Download Targeting Acetyl-CoA Carboxylases: Small

168
Recent Patents on Anti-Cancer Drug Discovery, 2012, 7, 168-184
Targeting Acetyl-CoA Carboxylases: Small Molecular Inhibitors and their
Therapeutic Potential
Di-Xian Luo1,2, Di-Jun Tong3, Sandeep Rajput2, Chun Wang4,5, Duan-Fang Liao4,5, Deliang Cao2
and Edmund Maser6,*
1
Institute of Translational Medicine & Department of Laboratory Medicine, The First People's Hospital of Chenzhou,
102 Luojiajing Road, Chenzhou 423000, Hunan, P.R. China; 2Department of Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine. 913 N. Rutledge Street, Springfield, IL
62794, USA; 3Department of Cardiovascular Medicine, Central Hospital of Yiyang, Yiyang 41300, P.R. China;
4
Institute of Pharmacy and Pharmacology, College of Pharmaceutics and Life Science, University of South China, Hengyang 421001, P.R. China; 5Department of Traditional Chinese Diagnotics, School of Pharmacy, Hunan University of
Chinese Medicine, Changsha 420108, P.R. China; 6Institute of Toxicology and Pharmacology for Natural Scientists,
University Medical School Schleswig-Holstein, Campus Kiel. Brunswiker Str. 10 24105, Kiel, Germany
Received: November 1, 2011; Accepted: January 12, 2012; Revised: February 12, 2012
Abstract: Acetyl-CoA carboxylases (ACCs) play a rate-limiting role in fatty acid biosynthesis in plants, microbes, mammals and humans. ACCs have the activity of both biotin carboxylase (BC) and carboxyltransferase (CT), catalyzing carboxylation of Acetyl-CoA to malonyl-CoA. In the past years, ACCs have been used as targets for herbicides in agriculture
and for drug discovery and development of human diseases, such as microbial infections, diabetes, obesity and cancer. A
great number of small molecule ACC inhibitors have been developed, including natural and non-natural (artificial) products. These chemicals target BC reaction, CT reaction or ACC phosphorylation. This article provides a comprehensive review and updates of ACC inhibitors, with a focus on their therapeutic application in metabolic syndromes and malignant
diseases. The patent status of common ACC inhibitors is discussed.
Keywords: Acetyl-CoA carboxylases, cancer, fatty acid synthesis, inhibitors, metabolic syndromes, obesity.
1. INTRODUCTION
Obesity, a worldwide epidemic, not only impacts life
quality, but also leads to a variety of co-morbidities, such as
diabetes, hypertension, dyslipidemia, coronary heart disease,
stroke, atherosclerosis, and cancer, accelerating obesityrelated morbidity and mortality [1-6]. It is needed to develop
effective therapeutics of obesity and the ensuring comorbidities. Acetyl-CoA carboxylases (ACCs) are ratelimiting enzymes in fatty acid de novo biosynthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to malonylCoA [7-9]. This reaction continuously proceeds in two steps
in participation of biotin prosthetic group, i.e., an ATPdependent biotin carboxylation and an ATP-independent
transfer of the carboxyl group Fig. (1) [10].
In humans and other mammals, there are two ACCs:
ACC1 (also called ACC-) with 265kDa and ACC2 (also
known as ACC-) with 280kDa. ACC1 and ACC2 are encoded by different genes, but share 75% amino acid sequence similarity except for extra 114 amino acids in the Nterminus of ACC2, in which the first 20 amino acid residues
constitute a signal peptide targeting mitochondrial membrane
[11]. Thereby, these two ACCs have distinct subcellular
*Address correspondence to this author at the Institute of Toxicology and
Pharmacology for Natural Scientists, University Medical School SchleswigHolstein, Campus Kiel. Brunswiker Str. 10 24105, Kiel, Germany;
Tel: 0431-597-3540; Fax: 0431-597-3558; E-mail: [email protected]
-9/12 $100.00+.00
distribution and function although they both catalyze the
production of malonyl-CoA Fig. (1) [10]. ACC1 is expressed
mostly in lipogenic tissues (the liver, adipose and lactating
mammary gland) and catalyzes the rate-limiting reaction in
the biosynthesis of long-chain fatty acids in cytosol. The
product malonyl-CoA is used for the elongation of acyl
chains by fatty acid synthase (FAS) [12-15]. In contrast,
ACC2 is expressed mainly in the liver, skeletal muscle and
heart with high energy metabolic activity, where its product
malonyl-CoA participates in the regulation of fatty acid oxidation by inhibiting carnitine palmitoyltransferase I
(CPT-I) that catalyzes the transition of long-chain acyl-CoA
across mitochondrial membranes [16]. Therefore, malonylCoA is a dual functional metabolite involved in both fatty
acid synthesis and oxidation, and ACC1/2 isozyme-nonselective inhibitors may selectively reduce fatty acid synthesis in lipogenic tissues and increase fatty acid oxidation in
energy production organs [17, 18].
In view of the importance of ACCs in fatty acid synthesis
and oxidation, the investigation of ACC inhibitors have been
attracting the interest of researchers and many promising
inhibitors have been developed and used in preclinical and
clinical studies for the treatment of obesity and metabolic
syndromes or in the management of malignancies [19]. This
article reviews the recent updates of ACC inhibitor exploitation and their patent situations.
© 2012 Bentham Science Publishers
Acetyl-CoA Carboxylase Inhibitors
Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
169
O
O
O
O
HN
S
O
N
C
C
O
se
Biotin Carboxyl
Carrier protein
se
era
rase
nsf
oxyla
NH
ansfe
ytra
O
S
oxytr
Biotin
translocation
O
N
Bioti
n Ca
rb
Carb
box
Biotin Carboxyl
Carrier protein
B io ti n C ar b
o xy la se
Car
NH
HN
C
H2
S
Malonyl-CoA
CoA
O
C
S
xytran
C
Carbo
O
O
NH
sferas
e
Biotin Carboxyl
Carrier protein
HO
HN
Acetyl-CoA
ADP + Pi
C
N
CoA
O
O
O
S
B io ti n C ar b
o xy la se
C
H3
O
O
C
ATP
Fig. (1). ACC work mode. ACC has three functional domains and its catalyzation reaction occurs in two steps. The initial reaction is an
ATP-dependent transfer of CO2 from HCO3- to a nitrogen atom of the biotin prosthetic group of ACCs, and the 2nd step is an transfer of the
activated CO2 from biotin to acetyl-CoA, forming malonyl-CoA [10].
