Frankincense diterpenes as a bio-source for drug discovery

Figures & data

Table 1. Clinical studies of frankincense

Trial design	Dose	Effect	Ref
Diabetes: type 2 RCT, double blind, 56 patients, 56 days	Commercial B. serrata resin (500 mg per day)	Blood sugar↓, glycosylated hemoglobin↓, and triglyceride↓	[18]
Diabetes: type 2 RCT, double blind, 71 patients, 84 days	Commercial B. serrata resin (400 mg caps; two times per day)	blood glucose↓, HbA1c↓, serum insulin↓, serum cholesterol↓, LDL↓ and triglycerides↓	[19]
Diabetes: type 2 RCT, double blind, 56 patients, 58 days	Commercial B. serrata resin (250 mg; two times per day)	No significant effect	[20]
Diabetes: type 2 RCT, double blind, 60 patients, 42 days	Commercial B. serrata resin (900 mg per day)	Blood HDL↑, triglyceride↓, cholesterol↓, SGPT↓, LDL↓, fructosamine↓, and SGOT↓	[21]
Diabetes: type 1 RCT, double blind, one patient, 60 days	Commercial B. serrata resin (three times 800 mg per day)	Tyrosine phosphatase A 2 antibody (IA2 – A)↓	[22]
Diabetes: type 1 RCT, double blind, 60 patient, 90 days	Silybum marianum seeds, Urtica dioica leaves, and B. serrata resin capsule (three capsules per day)	Fasting Plasma Glucose (FPG)↓, glycosylated hemoglobin (HbA1c)↓, serum triglyceride↓, cholesterol↓,	[23]
Alzheimer<apos;>s disease RCT, double blind, 70 patients, 300 days	B. serrata and Melissa officinalis extracts tablets (two tablets per day)	Total memory score↑	[24]
Alzheimer<apos;>s disease RCT, double blind, 20 patients, 28 days	Boswellia sp. resin pills (500 mg two tablets per day)	memory acquisition↑, memory retention↑	[25]
Alzheimer<apos;>s disease RCT, double blind, 70 patients, 30 days	Boswellia sp. extracts	Total memory score↑	[26]
Ischemic stroke RCT, double blind, 60 patients, 30 days	Four capsules containing 500 mg frankincense per day	Improved muscle strength left limbs	[27]
Labor pain RCT, double blind, 126 women; the intervention was repeated for each woman every 30 min	Inhalation aromatherapy with B. carterii essential oil; a piece of gauze was soaked with 0.2 ml of 0.2% essential oil.	labor pain intensity↓	[28]
Menstrual bleeding: RCT, double blind, 102 women; 7 days	B. serrata (300 mg and ginger (300 mg); two times per day	Menstrual bleeding↓	[29]

Figure 1. Structures of compounds 1–10.

