ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/iedc20 Frankincense diterpenes as a bio-source for drug discovery Hidayat Hussain, Luay Rashan, Uzma Hassan, Muzaffar Abbas, Faruck L. Hakkim & Ivan R. Green To cite this article: Hidayat Hussain, Luay Rashan, Uzma Hassan, Muzaffar Abbas, Faruck L. Hakkim & Ivan R. Green (2022) Frankincense diterpenes as a bio-source for drug discovery, Expert Opinion on Drug Discovery, 17:5, 513-529, DOI: 10.1080/17460441.2022.2044782 To link to this article: https://doi.org/10.1080/17460441.2022.2044782 © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group Published online: 04 Mar 2022. Submit your article to this journal Article views: 3913 View related articles View Crossmark data Citing articles: 8 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iedc20
2022, VOL. 17, NO. 5, 513–529 https://doi.org/10.1080/17460441.2022.2044782 REVIEW Frankincense diterpenes as a bio-source for drug discovery Hidayat Hussaina, Luay Rashanb, Uzma Hassanc, Muzaffar Abbasd, Faruck L. Hakkime and Ivan R. Greenf a Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle, Germany; bMedicinal Plants Division, Research Center, Dhofar University, Salalah, Oman; cInstitute of Chemical Sciences, University of Peshawar, Peshawar, Pakistan; dFaculty of Pharmacy, Capital University of Science & Technology, Islamabad, Pakistan; eHormel Institute, University of Minnesota, Austin, USA; fDepartment of Chemistry and Polymer Science, University of Stellenbosch, Stellenbosch, South Africa ABSTRACT Introduction: Frankincense (Boswellia sp.) gum resins have been employed as an incense in cultural and religious ceremonies for many years. Frankincense resin has over the years been employed to treat depression, inflammation, and cancer in traditional medicines. Areas covered: This inclusive review focuses on the significance of frankincense diterpenoids, and in particular, incensole derivatives for establishment future treatments of depression, neurological dis orders, and cancer. The authors survey the available literature and furnish an overview of future perspectives of these intriguing molecules. Expert opinion: Numerous diterpenoids including cembrane, prenylaromadendrane, and the verticil lane-type have been isolated from various Boswellia resins. Cembrane-type diterpenoids occupy a crucial position in pharmaceutical chemistry and related industries because of their intriguing biological and encouraging pharmacological potentials. Several cembranes have been reported to possess anti-Alzheimer, anti-inflammatory, hepatoprotective, and antimalarial effects along with a good possibility to treat anxiety and depression. Although some slight drawbacks of these com pounds have been noted, including the selectivity of these diterpenoids, there is a great need to address these in future research endeavors. Moreover, it is vitally important for medicinal chemists to prepare libraries of incensole-heterocyclic analogs as well as hybrid compounds between incensole or its acetate and anti-depressant or anti-inflammatory drugs. 1. Introduction Frankincense has been grown in those areas having a distinct monsoon climate in the Arabian Peninsula, Ethiopia, Somalia, and India since ancient times. In addition, frankincense has been traded between Europe and China for the past 5000 years [1]. Another important aspect to be noted about frankincense is that it is expensive and thus considered to be a sign of wealth. In ancient times, frankin cense was one of the most important prosperity indicators in the Arabian Peninsula and considered to be a most pre cious resource in Europe. Frankincense resin has been employed for religious rituals in both Orthodox and Catholic churches and in funeral ceremonies. Frankincense has been used in numerous traditional medicines to treat cancer, stomach issues, flatulence, diabetes, Alzheimer's dis ease, central nervous system diseases, constipation, and inflammatory diseases [1–4]. Historically, frankincense has been employed since 2800 BCE and this plant is mentioned numerous times in ancient Egyptian medical records. It was employed in