2. STRUCTURE OF ACETYL-COA CARBOXYLASES
ACCs are conserved in their amino acid sequence and
function in most living organisms, such as archaea (~34%
similarity in amino acid sequence), bacteria (~34% similarity), yeast (~56% similarity), plants (~54% similarity), rodents (~98% similarity), and mammals (~98% similarity),
compared to humans. However, genes encoding ACCs are
varied Fig. (2A). In mammals and most eukaryotic organisms, ACCs are a multiple domain polypeptide composed of
biotin carboxylase (BC), biotin carboxyl carrier (BCCP), and
carboxyltransferase (CT) domains that are encoded by a single gene. ACCs from Streptomyces coelicolor (S. coelicolor)
comprise subunit containing BC and BCCP domains and subunit (CT domain), encoded by an accA1(A2) and pccB
gene, respectively [20-22]. ACC in Archaeal Acidianus brierleyi consists of 3 subunits encoded by accC, accB, and
pccB gene, respectively [23]. In Escherichia coli (E. coli),
carboxyltransferase of ACCs consists of subunit and subunit encoded by accA and accD, respectively [24]. Therefore, in many low grade organisms, ACC is an unstable
multi-submit enzyme comprised of BC, BCCP and CT
subunits. BC domain/subunit catalyzes carboxylation of N1
atom in ureido ring of biotin covalently linked to a lysine
residue in BCCP with bicarbonate as a donor of carboxyl
group and ATP as an energy source. CT domain/subunit
catalyzes the transfer of the carboxyl group from the N1
atom to the methyl group of acetyl-CoA [17]. Significant
sequence homology exist between the BC subunit and eukaryotic BC domain, but the conservation of the CT compo-
nent is much lower [25]. An exception appears in plants
where ACCs exist as a multi-functional single protein (MFACC) and a multi-subunit heteromeric complex (MS-ACC)
Fig. (2B) [26, 27].
2.1. BC Domain of acetyl-CoA Carboxylases
Crystal structure shows that yeast BC domain consists of
20 -strands (1-20) and 21 -helices (A–U), forming
three sub-domains (A, B, and C) and an ATP-grasp fold [2831] Fig. (3A). The A-domain (residues 1-175) consists of
helices A-G and strands 1-5; B-domain (residues 234293) holds helices K and L and strands 9-11; and Cdomain (residues 294-566) is composed of anti-parallel sheet (12-20) flanked with helices M-U. Residues 176233) comprise an AB linker (helices H-J and 6-8). A-,
C-domains and AB-linker form a cylindrical structure with
ATP located at one end and B-domain acts as a lid at another
end Fig. (3B). ATP binding site, i.e., the active site of enzyme is located at the interface of the B-domain and cylinder
[30]. The B-domain keeps open conformation to the entry of
substrate or the release of product, but is closed during the
catalytic process.
2.2. CT Domain of Acetyl-CoA Carboxylases
Crystal structures of human ACC CT domain in complex
with CP-640186 and bovine CT domain in complex with
novel inhibitors have been identified [32, 33]. Yeast CT domain dimer was also identified as a free enzyme or in complexes with CoA [25], herbicides haloxyfop/diclofop [34], or
170 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
A
BC
Mammalian/Wheat/Yeast
Luo et al.
a subunit
S. coelicolor
Encoding gene:
BC
Encoding gene:
accC
MF-ACC
b subunit
accA1 (A2)
BC
Acidianus brierleyi
CT
BCCP
BCCP
BCCP
accB
CT
MF/MS-ACC
CT
MS-ACC
pccB
pccB
CT
BC
E. coli
Encoding gene:
B
accC
Gramineae
MF-ACC
Plastid
MF-ACC
BCCP
accB
MS-ACC
accA
accD
Dicot
MF-ACC
Plastid
MS-ACC
Fig. (2). ACC function domain. (A) ACC protein domains and encoding genes. ACCs of mammalian, wheat and yeast are composed of BC,
BCCP, and CT domains encoded by a single gene. ACC from S. coelicolor consists of subunit consisting of BC and BCCP domains and subunit, encoded by an accA1 (A2) and pccB gene, respectively. ACC form Acidianus brierleyi consists of 3 subunits encoded by an accC,
accB, and pccB gene, respectively. In E. coli, carboxyltransferase of ACCs consists of subunit and subunit encoded by accA and accD
gene. (B) ACC forms in plant, a multi-functional single protein (MF-ACC) and a multi-subunit heteromeric complex (MS-ACC).
an inhibitor CP-640186 [35]. This yeast CT domain dimer is
formed by a side-to-side reverse arrangement of two monomers [36]. A yeast CT domain monomer comprises 24 helices and 29 -strands, constructing two sub-domains (Nand C-domains) intimately associated with each other Fig.
(3C). The N-domain consists of residues 1484-1824 (strands
1-13 and helices 1-8), and the C-domain is composed of
residues 1825-2202 (1-12 and helices 1-8). The N- and
C-domains share similar polypeptide backbone folds with a
central -- superhelix (strands 5, 7, 9, and 11 and
helix 6). Catalytic pocket/cavity is formed by small sheets and 6 helix of -- superhelix of two domains, featured with additional binding surface for CoA Fig. (3C and
3D). The active site is located at the middle site of the interface of N- and C-domains in the dimer. Conserved residues
in the active site, Arg 1954 and Arg 1731 in particular, are
important for carboxyl group recognition of malonyl-CoA,
and the N1 atom of biotin itself functions as a general base
[25].
2.3. BCCP Subunit/Domain of Acetyl-CoA Carboxylases
BCCP subunit in E. coli contains the essential biotin covalently bound to lys 35 from the C-terminus, and the integral BCCP has strong tendency to aggregate [37, 38]. The
molar ratio of BC to BCCP subunits in E. coli is 1:2 [39].
The N-terminus (residues 1-30) of BCCP is responsible for
the interaction with BC, and the BC·BCCP complex could be
biotinylated in vitro.
