabolic activity and found that activity was stimulated the most in the nucleus solitary tract, a part of the brain stem.

They did a further test for neuron RNA expression. Neurons that were activated by the GLP-1/CCK1 agonist combination had increased expression of a receptor for calcitonin gene-related peptide (CGRP). Neurons that were inhibited by the GLP-1/CCK1 agonist combination had increased expression of a receptor for pituitary adenylate cyclase-activating peptide (PACAP). The results of these studies suggest that CGRP and PACAP are themselves worth studying for their effects on type-2 diabetes and obesity.

Glucagon, Exendin, PACAP and Related Peptides

Calcitonin and Related Peptides

Cholecystokinin (CCK)   S3351

Roth E, Benoit S, Quentin B, et al. Behavioral and neurochemical mechanisms underpinning the feeding-suppressive effect of GLP-1/CCK combinatorial therapy. Molecular Metabolism. 2021 Jan;43:101118. PMID: 33221554 doi.org/10.1016/j.molmet.2020.101118

Bee venom is a complex mixture of enzymes, polypeptides, amino acids, and sugars. Traditional Chinese medicine uses bee venom acupuncture to treat arthritis and pain. However, the components of bee venom are the subject of biomedical research for their potential painkiller, antithrombotic, and antibiotic properties. The polypeptide melittin makes up 40-60 percent of the dry weight of bee venom and causes the pain of bee stings. Apamin, which makes up 2-3 percent of bee venom dry weight, is a neurotoxin that inhibits Ca++ -activated K+ channels in the central nervous system. It is used in biomedical research to study how these channels work.

In South Korea, manufacturers put bee venom extracts into skin care products, citing the benefits of traditional medicine. Consumers who use these products have inadvertently found an antifungal effect.

Recently, Park et al. investigated the antifungal properties of bee venom. The experimenters prepared cultures of Trichophyton rubrum, the pathogen responsible for athlete’s foot and jock itch, on potato dextrose cornmeal agar plates. They exposed each culture to one of four different treatments: raw bee venom, a commercial bee-venom-based skincare product, apamin, or melittin. They let each T. rubrum culture grow for two weeks.

Every two days, the experimenters calculated the growth rate of each T. rubrum culture. They found that melittin and apamin do not inhibit T. rubrumgrowth, but raw bee venom and the skincare product do inhibit growth. They conclude that bee venom does have antifungal potential, but neither melittin nor apamin can inhibit fungus alone. Bee venom will need more investigation before it can see clinical use.

A6002 Apamin

M1744 Melittin

Park J, Kwon O, An HJ, Park KK. Antifungal Effects of Bee Venom Components on Trichophyton rubrum: A Novel Approach of Bee Venom Study for Possible Emerging Antifungal Agent. (2018). Annals of Dermatology 30:2. doi: 10.5021/ad.2018.30.2.202.

Curcumin is the active ingredient found in turmeric, a common spice used all over the world. The beneficial effects of curcumin intake have been investigated extensively, but a new paper published in Proceedings from the National Academy of Sciences reports a new target for curcumin.

Researchers report evidence of the protein kinase dual-specificity tyrosine regulated kinase 2 (DYRK2) as a receptor for curcumin. In vitro biochemical assays show that curcumin had an IC50 value of 5 nM against DYRK2. Additionally in an assay against 144 different protein kinases, curcumin is a selective ligand for DYRK2, with an IC50 10 fold greater than the next nearest kinase. The authors further confirm DYRK2 as the target of curcumin by overexpressing DYRK2 in HEK293T cells, and noting a decrease in phosphorylation of tyrosine 25 in the RPT3 subunit of the 26S proteasome, the major target of DYRK2. Additionally, the researchers publish a crystal structure of DYRK2 with curcumin bound in the active site, noting the important amino acid residues for binding.

In cell-based experiments, curcumin shows anti-cancer capabilities. Curcumin shows anti-proliferative, anti-invasive and apoptotic tendencies in MDA-MB-231 triple negative breast cancer cells and HaCaT cells. The researchers also found a synergistic relationship between curcumin and carfilzomib, a proteasome inhibitor marketed for the treatment of triple negative breast cancer patients and multiple myeloma. Curcumin in conjunction with other proteasome inhibitors could make an interesting combination for the treatment of disease.

LKT Laboratories, Inc. offers curcumin for research at two different specifications, to meet all your research needs.

C8069 Curcumin, research grade
C8070 Curcumin, high purity
C0271 Carfilzomib

Banerjee S, Chenggong J, Mayefield JE, Goel A et al. “Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2.” Proc. Nat. Acad. Sci. 2018, 115(32): 8155-8160. doi: 10.1073/pnas.1806797115.

Theaflavin is a polyphenol found in black tea, along with related compounds theaflavin-3-gallate and Theaflavin-3,3’-digallate. Black tea, one of the most common beverages consumed worldwide, is made from the fermentation of green tea leaves. During this process, green tea polyphenols are modified into the theaflavins. These naturally occurring compounds demonstrate beneficial effects in a variety of diseases.