perfumes and as a burn incense along with being a component for the pre paration of balm and unguents for mummification. This is supported by writings about frankincense and myrrh being ARTICLE HISTORY Received 15 October 2021 Accepted 17 February 2022 KEYWORDS Frankincense; cembrane; prenylaromadendrane; verticillane; inflammation; depression; alzheimer’s renowned at the time the Bible was being written because both these compounds were extensively mentioned and observed to be the most often used together with important aromatic resins [5,6]. Frankincense was also employed in Islamic traditional medicine in Arabian countries because this plant is stated in Avicenna’s (Ibn Sina’s) Canon of Medicine. It was employed to treat tuberculosis, amnesia, infections, bruises, diarrhea, burns, stomach issues, and eye sores. Moreover, frankincense is employed in Ayurvedic medicine to treat various other diseases as well [2,7]. Notably, frankin cense was approved at the beginning of the 20th century to treat various inflammation diseases and is mentioned in the 7th supplement of the European Pharmacopoeia [2]. On the other hand, frankincense is also employed in Chinese tradi tional medicine because frankincense-based pills named ‘xihuang’ have been employed to treat bronchial, nasophar yngeal, or pancreatic carcinomas [2,8]. Frankincense is essentially a resin derived from the tree of the genus Boswellia and mainly from five species, i.e. B. carterii, B. serrata, B. papyrifera, B. sacra, and B. frerana. The Boswellia genus, incorporating over 30 species out of which 16 grow in tropical Africa and Asia [2]. Chemical investigation of frankin cense resin has revealed that it comprises over 200 different natural products, including penta- and tetracyclic triterpenoids, CONTACT Hidayat Hussain Hidayat.Hussain@ipb-halle.de Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany; Luay Rashan lrashan@du.edu.om Medicinal Plants Division, Research Center, Dhofar University, Salalah 211, Oman; Muzaffar Abbas muzaffar.abbas@cust.edu.pk Faculty of Pharmacy, Capital University of Science & Technology, Islamabad, Pakistan © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
H. HUSSAIN ET AL. Article highlights ● ● ● ● ● Frankincense resin has over the years been employed in traditional medicines to treat depression, inflammation, and cancer Various diterpenes have been isolated from frankincense and demon strated intriguing biological activities Among frankincense diterpenoids, incensole, and its acetate illu strated significant biological and pharmacological effects Frankincense diterpenoids possess anti- inflammatory, neuroprotec tive, hepatoprotective, antimalarial, and cytotoxic effects These diterpenoids have a great potential to be used in the treat ment of Alzheimer’s disease, anxiety, and depression This box summarizes key points contained in the article. diterpenoids, polyphenols, essential oils, and tannins [2,9–15]. Terpenes are considered to be one of the most structurally diverse groups among the spectrum of natural products. Furthermore, over 55,000 terpenes have been reported as iso lated from various natural sources featured intriguing chemical diversity along with interesting biological properties. Among the terpenes, diterpenes are one of the largest groups of sec ondary metabolites with over 18,000 molecules derived from GGPP (E,E,E-geranylgeranyl diphosphate). Moreover, these com pounds can be classified according to their biogenesis and over 126 different carbon skeletons have been reported to date [16]. Quite recently, Al-Harrasi et al. [17] published a review about the cembrane diterpenoids from the Boswellia species but their focus was more on the chemistry rather on their biology. In this review, we provide a comprehensive overview of detailed bio logical investigations of frankincense diterpenoids (cembrane and prenylaromadendrane-type diterpenes). 