3. REGULATION OF ACETYL-COA CARBOXYLASE
ACTIVITY
Due to the importance in energy and lipid metabolism,
ACCs activity is regulated at multiple levels, including transcriptional, posttranslational, and metabolite-allosteric regulations. Transcription of ACC1/2 genes is controlled by
sterol-regulatory-element binding protein 1 (SREBP-1), liver
X receptor, retinoid X receptor, peroxisome-proliferationactivated receptors (PPARs), forkhead box O (FOXO),
C/EBP and PPAR co-activator (PGC) [40-44]. By stimulating these signalings, a variety of factors and hormones, such
as glucose, insulin, and thyroid hormones regulate ACC expression. Please refer to the recent review articles for more
details [45-52].
Posttranslational regulation of ACC activity includes
phosphorylation and stabilization [53]. ACCs are phosphorylated as inactive monomers. On the contrary, dephosphorylation activates ACCs that self-associates for a functional multimeric filamentous complex. Induced polymerization of
mammalian acetyl-CoA carboxylase by MIG12 provides a
tertiary level of regulation of fatty acid synthesis [54]. AMPactivated kinase (AMPK), regulated by a variety of stress
signals and adipokines, (e.g. leptin and adiponectin), mediates the phosphorylation of ACC at Ser 79, Ser 1200, and
Ser 1215 [45, 55-57], and protein kinase A (PKA) activated
by low blood glucose phosphorylates ACCs at Ser 77, and
Ser 1200 [42, 58]. Additionally, breast cancer protein 1
Acetyl-CoA Carboxylase Inhibitors
Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
A
B
B-Domain
C-Domain
C
b11 b6
ATP
aR
B-Domain
aK
b9
aT
aS
b15 b16
b17 b14 b12
aI
b13
b19
Sor aN
b18
aM
b20
aD
aE
C
AB
linker
linker
aG
b1
aP
b 3 b 2 aF b 4
b5
aO
A-Domain
ATP
aJ
b8 b7 AB
aH
aC
B-Domain
aL
b10
aU
aQ
C-Domain
Sor
aA
aB
N
N
D
C
N Domain
CoA
N
Mol2
C domain
C Domain
b7D
A-Domain
Mol1
b7C
N domain b7A
b7B a3A
171
a6C
a6
a 6B
CoA a4
a6A
a5
a3
b11 b 9
a7
b6
b10 b
8
b12
a8
b13
b4
b3
a1
b2
a6
a6D
a7
b 10
a8A
N
a2
b8 b6
b 4A
a3
b4
b3
a2
a8
a8B
C
b 4B
a4
b9
b 11
b 12
b1
a5
N
a8C
b1
N
A
C-Domain
N Domain
C
Fig. (3). 3D structure of ACC domains. A and B: Crystal structure of BC domain of yeast ACC 1. C and D: Crystal structure of CT domain
of ACC 2. The crystal structure figures were produced with permission as indicated in footnote.
(BRCA1) prevents ACCs from dephosphorylation at Ser 79
and Ser 1263 [59, 60].
Recent studies from our laboratory have revealed a novel
regulatory mechanism on ACC activity. Aldo-keto reductase
family 1 member B10 (AKR1B10), a NADPH-dependent
xenobiotic reductase primarily expressed in the colon and
small intestine [61-63], upregulated simultaneously with
ACC1 in tumorigenic transformation of human mammary
epithelial cells. Through direct association with ACC1,
AKR1B10 blocks its ubiquitin-dependent degradation, mediating fatty acid synthesis and lipid metabolism [64, 65].
ACC activity is also regulated in molecular conformation
by local metabolites. Citrate, a precursor of acetyl-CoA, allosterically activates ACCs, stimulating conversion of excessive acetyl-CoA to malony-CoA [66]. In contrast, palmitoylCoA, an end-product of fatty acid synthesis, promotes the
inactive conformation of ACCs, diminishing malonyl-CoA
production [67].
1
Reprinted from Molecular Cell, Vol. 16, Shen Y, Volrath SL, Weatherly SC, Elich
TD, Tong L, A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A
carboxylase by soraphen A, a macrocyclic polyketide natural product, 881-91., Copyright (2004) , with permission from Elsevier.
2
, From Zhang H, Yang Z, Shen Y, Tong L, Crystal structure of the carboxyltransferase
domain of acetyl-coenzyme A carboxylase, 2003; 299: 2064-2067. Reprinted with
permission from AAAS.
4. ACETYL-COA CARBOXYLASE INHIBITORS
As critical enzymes in fatty acid synthesis and energy
metabolism, ACCs are pathogenically implicated in several
human diseases, including metabolic syndromes and deadly
172 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
malignancies, and thus may be potent therapeutic targets. In
the past decades, ACC inhibitors have been extensively explored in preclinical and clinical trials. Discussed below are
updates on the investigation and development of ACC inhibitors.
Luo et al.
domain [110]. These inhibitors include sulfonamide-containing spirochromane derivatives (JP119987, US20110077262A1 and US7935712) [113, 114], non-spirocyclic matter
(JP119987), spiro [chromene-2,4-piperidin]-4(3H)-ones
(WO07011809 and WO07011811), and pyrazolospiroketone
(US 20110028390) [115].
4.1. Categories of Acetyl-CoA Carboxylase Inhibitors
ACC inhibitors include two main classes: natural and
non-natural (artificial) compounds. As summarized in Table
1 [17, 68-72], natural ACC inhibitors are isolated from natural products, such as Soraphen A (WO03011867) from Sporangium cellulosum [73-75], avenaciolide (WO03094912
and JP035998) from Aspergillus avenaceus, chloroacetylated
biotin (US6242610 and US6485941) from beans, egg yolks,
and cauliflower [72, 76, 77], pseudopeptide pyrrolidine dione antibiotics (Moiramide and Andrimid, US7544709 and
US20050080129) from bacteria [78, 79], curcumin
(WO05113069 and US20050267221) from turmeric [80].
The natural products inhibit ACC activity by three modes.
Curcumin phosphorylates and inactivates ACC via activating
AMPK [81-83], Moiramide B and Andrimid act as a CT
inhibitor, and other natural products inhibit the BC activity
by interacting with the allosteric site [78, 79].
