DOI: 10.1002/cbdv.

201900366 REVIEW

Chemical and Biological Aspects of Garcinol and Isogarcinol:

Recent Developments
Rainer Schoberta and Bernhard Biersack*a
a
Organic Chemistry Laboratory, University of Bayreuth, 95447 Bayreuth, Germany,
e-mail: [email protected]

© 2019 The Authors. Published by Wiley-VHCA AG. This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The natural polyisoprenylated benzophenone derivatives garcinol and isogarcinol are secondary plant
metabolites isolated from various Garcinia species including Garcinia indica. This review takes stock of the recent
chemical and biological research into these interesting natural compounds over the last five years. New
biological sources and chemical syntheses are discussed followed by new insights into the activity of garcinol
and isogarcinol against cancer, pathogenic bacteria, parasite infections and various inflammatory diseases.

Keywords: garcinol, isogarcinol, cancer, inflammation, infectious diseases.

1. Introduction
Natural products and their semi-synthetic derivatives
occupy a salient position concerning activity and
percentage share of new investigational and eventu-
ally approved drugs for the clinic.[1] The traditional folk
medicine of East Asia (Traditional Chinese Medicine,
Kampo), South Asia (Ayurveda, Unani), the Middle-East
(traditional Greco-Arab and Islamic Medicine) and Figure 1. Structures of the natural products garcinol and
isogarcinol.
other Asian regions, in particular, proved to be a
valuable source of drug discovery based on natural
products.[2,3] In India, for example, plants or plant
products from Boswellia, Curcuma, Plumbago, Law- include the inhibition of NF-κ B and STAT as well as of
sonia, and Garcinia among others, whose manifold histone acetyl transferases (HATs).[11] Several reviews
activities were confirmed by modern laboratories and book chapters covered the extensive chemistry
meanwhile, have been applied by traditional healers and biological activities of garcinol and isogarcinol
until today.[4,5] Garcinia species produce the biolog- over the last decade.[4,6,7,10,11] The present review
ically active benzophenones/polycyclic polyprenylated highlights the most recent proceedings in this field.
acylphloroglucinols (PPAPs) garcinol and isogarcinol
which have raised the interest of chemists and
molecular biologists alike (Figure 1).[6,7] Garcinol is 2. An Update on The Isolation, Analysis, and
easily available in large amounts and high purity by
Synthesis of Garcinol and Isogarcinol
extraction of dried kokum plums (Garcinia indica)
followed by chromatographic purification and/or Garcinol and isogarcinol were isolated from various
crystallization.[6,8] Isogarcinol is easily prepared from Garcinia species. High yields of garcinol can be
garcinol by treatment with diluted hydrochloric acid.[9] obtained from dried kokum (Garcinia indica) plums
The activity spectra of garcinol and isogarcinol include while garcinol can be easily converted to isogarcinol
anticancer, antibiotic, antioxidant and anti-inflamma- under acidic conditions.[6,8] High yields of garcinol (up
tory effects.[10] Their modes of action are diverse and to 5 g from 500 g dried kokum plums) were achieved

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Chem. Biodiversity 2019, 16, e1900366