250 mg twice daily dose. Ahangarpour et al. [21] studied antidiabetic effects of B. serrata gum resin on patients with a 900 mg daily dose for 6 weeks. In this case, the authors noticed a remarkable enhancement in blood HDL along with a significant reduction in triglyceride, cholesterol, SGPT, LDL, fructosamine, and SGOT levels. Schrott et al. [22] in 2014 published a case report about the antidiabetic effects on one patient treated for 8.5 weeks with a B. serrata extract and the tyrosine phosphatase A2 antibody (IA2–A) marker was reduced from 25 K/U/1 to 10 K/U/1. In another report, Silybum maria num seeds, Urtica dioica leaves, and B. serrata resin capsules reduced the plasma glucose, glycosylated hemoglobin (HbA1c), serum triglyceride, and cholesterol [23]. Craft et al. [24] in a double-blind, randomized, placebocontrolled clinical trial demonstrated that B. serrata along with Melissa officinalis extract tablets improved total mem ory score in 70 elderly patients. Asadi et al. [25] showed that frankincense resin had a remarkable effect on the retention and acquisition of explicit motor memory, while Aghajani et al. [26] reported that 70 elderly patients they were treat ing experienced an enhanced memory after taking frankin cense extract for 30 days. Givad et al. [27] showed that 60 patients taking capsules containing 500 mg of powdered frankincense experienced improved muscle strength in their left limbs but interestingly, did not experience the same effect in their right limbs. Moreover, B. carterii essential oil inhalation aromatherapy was found to have a positive effect on the intensity of labor pain among women [28] and menstrual bleeding duration was reduced in the B. serrata and ginger group [29]. 3. Frankincense diterpenes 2. Clinical investigation of frankincense 3.1. Tetrahydrofurano cembranoids In this part, mainly randomized clinical trials (RCT) are pre sented (Table 1) excluding anticancer and anti-inflammatory activity because these two trials have already been covered in detail [2]. Mehrzadi et al. investigated the antidiabetic effects of B. Serrata in 56 diabetic patients and found that there was a marginal reduction in glycosylated hemoglobin, blood sugar, and triglyceride in the B. serrata gum resin group [18]. In another randomized, placebo-controlled trial, Azedmehr et al. [19] investigated the B. serrata gum resin effects on the 71 type 2 diabetes patients with frankincense resin of 400 mg, which was taken orally for the duration of 12 weeks. Additionally, the patients were also being treated with met formin. Notably, a significant reduction was observed in serum insulin, HbA1c, and fasting blood glucose along with some decrease in triglycerides, serum cholesterol, and LDL in com parison with the placebo group. In another placebo and randomized controlled trial, Mehrzadi et al. [20], investigated B. serrata effects on 56 type 2 diabetic patients and results showed that B. serrata gum resin did not affect the patients with a dose of 250 mg for 8 weeks. Moreover, this discrepancy between the Azedmehr et al. [19] study and this one [20] could be due to the 400 mg twice daily dose (higher dose of the resin) along with 12 weeks treatment rather than the 8 weeks treatment and The cembrane skeleton comprises a 14-membered carbocyclic core system ‘A’ (Figure 1) featuring an isopropyl group at C-1 along with three methyl groups at C-4, C-8, and C-12. Moreover, this skeleton is also diversified with other core skeletons having 12 or 13-membered carbon skeletons along with lactone, cyclic ether, or furan groups around the macro cyclic system [30]. Yu et al. [31] isolated six tetrahydrofuran cembranoids named boscartins AP (1), AR (2), AS (3), AT (4), AU (5), and AW (6) from B. carterii. Moreover, compounds 1–6 all featured a tetrahydrofuran ring along with an isopropyl group. Biological investigations of compounds 1–6 showed that com pound 1, bearing two hydroxyl groups (C-4 and C-6) along with one acetoxy group, illustrated significant antiinflammatory effects toward LPS-induced RAW 264.7 cells with IC50: 13.1 μM (Table 2) while the remaining compounds were not active (IC50: >50 μM). In addition, compounds 1–6 were tested for their activity toward hepatoprotective effects induced by APAP toward HepG2 cells. Notably, compound 1 proved to be the most potent and illustrated hepatoprotective activity with percentage inhibition: 30.7% at 10 μM and its effect was higher than the standard bicyclol (percentage inhi bition: 27.2%). In addition, the hepatoprotective activity of compounds 4 and 6 showed significant inhibitions with