Chemically synthesized inhibitors are composed of three
subclasses based on their chemical structures Table 2 [18,
33, 84-111]. The first subclass possess commonly extended
linear aliphatic region. Inhibitory activity of these compounds depends on their intracellular conversion to CoA
thioesters, inhibiting ACC activity by competing with acetylCoA in the CT catalyst. This subclass of ACC inhibitors
includes anthranilic acid derivatives (2-amino-,,trifluoro-p-toluic acids; US4307113 and JP11171848), sulfonamide derivatives (N-(1-[4-[2-(4-isopropoxyphenoxy)1,3-thiazol-5-yl]phenyl]ethyl)ethyl) acetamide; US0191323
and WO0202101), benzodioxepine derivatives (A1, 3,3Dimethyl-7-(4-methylsulfanyl-phenylethynyl)-3,4-dihydro2H-benzo[b][1,4] dioxepine; US0113374), alkynyl-substituted thiazole derivatives (A1, N-[4-(2-furyl)-5-(4-pyridyl)
thiazol-2-yl]pyridine-4-carboxamide; US0105919), heteroaryl-substituted thiazole derivatives (A1, 4-(6-((dimethylamino)methyl)pyridin-3-yl)-N-(4-(pentyloxy)-3(trifluoromethyl) phenyl) thiazol-2-amine; US0041720), ,
-dicarboxylic acid derivatives (MEDICA 16 and ESP55016; US4711896), benzoic acid derivative (S-2E;
US5145865), furan-2,5-dicarboxylic acid diamides (TOFA;
US3546255), aryloxyphenoxypropionate derivatives (Haloxyfop; US0014643), and cyclohexanedione derivatives
(sethoxydim, US4640706).
The second subclass of ACC inhibitors is bipiperidinylcarboxamide pharmacophores or cyclohexyl. They are potent, reversible, isozyme-nonselective inhibitors targeting the
CT domain of ACC [112], and however, the cyclohexyl derivatives exhibit potent inhibition of human ACC2, 10-fold
selectivity over inhibition of human ACC1 [33]. These compounds
include
bipiperidinylcarboxamide
analogs
(CP640186), (4-piperidinyl)-piperazine, pseudopeptide pyrrolidine dione antibiotics, benzthiazolylamide analogs, and
cyclohexyl derivative.
The third subclass of ACC inhibitors is spirochromanone
pharmacophores and they may inhibit ACC by targeting CT
4.2. Popular Acetyl-CoA Carboxylase Inhibitors
Although thousands of ACC inhibitors have been developed thus far, most published reports are based on studies
with these compounds Table 3, which are actively applied/investigated in agriculture for weeding and in laboratory animals for the treatment of obesity, type 2 diabetes
mellitus, or cancer.
4.2.1. Soraphen A
Soraphen A (1S,2S,3E,5R,6S,11S,14S,15R,16R,17S,
18S)-15,17-dihydroxy-5,6,16-trimethoxy-2,14,18-trimethyl11-phenyl-12,19-dioxabicyclo[13.3.1] nonadec-3-en-13-one)
(WO03011867) was isolated from the culture broth of
Sorangium cellulosum, a soil-dwelling myxobacterium [73,
74]. This polyketide natural product contains an unsaturated
18-membered lactone ring, an extracyclic phenyl ring, two
hydroxyl groups, three methyl groups, and three methoxy
groups [74, 116, 117]. Soraphen A is an allosteric inhibitor
of the BC domain, binding to the interface between the Adomain and C-domain, 25Å away from the putative ATP
binding site. ATP and Soraphen A molecules are located at
opposite ends of the cylindrical structure of the BC domain.
Soraphen A interacts with residues from helices N and O
and strands 17-20 in the C-domain, as well as several residues of helix C in the A-domain. Soraphen A is a noncompetitive eukaryotic ACC inhibitor with sensitivity at a
nanomolar level; soraphen A has no inhibitory activity towards the bacterial BC subunits [74, 118-120]. This species
selectivity of soraphen A is explained by the amino acid sequence and structural difference of the binding sites, e.g. the
absence of 18 in E. coli BC) [117].
4.2.2. Haloxyfop
Haloxyfop (2-[4-[3-chloro-5-(trifluoromethyl)pyridin-2yl] oxyphenoxy]propanoic acid) contains pyridine moiety,
and two forms of Haloxyfop are synthesized i.e. haloxyfopmethyl and haloxyfop-ethoxyethyl (US0184980). Haloxyfops are commercially used as pre- and post-emergence selective herbicides in broad leaf crops. They are absorbed by
the foliage and roots and hydrolyzed to haloxyfop, inhibiting
growth of meristematic tissues. The (R)-isomer, not (S)isomer, of haloxyfop is herbicidally active [34]. Another
derivative, diclofop (2-(4-(2,4-dichlorophenoxy) phenoxy)propionate) (US0184980) inhibits fatty acid synthesis
in Zea mays. Haloxyfop or diclofop binds to the active site at
the interface of CT dimer and leads to large conformational
changes of several residues, creating a highly conserved hydrophobic pocket extended into the core of the dimer [34].
Two residues Leu 1705 and Val 1967 that affect herbicide
sensitivity are located in this binding site, and their mutation
disrupts the structure of the domain and affect the response
to this inhibitor.
Acetyl-CoA Carboxylase Inhibitors
Table 1.
Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
173
Natural ACC Inhibitors.
ACC Inhibitors
Chemical Formula
Action Mechanism
Sources
Active Species
Selectivity
Ref.
Soraphen
OMe
Inhibit BC reaction
Myxobacteria
Sorangium
Cellulosum
Fungal
ACC1
[17, 68]
Eukaryote
ACC2
Bacteria
ACC2?
[69-71]
[72]
(e.g. Soraphen A)
OMe
O
O
O
OH
OMe
OH
O
Avenaciolide
O
H
O
O
ACC1
Eukaryote
ACC2
Inhibit CT reaction
Bacteria
Bacteria
--
[131,
133, 138]
Activate AMPK
Turmeric
Mammalian
ACC2
[82]
Eukaryote
O
O
R2
R3
O
NH
N
H
N
H
O
Curcumin derivative
O
O
O
HO
OH
OCH3
Table 2.