by extraction of chopped dried kokum plums with Garcinia indica samples and of the commercially
methanol, evaporation of the solvent, redissolution of available formulations Tryodashang Guggul and Slim-
the methanol extract in ethyl acetate, washing of the merz capsules was determined by High Performance
latter with water, column chromatography of the Thin Layer Chromatography (HPTLC). It was shown
concentrated ethyl acetate extract (silica gel 60, ethyl that the dried fruit rinds of Garcinia indica contained
acetate/hexane 1:2) followed by crystallization of the 2.5 % garcinol while Tryodashang Guggul had 0.701 %
concentrated eluate from hexane to give yellow and Slimmerz capsules 0.760 % garcinol.[23] With
needles.[6] Isogarcinol can be easily prepared by treat- aqueous two-phase systems (ATPS) containing ethanol
ment of garcinol with aqueous HCl in toluene at room and ammonium sulfate garcinol and isogarcinol accu-
temperature.[6] Another suitable large scale isolation mulated in the ethanol phase while anthocyanin and
method initially removed hydroxycitric acid from hydroxycitrate built up in the salt-rich phase.[24] Gold
Garcinia indica fruits by washing with water, followed nanoparticles (AuNPs), prepared from G. indica fruit
by methanol extraction of the fruits, adsorption of the rind extract, showed distinct catalytic activities such as
concentrated methanol extract on Celite and extrac- a reduction of toxic 4-nitrophenol to 4-aminophenol
tion of the methanol extract loaded Celite with hexane when combined with NaBH4.[25]
followed by column chromatography of the hexane Distinct progress has also been achieved in the
extract.[8] Recently, garcinol and isogarcinol were field of the total synthesis of garcinol and isogarcinol.
isolated from fruits of Garcinia multiflora, a medicinal Socolsky and Plietker described a concise total syn-
plant of South China known for its antioxidant thesis of racemic garcinol and isogarcinol in 13 steps
activity.[10,12] The authors obtained 500 mg garcinol starting from acetylacetone, which was α-prenylated
and 101 mg isogarcinol from 5.2 kg dried G. multiflora and reacted with formaldehyde via deacetylating
fruits (powdered dried G. multiflora fruits were ex- aldol-type condensation to give enone 1 (Scheme 1).
tracted with 95 % ethanol and the ethanol extract was The latter was submitted to a domino Michael
extracted with petroleum ether followed by column addition–Knoevenagel condensation with dimethyl
chromatography on silica gel and recrystallization to 1,3-acetonedicarboxylate to afford the cyclohexanone
obtain garcinol).[12] Garcinol was also detected in and hub of intermediates 2 and 3. Allylation of the keto
isolated from plants of the Garcinia species G. morella, ester 3 with 4-acetoxyprenyl chloride gave trans-
G. yunnanensis, G. xanthochymus and G. selectively 4, which was β-methylated and O-alloc
travancorica.[13– 16] In addition, garcinol and isogarcinol protected to furnish enol allyl carbonates 5a and 5b.
were recently found in the stem bark of the Garcinia Both regioisomers 5 underwent a carboxylative, dia-
species G. buchananii.[17] Isogarcinol was also isolated stereoselective, Pd-catalyzed Tsuji–Trost allylation
from G. punctata and G. ovalifolia.[18,19] yielding the same cyclohexanone 6. Its subsequent Pd-
Quantitative analyses of garcinol contents in bio- catalyzed allyl-allyl cross-coupling with allylpinacolbor-
logical material are usually carried out by LC/MS and ane afforded exclusively the 1,5-dienyl derivative 7,
HPLC methods.[20–22] Recently, the garcinol contents of which was submitted to a Dieckmann condensation

Bernhard Biersack holds a diploma Rainer Schobert received his doc-

in Biochemistry (2004) from the toral degree in 1985 for syntheses
University of Bayreuth, Germany, of macrolide antibiotics in the
and completed his doctorate at group of Hans-Juergen Bestmann
the Organic Chemistry Laboratory at the University of Erlangen. After
(Prof. Rainer Schobert) of the Uni- a postdoctoral year with Steve Ley
versity of Bayreuth in 2009. He at the Imperial College in London
was visiting professor at the De- he went back to Erlangen to finish
partment of Chemistry of the his habilitation on early transition
Abeda Inamdar Senior College metallocenes in 1993. From 1999
(2013). Dr. Biersack is member of until 2001 he was a senior lecturer
the Cancer Epigenetics Society at The Queens University Belfast.
(CES) and author of more than 80 research and review He currently holds the Chair of Organic Chemistry at the
articles, four book chapters and one approved patent. University of Bayreuth. His research interests span a wide
range including bioactive tetramic acids, macrolides, and
metallodrugs.

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Scheme 1. Total synthesis of garcinol published by Socolsky and Plietker.[26]

leaving bicyclo[3.3.1]nonatrione 8. Its cross-metathesis κ B signaling, and STAT-signaling. Meanwhile, new

with amylene to introduce the prenyl residues, promising results were disclosed (Table 1).
followed by benzoylation and deprotection finally Lung cancer is one of the most lethal cancers and
yielded the natural product garcinol.[26] leads annually to ca. 1.2 million deaths worldwide.[27]
Non-small cell lung cancer cells were sensitized to
cisplatin and erlotinib treatment by garcinol. This
3. An Update on The Activities of Garcinol and effect was mediated by miRNAs and garcinol was able
to upregulate EMT-modulating miRNAs such as let-7c
Isogarcinol against Tumor Models
and miR-200b.[28] Lung cancer stem cells (LCSCs) were
The significant activity of garcinol and isogarcinol also targeted by garcinol and repression of the Wnt/β-
against various tumor models is largely attributed to catenin/STAT3 signaling pathway by garcinol treat-
the inhibition of histone acetyl transferases (HATs), NF- ment suppressed the ability of NSCLC cells to form

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Table 1. Recently discovered antitumor effects of garcinol and isogarcinol.