Recent studies have found that theaflavins reduce cell proliferation and induce apoptosis of ovarian cancer cells. These compounds also work against a cisplatin resistant ovarian cancer cell line A2780/CP70. Further studies with theaflavin-3, 3’-digallate showed that cells were arrested in the G2 stage of the cell cycle.

Additionally, theaflavins can act as anti-inflammatory compounds. When used in the LPS model for inflammation, theaflavin-3,3’-digallate decreased expression of cytokine inflammation markers TNFa, IL-1b, and IL-6. This occurred in both an in vitro and in vivo system, while showing very little cytotoxic effects.

An antimicrobial mechanism is postulated for Theaflavins. A recent manuscript shows that all of the theaflavins can inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), a key enzyme in bacterial terpenoid biosynthesis, in an uncompetitive manner.

The Theaflavin family of molecules is available from LKT Laboratories, Inc.

T286161 Theaflavin

T286165 Theaflavin-3-gallate

T286163 Theaflavin-3, 3’-digallate

References:

1. Gao Y., Rankin GO., Tu, Y., and Chen YC., “Inhibitory Effects of the Four Main Theaflavin Derivatives Found in Black Tea on Ovarian Cancer Cells.” Anticancer Res. 2016 Feb;36(2):643-51.

2. Tu Y., Kim E., Gao Y., et al. “Theaflavin-3,3’-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells.” Int. J. Oncol. 2016 Jun;48(6):2657-65. Doi: 10.3892/ijo.2016.3472.

3. Wu Y., Jin F., Wang Y., et al. “In vitro and in vivo anti-inflammatory effects of theaflavin-3,3’-digallate on lipopolysaccharide-induced inflammation.” Eur. J. Pharmacol. 2017 Jan 5;794:52-60. Doi:10.1016/j.ejphar.2016.11.027

4. Hui X., Yue, Q., Zhang DD., et al. “Antimicrobial mechanism of theaflavins: They target 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the key enzyme of the MEP terpenoid biosynthetic pathway.” Sci Rep. 2016 Dec 12;6:38945. Doi: 10.1038/srep38945.

Sponges are known to produce secondary metabolites that act as chemical defense mechanisms. Because the sponge is a sessile organism with a fragile body, it has limited capability to defend itself otherwise. The sponge’s secondary metabolites act as chemical weapons and can ward off dangers such as attacking predators or bacterial infections. One of these secondary metabolites, produced by sponges belonging to the order Verongida, is the compound Aeroplysinin.

Aeroplysinin has been studied in several biological systems in the lab for its potential use against human diseases. Recently, Park, et al has done studies that indicate aeroplysinin attenuates the Wnt/b-catenin signaling in DLD-1 colon cancer cells. b-Catenin is involved in the development and progression of colon cancer, and so it may make a useful target on which to focus therapeutics or chemopreventive agents. Experimental treatment of HEK293 cells with aeroplysinin decreased the amount of intracellular b-catenin, meaning that aeroplysinin may make a useful chemopreventive agent and should be further investigated for this use.

In addition to showing inhibition of colon cancer, other studies have found aeroplysinin to demonstrate antibiotic, antimicrobial, antiviral, anti-inflammatory, and anti-angiogenic activities.

There are thousands of species of marine sponges alive today and each produces a unique set of secondary metabolites necessary for its own survival. Each of these secondary metabolites is a compound with some bioactivity that may provide a useful starting point for developing new compounds to battle human diseases.

Several compounds found in marine sponges are available from LKT Labs including:

A1865 Aeroplysinin

G0244 alpha-Galactosylceramide

M0255 Manzamine A

P8382 Puupehenone

V3212 Vidarabine

V3213 Vidarabine Monophosphate

Garcia-Vilas JA, Martinez-Poveda B, Quesada AR, Medina MA. Aeroplysinin-1, a sponge-derived multi-targeted bioactive marine drug. Mar Drugs. 2015 Dec 22;14(1):1. Doi: 10.3390/md14010001

Park S, Kim JH, Kim JE, et al. Cytotoxic activity of aeroplysinin-1 against colon cancer cells by promoting b-catenin degradation. Food Chem Toxicol. 2016 Jul;93:66-72. Doi: 10.1016/j.fct.2016.04.019

4-O-Methylhonokiol (M184770) is isolated from the bark of Magnolia officinalis along with the natural products honokiol and magnolol. This lignan has found utility in a range of research fields, from neuroscience to cancer.

Researchers have found that 4-O-Methylhonokiol can act as a neuroprotective agent, potentially by acting as an acetylcholinesterase inhibitor in mice. In a Morris water maze assay, after scopoloamine treatment to induce memory impairment, mice that received 4-O-Methylhonokiol performed better with reduced escape latency time compared with control mice. This was found in conjunction with suppressed acetylcholinesterase activity in mouse hippocampus and cortex with 4-O-Methylhonokiol treatment.