Table 2. Biological effects of diterpenes 1–44

Compound	Effects	Ref.	Compound	Effects	Ref.
Boscartin AP (1)	Anti-inflammatory activity: IC50: 13.1 µM; Hepatoprotective activity: % inhibition: 30.7%	[31]	Boscartin AP (23)	Hepatoprotective activity: cell viability: 77.3%; inhibition: 20.7% Neuroprotective effects in SK–N-SH cells: cell viability: 74.6%; inhibition: 17.0%	[34]
Boscartin AR (2)	Hepatoprotective activity: inhibition: 12.5%	[31]	Boscartin AR (24)	Neuroprotective effects in against glutamate-induced toxicity in primary cultured fetal rat cortical neurons: cell viability: 70.2%; inhibition: 17.0%	[34]
Boscartin AS (3)	Hepatoprotective activity: inhibition: 26.7%	[31]	Boscartin AC (25)	Hepatoprotective activity: cell viability: 76.6%; inhibition: 19.7%	[34]
Boscartin AT (4)	Hepatoprotective activity: inhibition: 12.7%	[31]	Boscartin AG (26)	Neuroprotective effects in against glutamate-induced toxicity in primary cultured fetal rat cortical neurons: cell viability: 73.8%; inhibition: 23.0%	[34]
Boscartin AU (5)	Hepatoprotective activity: inhibition: 25.9%	[31]	Compound 27	Hepatoprotective activity: cell viability: 72.5%; inhibition: 13.2%	[34]
Boscartin AW (6)	Hepatoprotective activity: inhibition: 15.1%	[31]	Boscartin AH (28)	Hepatoprotective activity: cell viability: 75.5%; inhibition: 45.7%	[35]
Boscartins A (7)	Antiulcerative colitis activity: EC50: 0.34 µM	[32]	Boscartin AI (29)	Hepatoprotective activity: cell viability: 68.0%; inhibition: 21.0%	[35]
Boscartin E (8)	Antiulcerative colitis activity: EC50: 1.14 µM	[32]	Boscartin AJ (30)	Hepatoprotective activity: cell viability: 57.5%; inhibition: 6.1%	[35]
Boscartin F (9)	Antiulcerative colitis activity: EC50: 0.88 µM	[32]	Boscartin AK (31)	Hepatoprotective activity: cell viability: 63.6%; inhibition: 13.6%	[35]
Boscartin G (10)	Antiulcerative colitis activity: EC50: 0.42 µM	[32]	Boscartin AL (32)	Hepatoprotective activity: cell viability: 51.9%; inhibition: 2.5%	[35]
Boscartin P (11)	Hepatoprotective activity: inhibition: 26.2%	[33]	Boscartin AM (33)	Hepatoprotective activity: cell viability: 61.8%; inhibition: 9.3%	[35]
Boscartin U (12)	Hepatoprotective activity: inhibition: 24.3%	[33]	Boscartin AN (34)	Hepatoprotective activity: cell viability: 49.4%; inhibition: −2.9%	[35]
Boscartin V (13)	Hepatoprotective activity: inhibition: 22.4%	[33]	Boscartin AO (35)	Hepatoprotective activity: cell viability: 44.0%; inhibition: −4.6%; Anti-inflammatory activity: NO production (IC50: 14.8 µM)	[35]
Boscartin W (14)	Hepatoprotective activity: inhibition: 24.3%	[33]	Compound 36	Hepatoprotective activity: cell viability: 18.6%; inhibition: −19.5%	[36]
Boscartin X (15)	Hepatoprotective activity: inhibition: 31.6%	[33]	Boscartin L (37)	Hepatoprotective activity: cell viability: 21.9%; inhibition: −14.8%	[36]
Boscartin Y (16)	Hepatoprotective activity: inhibition: 53.7%	[33]	Boscartin M (38)	Hepatoprotective activity: cell viability: 32.8%; inhibition: 1.3%	[36]
Boscartin AA (17)	Hepatoprotective activity: inhibition: 24.3%	[33]	Boscartin N (39)	Hepatoprotective activity: cell viability: 27.5%; inhibition: −6.5%	[36]
Boscartin AB (18)	Hepatoprotective activity: inhibition: 38.3%	[33]	Sacraoxides C (40)	Anti-inflammatory effects: IC50: 72.1 μM	[37]
Boscartin AE (19)	Hepatoprotective activity: inhibition: 31.6%	[33]	Sacraoxides E (41)	Anti-inflammatory effects: IC50: 36.4 μM	[37]
Boscartin AF (20)	Hepatoprotective activity: inhibition: 31.6%	[33]	Sacraoxides F (42)	Anti-inflammatory effects: IC50: 24.9 μM	[37]
Compound 21	Hepatoprotective activity: inhibition: 39.9%	[33]	Boswellian B (43)	Wound healing activity: promotes HUVECs proliferation in a dose dependent manner; migration capacity of HUVECs↑, F-actin↑	[40]
Boscartin AN (22)	Hepatoprotective activity: cell viability: 80.5%; inhibition: 25.8%	[34]	Boswellian C (44)	Wound healing activity: promotes HUVECs proliferation in a dose dependent manner; HUVECs cell proliferation↑, HUVECs tube formation↑	[40]

Figure 2. Structures of compounds 11–27.