Cancer type Effects Mechanisms In vivo activity
Lung cancer Sensitization to cisplatin and erlotinib Upregulation of let-7c and miR-200c Inhibition of H441 LCSC mouse
(garcinol),[28] suppression of cancer (garcinol),[28] suppression of Wnt/β-cat- xenograft tumor growth
stem cells (garcinol),[29,30] increased enin/STAT3 and ALDH1 A1 (garcinol),[29] (garcinol)[29]
TRAIL-based apoptosis (garcinol)[54] activation of DDIT3, induction of DR5
(garcinol),[30] suppression of c-FLIP
(garcinol)[54]
Colorectal Increased apoptosis and cell growth Suppression of mPGES1, HIF-1α, VEGF, –
cancer inhibition (garcinol),[33] inhibition of MMP (garcinol),[33] inhibition of base
angiogenesis and invasion (garcinol),[33] excision repair via HAT inhibition
inhibition of DNA repair (garcinol)[34] (garcinol)[34]
Breast cancer Sensitization to taxol (garcinol),[36] in- Suppression of caspase-3/iPLA2 and NF- Sensitization to taxol in ortho-
creased apoptosis (garcinol)[13] κ B/Twist1 signaling (garcinol),[36] p53 topic 4T1 mammary carcinoma
dependent induction of Bax (garcinol)[36]
(garcinol),[13] suppression of Bcl-XL
(garcinol),[13] proteasome-based degra-
dation of ADA3 (garcinol)[55]
Prostate can- Increased apoptosis, inhibition of au- Induction of Bax, suppression of Bcl-2 Inhibition of PC-3 mouse xeno-
cer tophagy (garcinol)[38] and mTOR (garcinol)[38] graft tumor growth
(garcinol)[38]
Pancreatic Suppression of cancer stem cell charac- Suppression of Mcl-1, EZH2, ABCG2, Inhibition of tumor growth in
cancer ter (garcinol),[40] tumor growth inhibi- Gli-1, and Notch-1, induction of miR- KPC mice: K-ras and p53 condi-
tion (garcinol)[41] 200c (garcinol)[40] tional mutant mice
(garcinol)[41]
Oral squa- Inhibition of tumor cell growth, induc- Inhibition of NF-κ B and COX-2, suppres- –
mous cell car- tion of apoptosis, inhibition of angio- sion of VEGF (garcinol)[43]
cinoma genesis and colony formation
(garcinol)[43]
Cervical can- Inhibition of tumor cell growth Activation of PI3 K/AKT signaling Induction of T-cadherin in vivo
cer (garcinol),[48,53] suppression of tumori- (garcinol),[48] suppression of HIF-1α (garcinol)[48]
genesis (garcinol),[48] sensitization to (garcinol)[49]
radiotherapy (garcinol)[49]
Miscellaneous Tumor cell growth inhibition [gallblad- Suppression MMP2 and MMP9 (gall- Moderate accumulation of gar-
cancers der carcinoma (garcinol),[50] neuroblas- bladder carcinoma) (garcinol),[50] syner- cinol nanoparticles in tumors
toma (garcinol),[51] melanoma (GAR- gism with STAT5 inhibition via HAT of B16-F10 tumor bearing mice
NPs),[53] hepatoma (GAR-NPs),[53] leuke- inhibition (leukemia, garcinol),[52] in- (GAR-NPs)[53]
mia (isogarcinol)],[19] synergism with creased TRAIL-based apoptosis by in-
STAT5-SH2 domain inhibitor AC-4-130 duction of DR5 and suppression of c-
(leukemia, garcinol),[52] induction of FLIP (hepatoma, renal cancer,
apoptosis and G2/M arrest (leukemia, garcinol),[54] LC-3 shift (osteosarcoma,
isogarcinol),[19] induction of autophagy garcinol)[56]
(osteosarcoma, garcinol)[56]

spheres and reduced the tumor growth in the H441 creased apoptosis rates, reduced cell growth, and a
LCSC mouse xenograft model.[29] In addition, garcinol less pronounced tendency to angiogenesis and inva-
activated DDIT3 (DNA damage-inducible transcript 3) sion due to downregulation of mPGES1, HIF-1α, VEGF
and suppressed the cancer stem cell marker ALDH1 A1 and MMP expression.[33] In HCT-116 CRC cells, the HAT
(aldehyde dehydrogenase 1 family member A1) in inhibitory activity of garcinol reduced 8-oxoG damage
A549 NSCLC cells.[30] repair by suppression of base excision repair (BER).[34]
Colorectal cancer (CRC) also belongs to the most Breast cancer is the most prevalent cancer type of
lethal cancer diseases worldwide.[31] The emergence of women.[35] Resistance to chemotherapy is a big
CRC is closely connected with genetic factors (ca. 25 % problem. Garcinol was able to sensitize breast tumors
of CRC appears in people with close relatives suffering to treatment with taxol in vitro and in vivo (orthotopic
from CRC), as well as obesity and dietary factors.[32] 4T1 mammary carcinoma). Synergistic tumor growth
HT-29 CRC cells treated with garcinol showed in- inhibition and anti-metastatic activity were observed