A similar study showed that 4-O-Methylhonokiol decreases the effect of LPS (lipopolysaccharides)-induced memory impairment in mice. In a Morris water maze experiment, mice performed better after LPS injection when treated with 4-O-Methylhonokiol, compared to control. Further experiments showed that 4-O-Methylhonokiol does this by inhibiting NF-κB, which in turn decreased the expression of Aβ1-42 in mouse brains. Additionally, 4-O-Methylhonokiol reduced expression of nitric oxide and PGE2, which are over-expressed in LPS-treated mice models.

More neuroprotective studies of 4-O-Methylhonokiol have shown that it increases the amount of 2-arachidonyl glycerol in mice brain by activating cannabinoid type-2 receptor (CB2), and acting as a substrate-specific inhibitor of COX-2. The inhibtion of COX-2 was shown by a decrease in the presence of PGE2 in mouse brain. This dual activity could allow for beneficial effects in neuroinflammatory states with over-expressed CB2 and COX-2 proteins.

In addition to neuroprotective studies, 4-O-methylhonokiol also has activity as an anti-cancer compound, as well as other disease states. 4-O-Methylhonokiol (M184770) is now available from LKT Laboratories, Inc. in 5, 10, 25, and 100 mg size bottles.

M184770 4-O-Methylhonokiol

H5654 Honokiol

M0125 Magnolol

Lee, Y. K., Yuk, D. Y. et al. “Protective effect of the ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on scopolamine-induced memory impairment and the inhibition of acetylchlinesterase activity” J Nat Med. 2009 Jul; 63(3):274-282 PMID: 19343477

Lee, Y.J., Choi, D.Y. et al. “Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models” J Neuroinflammation. 2012 Feb 19;9:35 PMID: 22339795

Chicca, A. Gachet, M.S. et al. “4’-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation” J Neuroinflammation. 2015 May 13; 12:89 PMID: 25962384

Type 2 diabetes is a chronic condition in which the body resists the effects of insulin or doesn’t produce enough insulin to maintain a healthy glucose level. Since insulin is a hormone that regulates the the metabolism of sugar, type 2 diabetes typically leads to high blood sugar, which can lead to heart disease or kidney failure.

Sulforaphane, a natural compound found in broccoli, cauliflower, and other cruciferous vegetables, has been identified as a possible counter to type 2 diabetes. In a study published in June of 2017 by Lund University, R-Sulforaphane from LKT Labs was shown to suppress glucose production from hepatic cells by nuclear translocation of NRF2, and decreased the expression of important enzymes in gluconeogenesis. Sulforaphane also reversed the disease signature in the livers of diabetic animals. Finally, sulforaphane was also administered to obese patients with dysregulated type 2 diabetes, and was shown to reduce fasting blood glucose and glycated hemoglobin.

R,S-Sulforaphane is a synthetic organosulfur compound that displays a variety of interesting characteristics, including anticancer, antimicrobial, antioxidative, anti-inflammatory, and neuroprotective activities. It is a phase II enzyme inducer and induces the expression of the transcription factor Nrf2.

R-Sulforaphane is found naturally in cruciferous vegetables such as broccoli, and has been continuously studied for its health benefits, sometimes showing increased effectiveness compared to its synthetic R,S counterpart in various models.

S8044 R,S-Sulforaphane, High Purity (≥99%)

S8047 R,S-Sulforaphane, Research Grade (≥97%)

S8046 R-Sulforaphane, High Purity (≥99%)

S8048 R-Sulforaphane, Research Grade (≥97%)

1. Axelsson AS, Tubbs E, Rosengren AH, et al. “Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes.“. Sci Transl Med. 2017 Jun 14;9(394).

β-cembrenediol ((1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol) is a diterpenoid that is isolated from the leaves of nicotiana tabacum (tobacco) plants. β-cembrenediol has been found to have neuro-protective effects in mice, reducing ischemic brain injury. The effect was found in both pre-treated and post-injury mice. It does this by increasing the phosphorylation of Akt, a well-known neuroprotective pathway. Additionally, β-cembrenediol and analogs have been found as anti-migratory compounds in wound healing assays with prostate cancer cells.

β-cembrenediol, and it’s C-4 epimer α-cembrenediol are in stock and available for research use.

C1649 β-cembrenediol

C1648 α-cembrenediol

C1650 β-cembrenediol Methyl Ether

Martins A. H. , Hu, J., et al. “Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and In vivo in Rodent Models of Brain Ischemia” Neuroscience. 2015, Apr 16; 291: 250-259. Doi: 10.1016/j.neuroscience.2015.02.001

Baraka, H. N., Khanfar, M. A., et al. “Bioactive Natural, Biocatalytic, and Semisynthetic Tobacco Cembranoids” Planta Med 2011 Mar:77(5):467-476. Doi: 10.1055/s-0030-1250478.