515 Table 1. Clinical studies of frankincense. Trial design Diabetes: type 2 RCT, double blind, 56 patients, 56 days Diabetes: type 2 RCT, double blind, 71 patients, 84 days Diabetes: type 2 RCT, double blind, Diabetes: type 2 RCT, double blind, Diabetes: type 1 RCT, double blind, Diabetes: type 1 RCT, double blind, Dose Commercial B. serrata resin (500 mg per day) Effect Ref Blood sugar↓, glycosylated hemoglobin↓, and [18] triglyceride↓ Commercial B. serrata resin (400 mg caps; two times blood glucose↓, HbA1c↓, serum insulin↓, serum [19] cholesterol↓, per day) LDL↓ and triglycerides↓ Commercial B. serrata resin (250 mg; two times per day) No significant effect [20] 56 patients, 58 days Commercial B. serrata resin (900 mg per day) 60 patients, 42 days one patient, 60 days 60 patient, 90 days Alzheimer
H. HUSSAIN ET AL. Figure 1. Structures of compounds 1–10. protection effects with cell viability rates of 74.6% and 71.6%, respectively, which effects were higher than the standard PHPB: 70.0%) [34]. Boscartins AH–AO (28–35) (Figure 3) is produced by B. carterii and only compound 35, which features an α,βunsaturated keto group along with an epoxide and acetyl group, illustrated significant anti-inflammatory effects via inhi bition of NO production with an IC50: 14.8 µM. On the other hand, the same compound was the least active in terms of its hepatoprotective effects with cell viability rates of 44.0%. Moreover, compounds 28 and 29 displayed potent hepato protective effects with cell viability rates of 75.5% and 68.8% respectively [35]. Notably, these compounds have better hepa toprotective effects than the standard bicyclol (67.7%). SAR studies showed that compounds 28 and 29 possessed better effects and it should be noted that they possess one furan ring and two epoxide rings. Additionally, both compounds have the same core structure except for the position of their double bonds viz. (28: C-8/C-9 double bond vs 29: C-8/C-19 double bond). Although compound 30, which is less active than compounds 28 and 29, also has one furan ring and two epoxide rings. However, this former compound (30) has the second epoxide ring at a different position compared to compounds 28 and 29 [35]. (1S, 3 R, 11S, 12 R, 7E)-1,12-Epoxy-4-methylenecembr-7-ene3,11-diol (36) along with boscartins L–M (37–39) were isolated from B. sacra. It was found that these compounds illustrated moderate hepatoprotective effects with cell viability rates ran ging from 18.6% to 36.6% and these activities were less than the standard bicyclo (53.0%) (Table 2) [36]. Moreover, the position of the double bonds and stereochemistry of the hydroxyl group impact the biological effects because diter pene 38 showed better effects (32.8%) when compared to isomer 37 (21.9%). On the other hand, sacraoxides C (40), E (41), and F (42) were reported to also be isolated from B. sacra and were evaluated for their anti-inflammatory effects. Secondary metabolites 41 and 42 having keto, double bond and acetate groups demonstrated the most significant inhibi tory effects toward LPS-induced NO production with IC50: 36.4 and 24.9 μM, respectively, while compound 40 which featured two double bonds, one hydroxyl, and one acetate group proved to be only moderately active with IC50: 72.1 μM [37]. Literature revealed that Boswellia species, interestingly, demonstrated wound healing properties. For example, B. serrata oleo-gum resin was able to effectively induce wound contraction [38]. In addition, B. serrata resin possesses peptic ulcer and colon ulcer healing properties [39]. Boswellians B (43) and C (44), two 4,5-seco cembrane-type diterterpenes, were isolated from B. papyifera and displayed significant wound heal ing properties at a 20 μ mol/L concentration. Both molecules effectively stimulate proliferation, tuber formation, and mobility of HUVECs (vein endothelial cells) [40].