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for this promising drug combination at low doses The total synthesis and testing of an 8-methyl garcinol
(1 mg/ kg garcinol orally three times per week + 5 mg/ derivative showed the high importance of the 8-prenyl
kg taxol i. p. once per week) attributable to the group of natural garcinol for activity against SCC15
downregulation of caspase-3/iPLA2 and NF-κ B/Twist1 cells.[45] In contrast, the synthetic 8-allyl garcinol
signaling.[36] The chloroform extract of G. morella rich derivative displayed a strong growth inhibition of oral
in bioactive garcinol exhibited distinct growth inhib- cancer cells.[46]
itory effects against three breast cancer cell lines Cervical carcinoma (CC) is the cause of death of
(MCF-7, MDA-MB-231, SKBR3). MCF-7 cells treated with 300,000 women globally every year and patients with
the G. morella chloroform extract revealed increased metastases and suffering from relapse have a poor
apoptosis levels by p53 dependent induction of Bax prognosis.[47] Garcinol showed activity against CC
and suppression of Bcl-XL.[13] models. Tumorigenesis of CC was correlated with T-
In the Western world prostate cancer is the second cadherin expression and garcinol induced T-cadherin
most frequent cause of cancer-related death after lung in vitro and in vivo via activation of PI3 K/AKT signaling
carcinoma.[37] In PC-3 prostate carcinoma cells, garci- in CC.[48] Radiation therapy is customarily applied for
nol induced apoptosis by induction of Bax and CC patients and, thus, it is interesting to note that
suppression of Bcl-2 as well as by inhibition of garcinol increased the sensitivity of oxygen-deficient
autophagy via activating phosphorylation of mTOR. HeLa CC cells to radiation by suppression of HIF-1α.[49]
Garcinol (50 mg/kg five times per week for 40– In addition, the effects of garcinol and isogarcinol
50 days, i. p. or orally) also inhibited tumor growth of were studied in various other cancers. Garcinol
PC-3 mouse xenografts by 80 %.[38] inhibited gallbladder carcinoma (GBC) cell growth and
Individuals diagnosed with pancreatic cancer (PC) cell invasion by suppression of the matrix metal-
still face a poor prognosis.[39] The high incidence of loproteinases MMP2 and MMP9. Both STAT3 and Akt
resistance and metastasis of pancreatic cancer was were downregulated by garcinol in GBC-SD cells.[50]
correlated to the presence of cancer stem-like cells Garcinol and the chloroform extract of G. morella
that are also called side population (SP) cells. Garcinol inhibited the growth of the childhood tumor and
suppressed the stem cell character of Panc-1 SP cells neuroblastoma cell line SH-SY5Y (IC50 = 6.3 μM for
by inhibition of crucial SP-related factors such as Mcl- garcinol).[51] Both garcinol and isogarcinol displayed
1, EZH2, ABCG2, Gli-1, and Notch-1. In addition, activities against leukemia models. The STAT5-SH2
upregulation of the tumor suppressor microRNA miR- domain inhibitor AC-4-130 showed strongly synergistic
200c (target: Notch-1) was observed upon garcinol effects against acute myeloid leukemia (AML) cells
treatment.[40] In transgenic PC mice (KPC mice: K-ras MV4-11 and MOLM-13 in combination with the HAT
and p53 conditional mutant mice), garcinol and the inhibitor garcinol probably because acetylation of
combination of a garcinol diet with injected gemcita- STAT5 by the HATs p300 and PCAF is of importance
bine inhibited tumor growth.[41] for the regulation of STAT5 phosphorylation/
With more than 300,000 people suffering from oral dimerisation.[52] Isogarcinol isolated from G. ovalifolia
squamous cell carcinoma (OSCC) every year all over roots exhibited distinct activity against HL-60 promye-
the world, this malignancy is the sixth most common locytic leukemia cells (IC50 = 4 μg/mL) and induced G2/
tumor disease and many cases go on developing M arrest as well as apoptosis via mitochondrial
countries.[42] Garcinol inhibited the tumor cell growth damage in these leukemia cells.[19] While garcinol is
of the OSCC cell lines SCC-4, SCC-9 and SCC-25 in vitro only poorly soluble in water, PLGA nanoparticles
(IC50 = 5 15 μM), induced apoptosis in these cancer modified with vitamin E as carriers of garcinol (GAR-
cells, blocked angiogenesis and reduced significantly NPs) revealed significant growth inhibitory activities
the number of formed colonies by SCC-4 and SCC-9 against B16-F10 melanoma, HepG2 hepatocellular
cells. Inhibition of NF-κ B and of COX-2 as well as carcinoma, and KB cervical carcinoma cells. The GAR-
suppression of VEGF were identified as modes of NPs showed improved uptake rates, time-dependent
action of garcinol in these OSCC cells.[43] The chemical accumulation in B16-F10 tumor bearing mice as well
modification of garcinol allowed insights into the as apoptosis induction.[53]
importance of functional groups of this compound New discoveries concerning mechanisms of action
concerning activity against tumor models. For in- of garcinol and isogarcinol in tumor models were
stance, the 13,14-dihydroxy groups proved essential disclosed. In hepatoma (SK-Hep1), lung (A549) and
for the activity of garcinol because their methyl ethers renal carcinoma cells (Caki, ACHN, A498) garcinol
exhibited weaker activity against SCC15 OSCC cells.[44] increased TRAIL-based apoptosis by induction of DR5