Figure 3. Structures of compounds 28–44.

Figure 4. Structures of compounds 45–59.

Table 3. Biological effects of diterpenes 45–59

Compound	Effect/Mechanism	Ref.
Incensole (45)	Anti-inflammatory activity: inhibit IκBα degradation, mediated the degradation of IκBα in HeLa cells stimulated with TNFα; Neuroprotective effects: TRPV3: EC50: 2.1 µM; Hepatoprotective activity: cell viability: 78.0%; inhibition: 58.8%; Antidepressant effect: reduce the immobility time forced swim test (FST) at the 0.1–3 mg/kg dose, induced elevated brain GABA levels, involvement of a GABAergic mechanism	[33,41,52,81]
Incensole acetate (46)	Anti-inflammatory activity: inhibit IκBα degradation, inhibit IKK phosphorylation, TAK/TAB mediated phosphorylation↓, prevent NF-κB activation, mediated the degradation of IκBα in HeLa cells stimulated with TNFα	[41]
Incensole acetate (46)	Neuroprotective effects: expression of IL-1β↓, expression of TNF-α mRNAs↓, activation of glial cells↓, inhibit inflammatory cytokines, memory↑, inhibit NF-κB activation, neurodegeneration↓, improves post-closed head injury cognitive function, neuroprotection due to anti-inflammatory effect	[45]
Incensole acetate (46)	Neuroprotective effects: TRPV3: EC50: 1.4 µM; Anti-inflammatory activity: IL-6-induced STAT3 activation: IC50: 15.8 μM	[52]
Incensole acetate (46)	Alzheimer<apos;>s disease: memory and learning function↑, expression of MDA↓, catalase↑, superoxide dismutase↑, glutathione peroxidase↑, ROS↑, memory impairment↓, spatial learning↑, NO level↓, Aβ-mediated apoptosis↓, Bax↓, caspase 8↓, cyto c↓, Bcl2↑, BDNF expression↑	[65,71]
Incensole acetate (46)	Anxiety and depression: c-Fos↑, serum corticosterone level↓, CRF mRNA contents↓, corticosterone↓, expression of CRF↓, gene expression↑; Antidepressant effect: reduce the immobility time forced swim test (FST) at the 0.1–3 mg/kg dose, induced elevated brain GABA levels, involvement of a GABAergic mechanism	[53,77,81]
47	Neuroprotective effects: TRPV3: EC50: 5.6 µM; Anti-inflammatory activity: IL-6-induced STAT3 activation: IC50: 38.7 μM	[52]
48	Neuroprotective effects: TRPV3: EC50: 4.4 µM	[52]
49	Neuroprotective effects: TRPV3: EC50: 1.2 µM; Anti-inflammatory activity: IL-6-induced STAT3 activation: IC50: 22.4 μM	[52]
50	Neuroprotective effects: TRPV3: EC50: 10.5 µM	[52]
51	Neuroprotective effects: TRPV3: EC50: 25.4 µM	[52]
52	Neuroprotective effects: TRPV3: EC50: 8.8 µM	[52]
53	Neuroprotective effects: TRPV3: EC50: 8.6 µM	[52]
54	Neuroprotective effects: TRPV3: EC50: 2.4 µM; Antidepressant effect: reduce the immobility time forced swim test (FST) at the 0.1–3 mg/kg dose, induced elevated brain GABA levels, involvement of a GABAergic mechanism	[52,81]
55	Neuroprotective effects: TRPV3: EC50: 7.3 µM	[52,81]
56	Antidepressant effect: reduce the immobility time forced swim test (FST) at the 0.1–3 mg/kg dose, induced elevated brain GABA levels, involvement of a GABAergic mechanism
Incensole oxide (57)	Hepatoprotective activity: cell viability: 79.0%; inhibition: 60.4%	[33]
Incensole oxide acetate (58)	Hepatoprotective activity: cell viability: 69.0%; inhibition: 43.1%	[33]
Isoincensole epoxide (59)	Antimalarial effects: Plasmodium falciparum: IC50: 9.6 µM; Cytotoxic effects: L6 rat skeletal myoblasts: IC50: 84 µM	[82]

Figure 5. Structures of compounds 60–66.