517 Table 2. Biological effects of diterpenes 1–44. Compound Boscartin AP (1) Boscartin AR (2) Boscartin AS (3) Boscartin AT (4) Boscartin AU (5) Boscartin AW (6) Boscartins A (7) Boscartin E (8) Boscartin F (9) Boscartin G (10) Boscartin P (11) Boscartin U (12) Boscartin V (13) Boscartin W (14) Boscartin X (15) Boscartin Y (16) Boscartin AA (17) Boscartin AB (18) Boscartin AE (19) Boscartin AF (20) Compound 21 Boscartin AN (22) Effects Anti-inflammatory activity: IC50: 13.1 µM; Hepatoprotective activity: % inhibition: 30.7% Hepatoprotective activity: inhibition: 12.5% Hepatoprotective activity: inhibition: 26.7% Hepatoprotective activity: inhibition: 12.7% Hepatoprotective activity: inhibition: 25.9% Hepatoprotective activity: inhibition: 15.1% Antiulcerative colitis activity: EC50: 0.34 µM Antiulcerative colitis activity: EC50: 1.14 µM Antiulcerative colitis activity: EC50: 0.88 µM Antiulcerative colitis activity: EC50: 0.42 µM Hepatoprotective activity: inhibition: 26.2% Hepatoprotective activity: inhibition: 24.3% Hepatoprotective activity: inhibition: 22.4% Hepatoprotective activity: inhibition: 24.3% Hepatoprotective activity: inhibition: 31.6% Hepatoprotective activity: inhibition: 53.7% Hepatoprotective activity: inhibition: 24.3% Hepatoprotective activity: inhibition: 38.3% Hepatoprotective activity: inhibition: 31.6% Hepatoprotective activity: inhibition: 31.6% Hepatoprotective activity: inhibition: 39.9% Hepatoprotective activity: cell viability: 80.5%; inhibition: 25.8% Ref. Compound Effects [31] Boscartin AP Hepatoprotective activity: cell viability: 77.3%; inhibition: 20.7% (23) Neuroprotective effects in SK–N-SH cells: cell viability: 74.6%; inhibition: 17.0% [31] Boscartin AR Neuroprotective effects in against glutamate-induced toxicity in primary (24) cultured fetal rat cortical neurons: cell viability: 70.2%; inhibition: 17.0% [31] Boscartin Hepatoprotective activity: cell viability: 76.6%; inhibition: 19.7% AC (25) [31] Boscartin Neuroprotective effects in against glutamate-induced toxicity in primary AG (26) cultured fetal rat cortical neurons: cell viability: 73.8%; inhibition: 23.0% [31] Compound Hepatoprotective activity: cell viability: 72.5%; inhibition: 13.2% 27 [31] Boscartin Hepatoprotective activity: cell viability: 75.5%; inhibition: 45.7% AH (28) [32] Boscartin AI Hepatoprotective activity: cell viability: 68.0%; inhibition: 21.0% (29) [32] Boscartin AJ Hepatoprotective activity: cell viability: 57.5%; inhibition: 6.1% (30) [32] Boscartin Hepatoprotective activity: cell viability: 63.6%; inhibition: 13.6% AK (31) [32] Boscartin AL Hepatoprotective activity: cell viability: 51.9%; inhibition: 2.5% (32) [33] Boscartin Hepatoprotective activity: cell viability: 61.8%; inhibition: 9.3% AM (33) [33] Boscartin Hepatoprotective activity: cell viability: 49.4%; inhibition: −2.9% AN (34) [33] Boscartin Hepatoprotective activity: cell viability: 44.0%; inhibition: −4.6%; AntiAO (35) inflammatory activity: NO production (IC50: 14.8 µM) [33] Compound Hepatoprotective activity: cell viability: 18.6%; inhibition: −19.5% 36 [33] Boscartin Hepatoprotective activity: cell viability: 21.9%; inhibition: −14.8% L (37) [33] Boscartin Hepatoprotective activity: cell viability: 32.8%; inhibition: 1.3% M (38) [33] Boscartin Hepatoprotective activity: cell viability: 27.5%; inhibition: −6.5% N (39) [33] Sacraoxides Anti-inflammatory effects: IC50: 72.1 μM C (40) [33] Sacraoxides Anti-inflammatory effects: IC50: 36.4 μM E (41) [33] Sacraoxides Anti-inflammatory effects: IC50: 24.9 μM F (42) [33] Boswellian Wound healing activity: promotes HUVECs proliferation in a dose B (43) dependent manner; migration capacity of HUVECs↑, F-actin↑ [34] Boswellian Wound healing activity: promotes HUVECs proliferation in a dose C (44) dependent manner; HUVECs cell proliferation↑, HUVECs tube formation↑ 4. Incensole derivatives 4.1. Anti-inflammatory effects The frankincense resin containing incensole (45) and its acetate derivative, incensole acetate (IA, 46) (Figure 4) has been used globally to manage inflammatory disorders and is currently in use for its anti-inflammatory potential. It is used as an anti-inflammatory agent in Asia and Europe as Jerusalem Balsam [41]. The extracts of Boswellia resin are also incorporated as supplements in foods for the manage ment of arthritis in Europe and the USA. Moussaieff et al. [42] reported that these readily available products need to be standardized for their active components, including