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and suppression of c-FLIP.[54] The HAT inhibitor Table 2. Recently discovered effects of garcinol on infection-
garcinol also led to proteasome-based degradation of causing agents.
the factor ADA3 (alteration/deficiency in activation 3) Infection Effects Mechanisms
in immortalized 76 N-TERT cells (human mammary
Influenza Regulation of viral polymer- Inhibition of PCAF
epithelial cells) by inhibition of stabilizing ADA3
A[61] ase function and GCN5
acetylation via p300/PCAF inactivation.[55] In this way, Bacillus Antidote for LT intoxication Reduction of
garcinol may show synergistic effects in combination anthracis[62] stress-fiber forma-
with EGFR inhibitors. In U2OS osteosarcoma cells tion
garcinol induced autophagy and a correlated LC3-shift Candida Induction of apoptosis, in- –
by inhibition of EP300 (E1 A-binding protein p300).[56] albicans[15] hibition of biofilm formation
Toxoplasma Inhibition of replication Inhibition of
The HAT BRD4 (bromodomain protein 4) enhanced the gondii[63] TgGCN5b
transcription of target genes such as MYC, FOS and
AURKB (Aurora kinase B) but BRD4 was efficiently
inhibited by garcinol while another pan-inhibitor
(curcumin) displayed no BRD4 inhibitory effects.[57] viral polymerase function. Interestingly, both HATs
Hence, BRD4 inhibition can contribute to the activity target different lysines of the nucleoprotein: while
of garcinol. Garcinol was described as a time- and PCAF acetylate Lys-31, GCN5 acetylates Lys 90. Both
detergent-dependent inhibitor of lysine acetyltransfer- lysines regulate opposite effects: deacetylated Lys-31
ases (KATs, a more specific name for HATs). High (by suppression of PCAF) enhanced viral polymerase
Triton-X-100 concentrations (0.05 %) reduced the KAT- activities while deacetylated Lys-90 (by suppression of
inhibitory activity of garcinol for p300 and GCN5 KATs GCN5) decreased the viral polymerase function.[61]
when compared with experiments using low Triton-X- The lethal toxin (LT) of the Gram-positive bacterium
100 concentrations (0.01 %), which is of great impor- Bacillus anthracis induces actin stress fiber formation
tance for future biological tests with garcinol in order in infected cells by suppression of HDAC expression
to obtain reasonable results.[58] Because of these and, thus, this process is controlled by histone
findings an aggregation-based mode of KAT inhibition acetylation. In contrast to LT, the HAT inhibitor
was suggested for garcinol. Based on the lead garcinol reduced stress fiber formation in LT-treated
compound garcinol, a synthetic and non-competitive, HUVEC cells and so might act as an antidote for LT
selective and reversible inhibitor (EML245) of the KAT3 intoxication.[62]
enzymes p300 (Ic50 = 2.9 μM) and CBP (IC50 = 1.1 μM) The activity of garcinol against cells of the patho-
was obtained. EML245 showed significant cell perme- genic fungus Candida albicans was studied as well.
ation and reduced lysine H4 K5 and H3 K9 acetylation Garcinol and xanthochymol induced apoptosis in C.
in U937 leukemia cells leading to G0/G1 arrest and albicans hyphae and inhibited biofilm production by
formation of hypodiploid nuclei.[59] this fungus.[15]
The viability of Toxoplasma gondii, which is a
protozoal parasite causing toxoplasmosis, is regulated
4. An Update on The Activities of Garcinol by lysine acetylation. The GCN5 family KAT TgGCN5b
against Viruses, Bacteria, Yeasts, and of T. gondii is crucial for replication of the T. gondii
tachyzoites. Garcinol treatment led to decreased levels
Protozoal Parasites
of acetylated histone H3 of TgGCN5b and to an
Garcinol has shown promising activity against causing inhibition of replication (IC50 = 1.7 μM). Similar replica-
agents and consequences of various infectious dis- tion inhibitory effects were observed for the malaria
eases. Table 2 summarizes a few of the more interest- parasite Plasmodium falciparum (IC50 = 1.69 μM for
ing findings. chloroquine-sensitive HB3 strains, and IC50 = 2.05 μM
As early as 2007, the suppression of viral tran- for chloroquine-resistant Dd2 strains; inhibition of
scription by HIV was documented for isogarcinol erythrocytic asexual replication).[63]
derivatives as well as their p300 inhibitory activity.[60]
Recently, a similar mode of action against the
influenza virus was reported of garcinol. Garcinol
inhibited both PCAF (p300/CBP-associated factor) and
GCN5 in influenza A leading to a reduced acetylation
of the viral nucleoprotein and to the regulation of the