Bacteria
O
H
Pseudopeptide
pyrrolidine dione
R1
Beans, egg
yolks, and
cauliflower
NH
N
H
S
(e.g. Andrimid,
Moiramide B)
Inhibit BC reaction
Fungal
C8H17
O
Cl
Aspergillus
avenaceus
H
O
Chloroacetylated
biotin
Inhibit glutamate
transport in
mitochondria ?
OCH3
Non-natural ACC Inhibitors.
ACC Inhibitors
Chemical Formula
Action Mechanism
Active Species
Selectivity
Ref.
Inhibitors with Linear Aliphatic Region
Anthranilic acid derivatives
O
Inhibit carboxylase
reaction?
Bacteria
ACC1, ACC2
[84-85]
Suppress
Eukaryote
ACC1, ACC2
[86]
Mammalian
ACC2
[87]
Eukaryote
NH
OR1
H
N R1
Sulfonamide derivatives
O
H
S N
O2
Benzodioxepine derivatives
R
O
O
ACC activation?
O
R2
?
174 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
Luo et al.
(Table 2) Contd….
ACC Inhibitors
Chemical Formula
O
Alkynyl-substituted thiazole derivatives
Action Mechanism
S
Selectivity
Ref.
?
Eukaryote?
ACC2
[88-91]
?
Eukaryote?
ACC1, ACC2
[92]
Inhibit CT reaction
Eukaryote
ACC1, ACC2
[93-94]
Noncompetitively
inhibit ACC by S-2ECoA
Eukaryote
ACC1, ACC2
[95-97]
Inhibit CT reaction
Bacteria
ACC1, ACC2
[111]
NH
R1
O
O
Heteroaryl-substituted
thiazole derivatives
R3
N
R2
N
R1
Alkanedicarboxylic derivatives
Active Species
O
O
O
OH
HO
(e.g. MEDICA 16,
ESP-55016)
R2
Benzoic acid derivative
(e.g.S-2E)
O
O
R1
R2
Furan-2,5-dicarboxylic
acid diamides
Eukaryote
R1
(e.g. TOFA)
O
Aryloxyphenoxypropionates
R1
R2
(e.g. Haloxyfop)
Cyclohexanediones
N
O
COOH
Inhibit CT reaction
Grass
--
[98-100]
Inhibit CT reaction
Grass
--
[98-101]
Inhibit CT reaction
Eukaryote
ACC1, ACC2
[18, 102103]
Inhibit CT reaction
Eukaryote
ACC1, ACC2
[104]
Me
O
R1
O
(e.g. Sethoxydim)
N
O
O
R3
R2
Inhibitors with Bipiperidinylcarboxamide Pharmacophore or Cyclohexyl
Bipiperidinylcarboxamide analog (e.g.
CP640186)
O
N
O
N
N
O
O
(4-Piperidinyl)-piperazine
N
N
O
N
N
N
O
Acetyl-CoA Carboxylase Inhibitors
Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
175
(Table 2) Contd….
ACC Inhibitors
Chemical Formula
Benzthiazolylamide analogs
Action Mechanism
R2
O
Active Species
Selectivity
Ref.
Inhibit CT reaction
Eukaryote
ACC1, ACC2
Inhibit CT reaction
Mammalian
ACC1, ACC2
(10-fold selectivity over inhibition of human
ACC1)
[33]
Inhibit CT reaction
Mammalian
ACC1, ACC2
[107]
Inhibit CT reaction
Mammalian
ACC1, ACC2
[108]
Inhibit CT reaction
Mammalian
ACC1, ACC2
[109]
Inhibit CT reaction
Mammalian
ACC1, ACC2
[110]
N
[18, 105106]
NH
S
NHR1
O
O
Cyclohexyl derivatives
O
NH
HN
O
R
Inhibitors with Spirochromaone Pharmacophore
Sulfonamide-containing
Spirochromane Derivatives
O
R1
R2
O
H
N
A
R3
R4
O
R3
Non-spirocyclic matter
R1
R4
R2
H
N
R5
R6
O
Spiro[chromene-2,4piperidin]-4(3H)-ones
O
R1
O
N
R2
O
O
Azaspirochromanones
R1
N
O
N
R2
O
176 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
Table 3.
Luo et al.
Popular ACC Inhibitors.
Inhibitors
Chemical
(Abbr.)
Formula
Soraphen A
O
O
Chemical Name
Molecular
Weight
Molecular
Formula
(1S,2S,3E,5R,6S,11S,14S,15R,16R,17S,18S
)-15,17-Dihydroxy-5,6,16-trimethoxy2,14,18-trimethyl-11-phenyl-12,19dioxabicyclo [13.3.1]nonadec-3-en-13-one
520.65
C29H 44O8
(2E,4E,6E)-N-[(1S)-3-[[(2S)-3-Methyl-1[(3R,4S)-4-methyl-2,5-dioxopyrrolidin-3yl]-1-oxobutan-2-yl]amino]-3-oxo-1phenylpropyl]octa-2,4,6-trienamide
479.57
C27H 33N3 O5
(2E,4E)-N-[(1S)-3-[[(2S)-3-Methyl-1[(3R,4S)-4-methyl-2,5-dioxopyrrolidin-3yl]-1-oxobutan-2-yl]amino]-3-oxo-1phenylpropyl]hexa-2,4-dienamide
453.53
C25H 31N3 O5
2-[4-[3-Chloro-5-(trifluoromethyl)pyridin2-yl]oxyphenoxy]propanoic acid
361.70
C15H 11ClF3NO4
2-[1-(Ethoxyamino)butylidene]-5-(2ethylsulfanylpropyl)cyclohexane-1,3-dione
327.48
C17H 29NO 3S
5-Tetradecoxyfuran-2-carboxylic acid
324.45
C19H 32O4
OH
O
O
O
HO
Andrimid
O
H
N
O
O
H
N
O
H
N
O
O
Moiramide
B
H
N
O
O
H
N
O
H
N
O
O
Haloxyfop
Cl
HO
O
O
N
F
F
F
O
Sethoxydim
S
HN
O
O
ToFA
OH
O
O
O
Acetyl-CoA Carboxylase Inhibitors
Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
177
(Table 3) Contd….