incensole acetate (IA, 46) and incensole analogs along with boswellic acids. Moussaieff et al. [41] in 2007 demonstrated that incensole (45) and incensole acetate (IA, 46) mediated the degradation of IκBα in HeLa cells stimulated with TNFα. Ref. [34] [34] [34] [34] [34] [35] [35] [35] [35] [35] [35] [35] [35] [36] [36] [36] [36] [37] [37] [37] [40] [40] IA (46) significantly inhibited IκBα degradation. It was demonstrated that incensole acetate (IA, 46) inhibited IKK phosphorylation and consequently, activation in vivo, but not in vitro, indicating that IA (46) exerted its effect upstream of IKK. Moreover, IA (46) prevented NF-κB activa tion (Table 3) mediated through LPS and TNFα stimulation in Jurkat T cells that are co-stimulated. IA (46) reduced TAK/ TAB mediated phosphorylation of the IKKα/β and subse quently, the activation pathway through interference with a step that couples TAK to the phosphorylation of IKK. However, this attenuation seems to be specific as IA (46) does not inhibit TNFα-mediated activation of p38 MAPK and JNK. IA (46) inhibits the phosphorylation of IκBα and its degra dation, along with inhibition of phosphorylation of IKK at serine 536. The IKK plays a critical role both in p65 and IκBα phosphorylation [43]. Furthermore, as IA (46) does not
H. HUSSAIN ET AL. Figure 2. Structures of compounds 11–27. inhibit TRAF2-overexpressing cells and therefore supports a specific intervention of IA (46) at the TAK1-IKK activation stage. However, IA (46) effects on IKK are similar to that of tetracyclic kaurene diterpenes as reported earlier by Castrillo et al. [44], since both are inhibitors of the signaling pathway. This fact illustrates that the action of IA (46) is more related to the NF-κB pathway as kaurenes also decrease the phosphorylation of ERK1, ERK2, p38, and MAPK. The mechanism through which terpenes reduce IKK activation is poorly understood [44]. 4.2. Neuroprotective effects Moussaieff et al. [45] reported that IA (46) produces neuro protective effects in an animal model of traumatic brain injury (TBI). Their study demonstrated its prolonged effec tiveness on memory and motor functions that suggested that the significant prolonged neuroprotection of IA (46) after CHI linked to decreased expression of IL-1β and TNFα mRNAs and reduced activation of glial cells and thus neurodegeneration. The inhibition of inflammatory cyto kines by IA (46) and the beneficial effect produced by its administration on cognitive and motor recovery, are in line with the view that reduced expression of proinflammatory cytokines following brain injury is helpful for recovery [46]. Reduced immunoreactivity of GFAP is associated with the decreased labeling of microglial cells, indicating that IA (46) produces neuroprotection due to its anti-inflammatory effect. Since IA (46) produces an inhibitory effect on NFkB, reported by the same author in 2007 [41], and apoptosis in macrophages, it is possible that the anti-inflammatory potential of IA (46) following trauma is due to inhibition of NF-kB activation and occurs via apoptosis of the macrophage. The potential of IA (46) to decrease neurodegeneration within the hippocampus and to enhance memory suggests that the enhanced memory ability is due to at least the
519 Figure 3. Structures of compounds 28–44. decreased neuronal death within the hippocampus. Nevertheless, the involvement of other mechanisms respon sible for IA (46) beneficial effects cannot be ruled out such as involvement of the modulation of the NMDA receptor in memory impairment and recovery [47]. Further studies showed that IA (46) produces a mild hypothermia. Other studies have shown the involvement of crosstalk between anti-inflammatory action and hypothermia associated with injury in the central nervous system [48,49]. However, in studies conducted by Moussaieff et al. [45], involving the prevention of this hypothermic effect of IA (46), they found that it did not reduce its neuroprotective action. This inves tigation illustrated that the IA (46)-mediated hypothermic effect plays no central role in the functional neuroprotective action produced by it. This finding is not unexpected due to the modest and brief nature of the observed reduction on temperature. These results of Moussaieff et al. [45] are in line with findings of Schuhmann et al. [50], who demonstrated that B. carterii resin showed neuroprotective action following controlled cortical impact. However, the results of Moussaieff et al. [45] indicate that the neuroprotection exhibited by B. carterii resin might be due to IA (46) and its derivatives. Nevertheless, in contrast to results by Schuhmann et al. [50], the data of Moussaieff et al. [45] indicated that IA (46) did not produce any substantial inhibitory action on post-traumatic edema formation within the cerebrum in animal model studies on mice. The inconsistency between these findings could be due to the difference in species (mice versus rats) and the