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Table 3. Recently discovered effects of garcinol and isogarcinol on inflammation and neurodegenerative diseases.
Disease Effects Mechanisms
Skin inflammation Inhibition of 12-O-tetradecanoylphorbol induced Suppression of NF-κ B, ERK, JNK, p38 MAPK, PI3 K,
inflammation process and tumorigenesis in vitro and Akt[65]
and in vivo[65]
Intimal hyperplasia Suppression of leukocyte and vascular smooth Suppression of CCL2 and TNF-α[66]
muscle cell inflammation process in vitro, reduced
arterial adherence and infiltration by leukocytes
and macrophages in vivo[66]
LPS-induced inflamma- Increase of LPS-induced inflammation process in - Increased expression of TNF-α and IL-6[67]
tion vitro and in vivo[67]
Collagen-induced arthri- Suppression of CIA and ear edema, reduced bone Suppression of NF-κ B, iNOS, COX-2, NFAT and IL-
tis (CIA) and cartilage damage and low concentrations of 2[68]
inflammatory cytokines in vivo[68]
Systemic lupus erythe- Protection of kidneys in vivo, reduced renal histo- –
matosus (SLE) disease pathology and proteinuria, normalized serum bio-
chemical indicator[69]
Psoriasis Amendment of skin lesions induced by imiquimod, Suppression of IL-23/Th17 axis genes[70]
less toxic to liver and kidneys than cyclosporine A
in vivo[70]
Macrophages Beneficial effects on macrophages and peritoneal Suppression of collagenase, elastase and hyalur-
macrophages, reduced excretion of lysosomal onidase excretion[71]
enzymes in vivo[71]
Liver inflammation and Prolonged survival of mice with acute liver Suppression of histone acetylation[73]
acute liver failure failure[73]
Endometriosis Suppression of fibrosis in Klf11 / animals[74] Restoration of transcription factor KLF11 function,
suppression of scar-tissue collagen (COL1 A1/
Col1a1)[74]
Obesity-related inflam- Inhibition of high fat diet (HFD)-induced obesity in Increased levels of intestinal commensal bacteria
mation vivo[75] Akkermansia, suppression of glutamate pyruvate
transaminase, cholesterol and triacylglycerol[75]
Diabetes Normalization of diabetic parameters in vivo[77]
Osteolysis Suppression of osteoclastogenesis in vitro and in Suppression of PI3 K/Akt, MAPK and NF-κ B
vivo[79] signaling[79]
Multiple sclerosis, exper- Reduced intracranial lesions and demyelination of Targeting of JAK/STAT signaling pathway[80]
imental autoimmune en- the spinal cord in vivo[80]
cephalomyelitis
Neuropathic pain Prolonged thermal withdrawal latency[81] Suppression of acetyl-p65[81]
Neuroinflammation of Suppression of inflammation factors in vitro and in downregulation of NF-κ B signaling, reduced ex-
microglia vivo[82] pression of COX-2/PGE2, iNOS and interleukins (IL-
1b, IL-6)[82]
Parkinson’s disease Neuroprotective effects,[83] reduction of dopamine MAO B inhibition,[83] inhibition of catechol-O-
side-effects/dyskinesia[84,85] methyltransferase[85]
Epilepsy Decrease of mortality and of seizure scores in Suppression of BDNF and TrkB and upregulation
vivo[86] of GABAA and GAD65[86]
Cocaine abuse Support of drug abstinence[87,88] Inhibition of reinstatement by reconsolidation-
based modes[85,88]

5. New Effects on Inflammation Processes and

efficiently blocked skin inflammation and tumorigene-
Neurodegenerative Diseases
sis induced by 12-O-tetradecanoylphorbol 13-acetate
The antioxidant and anti-inflammatory properties of in mice by suppression of NF-κ B, ERK, JNK, p38 MAPK,
garcinol and isogarcinol are well described (Table 3).[10] PI3 K and Akt.[65] Intimal hyperplasia is based on
Only recently, isogarcinol was reported to have vascular inflammation and NF-kB activation and the
significant antioxidant effects rescuing human cells HAT PCAF promoted NF-κ B-regulated inflammation.
from oxidative stress while the genotoxicity of iso- Garcinol suppressed CCL2 and TNF-α expression in
garcinol was negligible.[64] Topically applied garcinol leukocytes and vascular smooth muscle cells and

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Chem. Biodiversity 2019, 16, e1900366