Inhibitors
Chemical
(Abbr.)
Formula
O
S-2E
N
Chemical Name
Molecular
Weight
Molecular
Formula
(+)-(S)p
-[1-(
p-Tertbutylphenyl)-2-oxo-4-pyrrolidinyl]methoxybenzoic acid
519.61
C28 H 42NO 6
3,3,14,14Tetramethylhexadecanedioic acid
342.51
C20H 38O4
8-Hydroxy-2,2,14,14-Tetramethylpentadecanedioic acid
344.49
C19H 36O5
[(3R)-1-[1-(Anthracene-9carbonyl)piperidin-4-yl]piperidin3-yl]-morpholin-4-ylmethanone
485.62
C30H 35N3 O3
O
OH
O
MEDICA
16
O
OH
HO
O
O
ESP55016
OH
HO
O
OH
CP640186
O
N
O
N
N
O
4.2.3. Sethoxydim
Sethoxydim (2-[1-(ethoxyamino)butylidene]-5-(2-ethylsulfanylpropyl)cyclohexane-1,3-dione) (US4602935 and
US0033897) inhibits lipid synthesis in two dicot species,
Nicotiana sylvestris (wild tobacco) and Glycine max (soybean) [121]. It is a selective post-emergence herbicide used
to control annual and perennial grass weeds in broad-leaved
vegetables, fruits, fields, and ornamental crops. Sethoxydim
is rapidly absorbed through the leaf surfaces, transported in
the xylem and phloem, and accumulated in the meristematic
tissues. Non-susceptible broadleaf species have a different
acetyl-CoA carboxylase binding site resistant to sethoxydim.
Sethoxydim is water-soluble and does not bind readily with
soils, thus being mobile.
4.2.4. TOFA
Five-tetradecyloxy-2-furoic acid (TOFA) (US3546255)
itself has no activity. In adipocytes and hepatocytes, TOFA
is converted to 5-tetradecyloxy-2-furoyl-CoA (TOFyl-CoA)
that binds to CT domain and exerts an allosteric inhibition on
ACCs. TOFA is a mammalian ACC inhibitor. The inhibitory
activity of TOFA depends on its concentration relative to
fatty acids, cells, and nutritional state. In isolated rat adipocytes, TOFA inhibits fatty acid synthesis and leads to accumulation of lactate and pyruvate, and release of CO2 by
blocking synthesis of malonyl-CoA [122]. Ketogenesis from
palmitate was slightly inhibited (~ 20%) by TOFA at a concentration less than CoA, but the inhibition was almost complete (up to 90%) at a concentration equal to or greater than
the CoA [15]. In some conditions, TOFA may inhibit fatty
acid synthesis, but not affect fatty acid oxidation [122-124].
TOFA can also inhibit glycolysis as a secondary effect of
fatty acid synthesis inhibition and resultant citrate accumulation, a metabolite inhibitor of phosphofructokinase [125].
TOFA inhibition of ACCs in human cancer cells is controversial. It has been reported that TOFA induces the apoptosis
of lung cancer cells NCI-H460 and colon carcinoma cells
HCT-8 and HCT-15, but not of some breast and ovary cancer
cells, such as MCF-7 [15, 126-129].
4.2.5. Andrimid
Andrimid
((2E,4E,6E)-N-[(1S)-3-[[(2S)-3-methyl-1[(3R,4S)-4-methyl-2,5-dioxopyrrolidin-3-yl]-1-oxobutan-2yl]amino]-3-oxo-1-phenylpropyl]octa-2,4,6-trienamide;
JP11171848) is a hybrid non-ribosomal peptide-polyketide
178 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
antibiotic that can block the carboxyl-transfer reaction.
Structure–activity studies have led to development of new
analogues with modified pseudopeptide motifs and improved
efficacies in vivo and in vitro [130].
Andrimid and moiramide (A, B and C) are both natural
antibiotics with a hybrid non-ribosomal peptide polyketide
scaffold that is acylated at the N-terminus and modified by a
pyrrolidine dione moiety at the C-terminus. This class of
molecules is widely distributed in nature and has received
considerable attention after their cellular target is discovered
as ACCs [131]. Low primary sequence homology and structural distinction between the prokaryotic and eukaryotic
ACCs has made bacterial ACCs a long appreciated target for
antibacterial drug development. The andrimid biosynthetic
gene cluster from Pantoea agglomerans encodes an admT
with homology to the arboxyltransferase (CT) -subunit encoded by accD. E. coli cells with admT overexpression are
resistant to andrimid. When AdmT and CT -subunit AccA
are overexpressed in E. coli cells, an active heterologous
tetrameric CT A2T2 complex is formed. Andrimid-inhibition
assay shows an IC50 of 500 nM for the A2T2 complex, compared to 12 nM for E. coli CT A2D2. These data suggested
that AdmT, as an AccD homolog, confers resistance to andrimid [130].
4.2.6. Moiramide B
Pseudopeptide pyrrolidine dione antibiotics are isolated
from three distinct bacterial species of proteobacteria: Enterobacter sp., Vibrio sp., and Pseudomonas fluorescens
[132]. These antibiotics have broad antibacterial activity
against Gram-positive bacteria, such as Staphylococci and
Bacilli, and Gram-negatives, such as E. coli. The chemical
Moiramide B ((2E,4E)-N-[(1S)-3-[[(2S)-3-methyl-1-[(3R,
4S)-4-methyl-2,5-dioxopyrrolidin-3-yl]-1-oxobutan-2yl]amino]-3-oxo-1-phenylpro-pyl]hexa-2,4-dienamide;
US7544709) inhibits carboxyltransferase activity of ACCs
[131, 133]. In vitro and bacterial studies indicates that
Moiramide B demonstrates inhibitory activity at nanomolar
levels[39, 133, 134].
