scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Recent developments in the synthesis and biological activity of acridine/acridone analogues

09 Mar 2017-RSC Advances (The Royal Society of Chemistry)-Vol. 7, Iss: 26, pp 15776-15804
TL;DR: This survey describes acridine and acridone derivatives reported since 2013, methods of their synthesis and their potential clinical applications, as well as investigating their clinical application in Alzheimer's disease and other diseases.
Abstract: Many people in the world struggle with cancer or bacterial, parasitic, viral, Alzheimer's and other diseases. Therefore, many scientists seek new, more effective, more selective and less toxic drugs. Acridine/acridone derivatives constitute a class of compounds with a broad spectrum of biological activity and are of great interest to scientists. To date, many acridine/acridone analogues have been obtained, which, inter alia, exhibit antitumour (e.g., (1–5)), antimicrobial (e.g., (59)), and antiviral (e.g., (61)) activities and are applicable in the treatment of Alzheimer's disease (e.g., (26)). However, in many cases, their clinical application is limited and excluded because of side effects. In this survey, we describe acridine and acridone derivatives reported since 2013, methods of their synthesis and their potential clinical applications.

Content maybe subject to copyright    Report

Recent developments in the synthesis and
biological activity of acridine/acridone analogues
Monika Gensicka-Kowalewska, Grzegorz Cholewi
´
nski and Krystyna Dzierzbicka
*
Many people in the world struggle with cancer or bacterial, parasitic, viral, Alzheimer's and other diseases.
Therefore, many scientists seek new, more eective, more selective and less toxic drugs. Acridine/acridone
derivatives constitute a class of compounds with a broad spectrum of biological activity and are of great
interest to scientists. To date, many acridine/acridone analogues have been obtained, which, inter alia,
exhibit antitumour (e.g.,(15)), antimicrobial (e.g.,(59)), and antiviral (e.g.,(61)) activities and are
applicable in the treatment of Alzheimer's disease (e.g.,(26)). However, in many cases, their clinical
application is limited and excluded because of side eects. In this survey, we describe acridine and
acridone derivatives reported since 2013, methods of their synthesis and their potential clinical applications.
Introduction
Acridine derivatives form an important class of heterocycles
containing nitrogen due to their broad range of pharmaceutical
properties. Acridine derivatives are characterized by unique
physical and chemical properties, biological activities, and
industrial applications. In the nineteenth century, acridine
derivatives were already used industrially as pigments and
dyes.
1
More critical to the pharmaceutical industry, acridine
derivatives have exhibited bioactivities such as anti-inamma-
tory,
2,3
anticancer,
4
antimicrobial,
5
antitubercular,
6,7
antipara-
sitic,
8
antimalarial,
911
antiviral
12,13
and fungicidal activities.
14
Acridine derivatives have been shown to be eective as inhibi-
tors of acetylcholinesterase.
15
Furthermore, acridines are used
as dyes, uorescent materials for visualization of biomolecules,
and in laser technologies.
16
These properties of acridines are
attributed to their semi-planar heterocyclic structure, which
appreciably interacts with dierent biomolecular targets.
Acridine/acridone derivatives are found in natural plants and
various marine organisms.
17,18
Notably, the anticancer activity of
acridine/acridone derivatives has attracted increasing interest.
To date, many derivatives of acridine have been synthesized and
tested for antitumour activity. The unique planar ring structure
allows acridone derivatives to act as DNA intercalators
19,20
and to
inhibit topoisomerase or telomerase enzymes.
2124
Avarietyof
acridine/acridone derivatives have been synthesized; analogues
such as N-(2-(dimethylamino)ethyl)acridine-4-carboxamide (DACA)
(1),
2527
triazoloacridone (C-1305) (2)
28
and amsacrine (m-AMSA)
(3)
29
(Fig. 1) have entered clinical studies. Among them, m-AMSA
(3)wastherst synthetic drug exhibiting clinical ecacy as
a topoisomerase inhibitor. Many m-AMSA derivatives (AHMA (4),
D3CLP (5)) (Fig. 1) have been developed for stronger anti-cancer
properties and removal of many harmful side eects.
27,30
Intermolecular interactions in acridine and acridinium
derivatives determine their biological and physical properties
including their chemiluminogenic abilities. Therefore,
hydrogen bonding and pp interactions within the Hirshfeld
surface have been studied. Recently, Wera and co-workers re-
ported the synthesis and structural investigations of some new
acridine and acridinium derivatives.
31
Naturally occurring acridine/acridone
Acridine/acridone alkaloids
Alkaloids are naturally occurring chemical compounds, which
have a wide range of pharmacological activities (e.g.,antima-
larial, anticancer, and antibacterial).
32
To date, the literature
describes a number of acridine/acridone alkaloids, which have
been tested as anticancer, antibacterial and antimalarial agents
and against Alzheimer's disease.
18
Examples of these compounds
are cystodytin A (6) (isolated from various marine organisms) and
acronycine (7) (isolated from bark of Australian scrub ash tree)
(Fig. 2).
3335
Arai et al. describe the bioassay-guided fractionation and
Ngn2 promoter activity of acridine alkaloids (8 10) from an
extract of a culture of Streptomyces sp. IFM 11440.
17
Inubosin B
(9) bearing a hydroxy group at the 4 position showed potent
Ngn2 promoter activity, which was dose-dependent. Moreover,
compound (9) demonstrated more activity than the positive
control baicalin (11), while Insubosin A (8) and Insubosin C
(10), which have a hydroxy group at the 5 position, did not show
signicant activity (Fig. 3).
17
The Wouatsa group isolated acridone alkaloids (1221)
(Fig. 4) from the MeOH extract of the fruits of Zanthoxylum
zanthoxyloides and Zanthoxylum leprieurii, of which six were new
Department of Organic Chemistry, Chemical Faculty, Gdansk University of Technology,
G. Narutowicza 11/12, 80-233 Gdansk, Poland. E-mail: krydzier@pg.gda.pl
Cite this: RSC Adv.,2017,7, 15776
Received 23rd January 2017
Accepted 4th March 2017
DOI: 10.1039/c7ra01026e
rsc.li/rsc-advances
15776 | RSC Adv.,2017,7, 1577615804
This journal is © The Royal Society of Chemistry 2017
RSC Advances
REVIEW
Open Access Article. Published on 09 March 2017. Downloaded on 8/26/2022 12:29:47 PM.
This article is licensed under a
Creative Commons Attribution 3.0 Unported Licence.
View Article Online
View Journal
| View Issue