Table 4. Biological effects of diterpenes 60–79.

Compd	Effects	Ref.	Compd	Effects	Ref.
Cembrene A (60)	Antimalarial effects: Plasmodium falciparum: IC50: 9.9 µM; Cytotoxic effects: L6 rat skeletal myoblasts: IC50: 84 µM	[82]	Boscartol C (70)	Hepatoprotective activity: cell viability: 70%; inhibition: 27%; Cytotoxic activity: U87-MG cells: inhibition: 44.7%	[86,88]
Serratol (61)	Antimalarial effects: Plasmodium falciparum: IC50: 83 µM; Cytotoxic effects: L6 rat skeletal myoblasts: IC50: 203 µM	[82]	Boscartol E (71)	Hepatoprotective activity: cell viability: 73%; inhibition: 36.3%; Cytotoxic activity: MCF-7: IC50: 6.3 µM;	[86,87]
1S,3E,7 R,8 R,11E-7,8-Epoxy-cembra-3,11-dien-1-ol (62)	Antimalarial effects: Plasmodium falciparum: IC50: 32 µM; Cytotoxic effects: L6 rat skeletal myoblasts: IC50: 111 µM	[82]	Boscartol F (72)	Hepatoprotective activity: cell viability: 88%; inhibition: 69.6%; Anti-inflammatory effects: 8.63 μM (n = 3; 95% confidence limits: 5.1–13.0); Cytotoxic activity: U87-MG cells: inhibition: 44.0%	[86,88]
Isodecaryiol (63)	Antimalarial effects: Plasmodium falciparum: IC50: 7.5 µM; Cytotoxic effects: L6 rat skeletal myoblasts: IC50: 137 µM	[82]	Boscartol H (73)	Hepatoprotective activity: cell viability: 68%; inhibition: 24.3%	[86]
Compound 64	Anti-inflammatory effects: NO inhibition with IC50: 1.32 µM	[83]	Boscartol I (74)	Hepatoprotective activity: cell viability: 73%; inhibition: 33.6%	[86]
Serratol (65)	Antimalarial effects: Plasmodium falciparum: IC50: 2.5 µM; Cytotoxic effects: L6 rat skeletal myoblasts: IC50: 39 µM; Antileishmanial effects: Leishmania donovani: IC50: 12 µM; Antiparasitic effect: Trypanosoma brucei rhodesiense: IC50: 3.8 μM; Trypanosoma cruzi: IC50: 44 μM; Neuroprotective effects: TRPV3: IC50: 0.15 μM	[52,84]	Boscartol K (75)	Anti-inflammatory effects: 2.22 μM (n = 3; 95% confidence limits: 0.31–4.5)	[87]
Boscartin AU (66)	Neuroprotective effects: 68.4%	[34]	Boscartol L (76)	Anti-inflammatory effects: 1.10 μM (n = 3; 95% confidence limits: 0.16–3.8)	[87]
Olibanumol D (67)	Anti-inflammatory effects: NO production: 35.8 %	[85]	77	Antimalarial effects: Plasmodium falciparum: IC50: 9.2 µM; SI: 8.8; Cytotoxic activity: L6 rat skeletal myoblasts: IC50: 81 µM	[82]
Boscartol A (68)	Hepatoprotective activity: cell viability: 69%; inhibition: 26.1%	[86]	78	Cytotoxic activity: U87-MG cells: inhibition: 55.3%	[88]
Boscartol B (69)	Hepatoprotective activity: cell viability: 73%; inhibition: 33.6%; Cytotoxic activity: MCF-7: IC50: 9.5 µM	[86,87]	79	Cytotoxic activity: U87-MG cells: inhibition: 39.9%	[88]

Figure 6. Structures of compounds 67–79 and their biological activities.

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