H. HUSSAIN ET AL. Figure 4. Structures of compounds 45–59. models used (CHI versus controlled cortical impact). Therefore, it is also likely that Boswellia resin, as reported by Schuhmann et al. [50], had additional compounds of a neuroprotective nature such as boswellic acids and their derivatives demonstrating their anti-inflammatory effects [51]. Pollastro et al. [52] evaluated incensole (45) and IA (46) along with the incensole semisynthetic derivatives 47–55 for their neuroprotective effects via TRPV3 activation. Incensole acetate (46) which features an acetate group at the C-5 hydro xyl group of incensole proved to be the most active com pound and activated the TRPV3-mediated calcium influx with EC50: 1.4 μM. Notably, the EC50 value observed in rTRPV3 was less than that reported by Moussaieff et al. [53] for mTRPV3 (EC50: 16 μM), indicating an excessive sensitivity to incensole acetate (46) for the rat orthologue. Moreover, cleavage of the acetate group leads to incensole (45) and this acetate clea vage reduces the activity (45: EC50: 2.1 μM). Oxidation of the C-5 secondary hydroxyl group in the later compound results in the formation of the corresponding keto comprising com pound, incensone (54) and this keto group slightly decreases activity (EC50: 2.1 vs 2.4 μM) (Table 3). Conversely, inverting the stereochemistry of the C-5 hydroxyl group (epimerization) of incensole (45) followed by acetylation produced epi-incensol acetate (55) which exhibited a decrease of the TRPV3activating effects (EC50: 7.3 μM). Additionally, epoxidation of incensole (45) to the 3-nonyl (52: EC50: 8.8 μM) and 7-epoxides (53: EC50: 8.6 μM) also displayed reduced efficacy [52]. The decrease in activity was further evident after substitu tion of the acetate group with a cinnamate moiety (50: EC50: 10.5 μM). Conversely, the decrease in neuroprotective effects was evident for the benzoate derivative 48 (EC50: 4.4 μM) along with the nonanoate analog 47 (EC50: 5.6 μM). On the other hand, compounds bearing a phenylacetate group (com pound 49: EC50: 1.2 μM) illustrated similar potency compared to incensole acetate (46). In addition, phenylacetate analog 49 demonstrated promising inhibitory effects on NF-κB with acti vations of IC50: 22.4 μM. Moreover, the incensol nonanoate (47) also inhibited STAT3 with IC50: 38.7 μM. However, the other incensole derivatives were inactive [52]. 4.3. Alzheimer’s disease and memory enhancement Frankincense has demonstrated an ability to produce devel opmental alterations in the brains of laboratory animals such as an increase in neuronal volume and dendritic spines num ber and promoting memory formation [54]. For instance, maternal administration of frankincense during gestation increased neuronal dendritic segments in the CA3 region of the hippocampus. Branching density of dendrites was also elevated in frankincense treated rats as compared to control animals [55]. Moreover, it was shown that the volume of the cellular layer of CA3 and dentate gyrus as well as individual neurons in the hippocampus were significantly increased dur ing lactation following maternal injection of frankincense [56]. Furthermore, this study also demonstrated that maternal administration of frankincense upregulated the signaling med iator, reflecting an increased expression of calcium/calmodulin kinase II-α (CaMKII-α) mRNA in the hippocampus and an improvement in memory formation during gestation and lac tation periods in juvenile rats [57]. Recently, Beheshti et al. [54] demonstrated that during gestation and lactation, maternal administration of frankin cense significantly enhanced spatial memory formation in off spring male rats. Moreover, long-term administration of a B. serrata aqueous extract increased spatial learning forma tion in animals [58,59]. In Iran, frankincense was employed by the famous physician, Avicenna, to reduce amnesia and enhance memory function during the 10th century [59].
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