(12, 13, 14, 19, 20 and 21). Acridone molecules (1921) that have
a tetracyclic acridone structure as their carbon skeleton have
been named as zanthacridone.
36
All newly discovered acridones (12, 13, 14, 19, 20 and 21)
were tested for antibacterial activity against Bacillus subtilis
(MTCC 121), Micrococcus luteus (MTCC 2470), Staphylococcus
aureus (MTCC 96), and Pseudomonas aeruginosa (MTCC 741).
Compounds (12, 14, 19, and 21) exhibited activity against MTCC
741 with MIC values equal to 500, 125, 250, and 250 mgmL
1
,
respectively. Furthermore, analogue (14) inhibited MTCC 2470
(MIC 125 m gmL
1
), while molecules (15 and 18) failed to show
appreciable activity against MTCC 741 but showed good activity
in the inhibition of MTCC 96 (MIC 250 and 500 mgmL
1
,
respectively), MTCC 121 (MIC 250 and 250 mgmL
1
, respec-
tively) and MTCC 2470 (MIC 125 and 500 mgmL
1
,
respectively).
36
Acridones (12, 15, 18, and 19) were also tested for in vitro
cytotoxicity against liver (WRL-68), colon (Caco2), breast (MCF-
7) and prostate (PC-3) cancer cell lines by MTT assay. Studies
indicated that compound (12) showed moderate cytotoxic
activity against WRL-68 with an IC
50
value equal to 86 m M.
35
Moreover, quantitative SAR and molecular modelling studies
Fig. 1 Structures of DACA (1), C-1305 (2), m-AMSA (3), AHMA (4), and D3CLP (5).
2730
Fig. 2 Structure of cystodytin A (6) and acronycine (7).
33
Fig. 3 Structure of acridine alkaloids (810) and baicalin (11).
17
Fig. 4 Structures of acridones (1221).
36
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 1577615804 | 15777
Review RSC Advances
Open Access Article. Published on 09 March 2017. Downloaded on 8/26/2022 12:29:47 PM.
This article is licensed under a
Creative Commons Attribution 3.0 Unported Licence.
View Article Online