reduced arterial adherence and infiltration by leuko- was regulated by garcinol via increase of levels of
cytes and macrophages in vivo when administered in a intestinal commensal bacteria Akkermansia. Garcinol
Pluronic gel enabling a slow garcinol drug release.[66] blocked the formation of high fat diet (HFD)-induced
In contrast to these and other previous findings about obesity and suppressed glutamate pyruvate trans-
the considerable anti-inflammatory activities of garci- aminase, cholesterol and triacylglycerol in the plasma
nol, a newer study described the enhancement of of animals fed with garcinol.[75] Pretreatment of leptin-
lipopolysaccharide(LPS)-induced inflammation by in- stimulated cells with garcinol (1 μM) also inhibited
traperitoneally administered garcinol (injection of leptin-associated cPLA2 expression via inhibition of
10 mg/kg in DMSO) both in vitro and in vivo.[6,67] The p300 HAT.[76] In addition, garcinol displayed beneficial
expression of TNF-α and IL-6 was markedly increased effects on diabetic Wistar rats and oral application of
by garcinol in this case, which was correlated with garcinol (10 mg/kg and 20 mg/kg) normalized diabetic
reduced acetylation of NF-κ B. Hence, more research is parameters in the rats similar to the antidiabetic drug
necessary into the positive and negative effects of glibenclamide.[77] Osteolysis is often based on acti-
garcinol on various forms of inflammation processes. vated osteoclasts which are bone-resorbing osteoim-
Orally administered isogarcinol (100 mg/kg) mune cells.[78] Osteoclastogenesis relies on RANKL
showed significant activity against collagen-induced (receptor activator of NF-κ B) and treatment of BMM
arthritis (CIA) and xylene-induced ear edema in mice. cells (bone marrow monocytes) with garcinol in vitro
Reduced bone and cartilage damage as well as low and of C57BL/6 mice in vivo (mouse calvarial osteolysis
concentrations of inflammatory cytokines were ob- model. sub-cutaneous injection of 5 mg/kg in) sup-
served upon isogarcinol treatment of CIA mice. pressed osteoclastogenesis by downregulation of
Suppression of the expression of NF-κ B, iNOS, COX-2, PI3 K/Akt, MAPK and NF-κ B signaling.[79]
NFAT and IL-2 was observed after treatment with Effects of garcinol and isogarcinol on various neural
isogarcinol from in vitro experiments.[68] The same inflammation and neural degenerative disease models
group investigated the activity of isogarcinol against were disclosed. Experimental autoimmune encephalo-
systemic lupus erythematosus (SLE). Mice with chronic myelitis (EAE) is a preclinical murine model for the
graft-versus-host disease (cGVHD, an SLE in vivo mod- investigation of multiple sclerosis (MS). EAE mice
el) were treated with isogarcinol (60 mg/kg) leading to treated with isogarcinol (100 mg/kg/day, orally)
reduced renal histopathology and proteinuria as well showed lower degrees of intracranial lesions and
as normalized serum biochemical indicator.[69] Isogarci- demyelination of the spinal cord due to drug interfer-
nol (100 mg/kg, orally) also amended skin lesions ence with the JAK/STAT signaling pathway.[80] Thus,
(similar to psoriasis) induced by exposure to imiqui- isogarcinol can be a little toxic alternative to currently
mod in mice. Suppression of IL-23/Th17 axis genes of applied drugs for the treatment of MS. Intrathecal
isogarcinol-treated mice was observed while isogarci- injections of garcinol in rats (L5 spinal nerve ligation/
nol was less toxic to liver and kidneys than cyclo- SNL model) prolonged thermal withdrawal latency
sporine A.[70] (TWL) and, thus, reduced neuropathic pain likely via
A diet of garcinol (5 mg/kg per day) in groundnut suppression of acetyl-p65.[81] Neuroinflammation of
oil was given to male Wistar rats in order to investigate microglia was suppressed by treatment with garcinol
any drug effects on peritoneal macrophages of and downregulation of NF-κ B signaling. Garcinol also
garcinol-fed rats. It showed positive effects and reduced the expression of COX-2/PGE2, iNOS and
reduced excretion of lysosomal enzymes such as interleukins (IL-1b, IL-6) in the SNL rat spinal cord.[82]
collagenase, elastase and hyaluronidase.[71] In addition, Monoamine oxidase-B (MAO B) metabolizes dopa-
isogarcinol exerted its immune modulatory effects by mine and, thus, represents a suitable target for the
direct binding and inhibition of calcineurin.[72] Histone treatment of Parkinson’s disease (PD) based on
acetylation was also correlated with liver inflammation dopamine depletion in certain parts of the brain.
and acute liver failure in mice and treatment with Garcinol exhibited a distinct MAO B inhibition similar
garcinol (20 mg/kg/day, i. p.) suppressed histone acety- to known MAO B inhibitors and together with its
lation and prolonged survival of mice suffering from neuroprotective effects, this compound appears partic-
acute liver failure.[73] In endometriosis models, garcinol ularly promising for the treatment of PD.[83] Garcinol
(0.2 μg/g/day, i. p.) could replace the function of the also reduced the side-effects of dopamine replace-
transcription factor KLF11, a repressor of scar-tissue ment therapy by L-DOPA. Dyskinesia induced by L-
collagen (COL1 A1/Col1a1), leading to fibrosis reversal DOPA in 6-hydroxydopamine (6-OHDA)-lesioned mice
in Klf11 / animals.[74] Obesity-related inflammation was reduced by co-treatment with garcinol (5 mg/kg,