4.2.7. ESP-55016
Luo et al.
enantiomers (1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid, N-[(S)-(-)-[4-methyl-(alpha-methyl)benzyl]]-1(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-carboxyamide, 4bromo-2-fluorobenzamide of (+)-4-[1-(4-tert-butylphenyl)-2oxo-pyrrolidine-4-yl]-methyloxy-benzoic acid) (US4831055)
showed an essentially equipotent activity in inhibiting fatty
acid- and sterol-biosynthesis, lowering down blood cholesterol and triglyceride levels [136, 137]. The in vivo active
form is S-2E ((+)-(S)-p-[1-(p-tert-butylphenyl)-2-oxo-4pyrrolidinyl] methoxybenzoic acid) that is converted into S2E-CoA in the liver, exerting non-competitive inhibition of
ACCs at Ki = 69.2M. S-2E-CoA also effectively inhibits 3hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase at Ki = 18.11M [136]. When administered at 10 mg/kg
orally, liver S-2E-CoA are sufficient to inhibit HMG-CoA
reductase and ACCs, and therefore S-2E may be useful in the
treatment of familial hypercholesterolemia and mixed hyperlipidemia [95, 96, 137].
4.2.9. CP-640186
CP-640186 ([(3R)-1-[1-(anthracene-9-carbonyl) piperidin-4-yl]piperidin-3-yl]-morpholin-4-ylmethanone; WO03072197) is a potent inhibitor of mammalian ACCs, which can
reduce body weight and improve insulin sensitivity in animals. It is non-selective towards two isoforms ACC1 and
ACC2 with an IC50 at 50nM in rat, mouse and monkey [68].
In experimental animals, CP-640186 decreases malonyl-CoA
in lipogenic and oxidative tissues, reducing fatty acid synthesis and stimulating fatty acid oxidation [18]. In sucrose-fed
rats, CP-640186 reduces triglycerides in the liver, muscle
and adipose, and body weight by selectively reducing fats
but not lean body mass. In these animals, CP-640186 also
reduces leptin levels and induces hyperinsulinemia stemmed
from high sucrose diet [18].
5. APPLICATIONS OF ACETYL-COA CARBOXYLASE INHIBITORS
5.1. Herbicides in Agriculture
The earliest application of ACC inhibitors is in agriculture. Two classes of herbicides targeting ACCs, aryloxyphenoxypropionates (Haloxyfop) and cyclohexanediones
(Sethoxydim), have been commercially used for more than
twenty years [118].
ESP-55016 (8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid; US4711896), a -hydroxy-alkanedicarboxylic acid, is converted in vivo into a CoA derivative, ESP55016-CoA, which markedly inhibits the activity of ACC.
ESP55016 dually inhibits fatty acid and sterol synthesis
in vivo and in primary rat hepatocyte culture [135]. In obese
female Zucker (fa/fa) rats [135], ESP55016 favorably reduces serum non-HDL-cholesterol (non-HDL-C), triglyceride,
and non-esterified fatty acid levels, but increases serum
HDL-C and -hydroxybutyrate in a dose-dependent manner.
ESP55106 also increases the oxidation of [14C]-palmitate in a
carnitine palmitoyl transferase-I (CPT-I)-dependent manner
[135]. This indicates that ESP-55016 affects both fatty acid
and sterol synthesis and fatty acid oxidation through the
ACC/malonyl-CoA/CPT-I axis.
ACC inhibitors are also used to control invading organisms that depend on lipid synthesis for rapid proliferation
[131, 138, 139]. Antibacterial ACC inhibitors include (-)avenaciolide, chloroacetylated biotin, and pseudopeptide
pyrrolidine dione antibiotics (Andrimid and Moiramide B).
Especially, Andrimid and Moiramide B are natural antibiotics with broad antibacterial activity against Gram-positive
and negative bacteria, such as Staphylococci, Bacilli, and E.
coli [131, 138]. Antifungal ACC inhibitors include soraphen
A, (-)-avenaciolide, CP640186, MEDICA-16, and TOFA
[39, 69, 73, 74].
4.2.8. S-2E
5.3. Treatment of Metabolic Syndromes
S-2 ((+/-)-4-[1-(4-tert-Butylphenyl)-2-oxo-pyrrolidine-4yl]methyloxybenzoic acid), a anti-lipidemic agent, and its
Over the past 30 years, a variety of ACC inhibitors have
demonstrated treatment activity in animal models of dyslipi-
5.2. Antibiotics in Infection Diseases
Acetyl-CoA Carboxylase Inhibitors
demia [140, 141]. For example, alkyloxyarylcarboxylic acids
(e.g., TOFA) showed marked hypolipidemic activity in both
rats and monkeys [142, 143], and MEDICA, MEDICA-16 in
particular, displayed hypolipidemic, anti-diabetic, and antiatherosclerotic activity in relevant animal models [144-146].
The alkylthioacrylic acids appear to have similar activity to
MEDICA in intervening dyslipidemia in animals [147-149].
In addition, S-2E may hold the promise for the treatment of
familial hypercholesterolemia and mixed hyperlipidemia [95,
96], and -hydroxy-alkanedicarboxylic acid, ESP 55016,
favorably alters serum lipid profile of the Zucker rat diabetic
dyslipidemia [135]. CP-640186 is an isozyme-nonselective
ACC inhibitor, equally inhibiting ACC1 and ACC2 in rat,
mouse, monkey, and human. This chemical reduces fatty
acid synthesis and triglyceride secretion without affecting
cholesterol synthesis, thus decreasing apo-B secretion but
not apo-A1; CP-640186 also stimulates fatty acid oxidation
[17, 18].
5.4. Cancer Therapy
Exploration of ACC inhibitors for anticancer therapy is a
novel attracting field. De novo fatty acid synthesis is required for carcinogenesis, and in cancer cells, up to 95%
fatty acids used are newly synthesized despite adequate nutritional lipid supplies [150]. The newly synthesized fatty
acids in malignant cells are used for biomembrane synthesis
and lipid second messengers, promoting cell growth and
proliferation [151]. Therefore, the lipogenesis pathway is a
cancer target [152]. As a critical, rate-limiting enzyme in
fatty acid de novo biosynthesis, ACC1 is upregulated in multiple types of human cancers, such as breast and prostate
tumors. ACC is a novel target for cancer therapy [153]. Specific silencing of ACC1 by RNA interference (RNAi) results
in caspase-mediated apoptosis of breast, colon and prostate
cancer cells by depleting fatty acids/lipids and inducing oxidative stress derived from membrane damage of mitochondria [154, 155]. Similarly, our studies revealed that
AKR1B10 mediates ACC1 stability and fatty acid synthesis,
and silencing of AKR1B10 triggers ACC1-mediated breast
cancer cell growth inhibition and apoptosis [65]. Therefore,
fatty acid synthesis is essential for cancer cell growth and
survival, and ACC inhibitors may represent a novel class of
potent antitumor agents [66, 155, 156].