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Chem. Biodiversity 2019, 16, e1900366

orally).[84] Garcinol also inhibited catechol-O-meth- Garcinol isolated from the fruits of the Thai plant
yltransferase leading to an increased L-DOPA bioavail- Garcinia dulcis also showed vasorelaxant activity. It
ability and it reduced hyperhomocysteinemia associ- might be a suitable drug for the treatment of hyper-
ated with L-DOPA treatment. This indicates the great tension due to its antioxidant activity. Injection of
potential of garcinol for the treatment of PD in hypertensive 2 K1 C (2-kidneys-1-clip) rats with low
combination with L-DOPA.[85] It was observed that doses of garcinol (0.1 mg/kg, i. v.) led to hypotensive
garcinol-pretreatment (50, 100 or 200 mg/kg, i. p.) of effects and reduced arterial blood pressure, heart rate,
mice with pentylenetetrazole (PTZ)-induced epilepsy plasma malondialdehyde values, and eNOS
led to a marked decrease of mortality and of seizure expression.[93]
scores. In addition, the memory and cognition of these Eryptosis is a programmed cell death process to
garcinol-treated mice improved distinctly. Suppression eliminate defective erythrocytes (prior to nephrotoxic
of BDNF and TrkB by garcinol as well as garcinol- hemolysis) analogously to apoptosis of damaged cells
induced upregulation of GABAA and GAD65 were with nuclei.[94] In particular, eryptosis has been identi-
identified as anti-epileptic modes of action of fied as a mechanism to fight infection with Plasmo-
garcinol.[86] Garcinol (10 mg/kg, i. p.) also showed dium (malaria), for example, in sickle-cell trait, in order
beneficial effects in rats exposed to cocaine and it to eliminate infected erythrocytes and the parasites
inhibited reinstatement by reconsolidation-based therein. Human erythrocytes treated with garcinol
modes following cocaine reactivation.[87,88] Reactivated (5 μM) underwent eryptosis according to increased
memories were affected by garcinol which displayed annexin-V binding, increased ROS formation and
long-lasting effects and, thus, garcinol can support reduced ATP level of the cytosol.[95] Thus, garcinol has
drug abstinence and be a suitable therapy for the potential to fight Plasmodium-caused diseases via
psychopathologies such as drug addiction. Indeed, this peculiar mode of action.
memory processes in honeybees strongly depend on
HAT activity and histone H3 acetylation by treatment
with garcinol or C646.[89]
7. Conclusions
The chemistry and biology of garcinol and isogarcinol
are active and prospering fields of research. The total
6. Miscellaneous Activities and Applications
synthesis of garcinol by Socolsky and Plietker repre-
The establishment of garcinol as a proper drug is in sents a chemical highlight of the past years and
progress. The Indian company Sami Labs Ltd. isolated enables the fine-tuning of the garcinol molecule
garcinol by extraction of dried kokum plum rinds with concerning improved biological activities by prepara-
hexane followed by column chromatography and tion of synthetic garcinol derivatives. The identification
crystallization from hexane and this company has of new HATs as targets of garcinol or isogarcinol
standardized garcinol (40 % garcinol in microcrystalline broadens the scope of application of these natural
cellulose) and evaluated the toxicity of 40 % garcinol products including activities against viral and parasitic
in Wistar rats. In fact, 40 % garcinol exhibited a low models. In addition, their distinct activities against
toxicity and no signs of any side-effects at doses of up cancer stem-like cells warrant studies against further
to 100 mg/kg/day (orally) after weeks and months.[90] tumor models. One report has appeared that de-
There are also successful efforts to produce fruit scribed a promoting effect on LPS-induced inflamma-
wines from kokum and the fermentation of a mixture tion processes. This is in stark contrast to many other
of kokum juice with banana juice generated an publications which describe garcinol or isogarcinol as
excellent wine which has the potential to conquer the potent agents against various inflammation processes.
exotic wine market in the future.[91] Future studies will show if this is just a solitary case. It
The preparation of effective sunscreens with kokum is noteworthy that garcinol was also found active
extract is also possible. The ethyl acetate extract of against models of various neurological diseases such
kokum, which is rich in garcinol, when washed with as EAE, Parkinson disease, epilepsy or drug addiction.
water in order to remove hydroxycitric acid, showed These discoveries underline once more the potential
significant UV-radiation protective effects. A cosmetic of garcinol and isogarcinol as valuable drug candi-
cream containing 5 % of the extract revealed a sun dates.
protection factor of 3.43 with boot star rating 5.[92]

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Chem. Biodiversity 2019, 16, e1900366

Author Contribution Statement Candida albicans biofilms’, Antimicrob. Agents Chemother.

2015, 59, 6032 –6038.
[16] A. P. A. Aravind, K. R. T. Asha, K. B. Rameshkumar, ‘Phyto-
Bernhard Biersack carried out the literature search and
chemical analysis and antioxidant potential of the leaves of
wrote the manuscript. Rainer Schobert revised and Garcinia travancorica Bedd’, Nat. Prod. Res. 2016, 30, 232 –
proofread the manuscript. 236.
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