TOFA (5-tetradecyl-oxy-2-furoic acid) decreases fatty
acid synthesis and induces caspase activation and cell death
in most PCa cell lines by reducing ACC-mediated fatty acid
synthesis and inhibiting expression of androgen receptor
(AR), neuropilin-1 (NRP1) and Mcl-1 [157]. ACC inhibitor
soraphen A at nanomolar levels can block fatty acid synthesis and stimulate fatty acid oxidation in LNCaP and PC-3M
prostate cancer cells, inducing apoptosis [19, 158], and
TOFA showed capability of triggering apoptosis of lung
(NCI-H460) and colon (HCT-8 and HCT-15) carcinoma
cells through disturbing their fatty acid synthesis [126]. It is
obvious that further studies are merited to develop ACC inhibitors as anticancer agents.
6. CURRENT & FUTURE DEVELOPMENTS
ACCs catalyze the production of malonyl-CoA from acetyl-CoA and malonyl-CoA is an essential component for
Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
179
fatty acid elongation and yet is an inhibitor of fatty acid oxidation. Therefore, ACCs are critical for fatty acid metabolism and organism growth and viability, explaining their
broadly conservation from bacteria to humans. Inhibition of
ACC activity is a potential treatment strategy for microbial
infections, metabolic syndromes, and cancer in humans. Currently available ACC inhibitors inhibit ACC activity through
binding to the carboxyltransferase-domain or the biotin carboxylase-domain. Among mechanistically distinct ACC inhibitors, isozyme-nonselective ACC inhibitors may hold
better therapeutic potential via decreasing fatty acid synthesis and enhancing oxidation. Isozyme-selective inhibitors
should have advantages and liabilities associated with a single isozyme inhibition. However, it should be noted that
isozyme nonselective ACC inhibitors may also have issues,
e.g. ACC1 knockout mice show embryonic lethality [159]
and also ACC2 inhibition may be ineffective [160]. The current intensive research on ACCs and inhibitors could lead to
the development of novel therapeutic agents against metabolic syndromes and cancers. Clinical efficacy of the ACC
inhibitors should be expected. Tissue fat reduction, weight
loss, improved insulin sensitivity, and relief of dyslipidemia
were observed in ACC2 knockout mice [161-163] and in
experimental animals treated with isozyme-nonselective
ACC inhibitors [18, 68] or ACC antisense oligonucleotides
[164], which compels a study in human clinics. The clinic
efficacy evaluation could focus initially on approved endpoints for obesity and dyslipidemia, improved insulin sensitivity, and reduction in hyperinsulinemia. Weight loss, percentage body fat, and regional fat distribution may be evaluated in longer-term clinical trials. The treatment outcomes
of coronary heart diseases and type 2 diabetes or other
significant health outcomes related to metabolic syndromes
could also be assessed [17].
Several potential hurdles hamper the application of ACC
inhibitors in humans. First, malonyl-CoA is important in
controlling insulin secretion in the pancreas. Reduction of
malonyl-CoA levels via ACC inhibition could offset beneficial effects on glucose-stimulated insulin secretion due to
reduction of pancreatic -cell fat contents [165-167]. It
remains to be determined whether ACC inhibition-induced
malonyl-CoA and subsequent fat content decrease in
pancreatic -cells adversely influence insulin secretion and
thus offsets beneficial effects in clinic [17]. Second, hypothalamic malonyl-CoA is a negative regulator of food intake
in feeding behavior [168], and thus reduction of malonylCoA in the hypothalamus may be undesirable. Consistent
with this observation, ACC2 knockout mice consume more
food even though they weigh less than wild-type animals
[161, 162], and Leptin-deficient Lepob/Lepob (ob/ob) mice
treated with CP-640186 increased food consumption concomitant with weight loss [68]. Therefore, weight reduction in
clinical trials with ACC inhibitors may occur together with
increased food consumption, and what is worse is that it
remains unknown whether this phenomenon counteracts the
positive metabolic effects of an ACC inhibitor, especially for
the inhibitors crossing the blood-brain barrier [169-172].
Third, studies in ex vivo working hearts suggest that elevated fatty acid oxidation during and after ischemia may
contribute to contractile dysfunction and increase ischemic
injury [173]. It remains to be understood whether ACC
180 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2
inhibition could potentially increase myo-cardial injury after
an ischemic event for fatty acid oxidation enhanced by ACC
inhibition [17]. Obviously, these concerns need to be taken
into consideration in the future efforts to develop ACC inhibitors for the treatment of metabolic syndromes and cancers,
and more ACC inhibitors are being invented for high
efficiency and low toxicity [174-176].
Luo et al.
[5]
[6]
[7]
ABBREVIATIONS
ACCs
=
Acetyl-CoA carboxylase
AKR1B10
=
Aldo-keto reductase family 1 member
B10
AMPK
=
AMP-activated kinase
AR
=
Androgen receptor
BC
=
Biotin carboxylase
BCCP
=
Biotin carboxyl carrier protein
BRCA1
=
Breast cancer protein 1
C/EBP
=
CCAAT-enhancer-binding proteins
CPT-I
=
Carnitine palmitoyltransferase I
CT
=
Carboxyltransferase
FOXO
=
Forkhead box O
HMG-CoA =
3-Hydroxy-3-methylglutaryl coenzymeA
NRP1
=
Neuropilin-1
PKA
=
Protein kinase A
PPARs
=
Peroxisome-proliferation-activated receptors
SREBP-1
=
Sterol-regulatory-element binding protein 1
TOFA
=
Five-tetradecyloxy-2-furoic acid
ACKNOWLEDGEMENTS
We thank Dr. Zhangyong Li in Department of Laboratory
Medicine, the First People’s Hospital of Chenzhou for drawing chemical structures in ChemDraw in this article.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
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