showed that molecules (12, 20, and 21) are inhibitors of aro-
matase and glycosyltransferase.
36
Further acridone alkaloids chlorospermine A (22 ), chlor-
ospermine B (23) and the known atalaphyllidine (24) and acri-
foline (25) (Fig. 5) were isolated from the stem bark of Glycosmis
chlorosperma by Beniddir et al.
37
They used bioassay-guided
isolation for this purpose.
Acridone molecules ( 2225) were tested for DYRK1A, CLK1,
CDK1, CDK5, GSK3, and CK1 activity. Acrifoline (25) showed
inhibition activities of DYRK1A, CLK1, GSK3, CDK1, and CDK5
with IC
50
values of 0.075, 0.17, 2, 5.3 and 9 mM, respectively.
Chlorospermine B (23) and atalaphyllidine (24) exhibited
activity against DYRK1A with IC
50
values of 5.7 and 2.2 mM,
respectively. Furthermore, compound (23) demonstrated inhi-
bition of CLK1 (IC
50
¼ 7 mM), while chlorospermine A (22) failed
to show any activity against various kinases. Thus, studies
performed suggest that acridine may constitute a molecular
skeleton in search of new inhibitors of DYRK1A.
37
Moreover,
a molecular docking study of (2235) showed that interactions
of the ligand with conserved Lys188 and backbone atoms in the
hinge region (Glu239 and/or Leu241) are necessary for good
biological activity. The most active compound (25) forms
hydrogen bonds between the hydroxy group at C-6 and Glu203
and the conserved Lys188 and interacts with backbone atoms of
Glu239 and Leu241 through hydrogen bonds involving the C-1
hydroxy group. Atalaphyllidine (24) is proposed to interact
with backbone atoms of Glu239, Leu241, and Ile165 through
hydrogen bonds involving the C-9, C-1, and C-5 oxygen atoms,
respectively. In turn, derivative (23) showed hydrogen bonds
between the hydroxy group in position C-5 and the side chains
of Glu203 and Lys188, while inactive chlorospermine A (22)
forms hydrogen bonds between its oxygen atoms at C-5, C-9,
and C-2
00
and backbone NH of Leu241 and side chains of
Asn244 and Asp307 (from the DFG motif), respectively.
37
Citrusinine-I (26) (Fig. 6) is an example acridone alkaloid
isolated from Swinglea glutinosa. These analogues were
described as herbicide models, and their inhibition of photo-
synthesis was investigated against both photosystem I and II.
Measurements in vitro demonstrated signicant inuence on
various stages of reactions in the course of photosynthesis;
however, extracts provided only several milligram amounts of
tested compounds, and design of multi-stage synthesis would
be necessary to accomplish in vivo examinations.
38
Teow presented the methods for treating various liver
diseases and certain cancers by used compositions of acridone,
xanthone, thioxanthone, tocotrienol and oleanolic triterpenoid
compounds.
39
He isolated hepatic therapeutic actives from the
dried stem, bark and roots of Cratoxylum cochinchinense plant.
The acridone molecules are at least one of the anti-viral
components in the hepatic pharmaceutical active which prob-
ably function by inhibiting the growth and multiplication of the
chronic hepatitis HBV and chronic hepatitis HCV in patients
aicted with chronic hepatitis B or chronic hepatitis C.
Synthetic derivatives of acridine/
acridone
Acridine/acridone as inhibitors of acetylcholinesterase
Alzheimer's disease (AD) is the most common form of
dementia, an incurable and neurodegenerative disease, which
manifests via progressive decline in intellectual abilities,
caused by the disappearance of nerve cells.
38,40
Because AD is
currently one of the largest global medical problems, it has
attracted the attention of medicinal chemists, who have studied
new drugs for this disease.
41
The drugs used in AD include
cholinesterase inhibitors, which enhance neurotransmission of
cholinergic synapses in the brain and thus enhance intellectual
activity.
42
The acridine derivative used in medicine as an anti-
AD drug is tacrine (27) (Fig. 7).
43
Acridines can be also used to diagnosis of neurodegenerative
disorders, such as AD. Fuchigami et al. developed
125
I-labeled
acridines possessing high anities for Ab aggregates involved in
these pathologies.
45
During in vivo experiments on Ab plaques in
the brain slices of Tg2576 mice, the most promising results were
obtained in case of 6-iodo-2-methoxy-9-methylaminoacridine and
2,9-dimethoxy-6-iodoacridine as potential imaging agents for
amyloid in living brain.
The Hamulakova group reported the potential of novel
tacrine/acridines (2830, 31ac) (Fig. 7) as human acetylcho-
linesterase (hAChE) and human butyrylcholinesterase (hBChE)
inhibitors.
46
In vitro studies have shown that the compounds
(29, 30, 31b and 31c) proved to be especially potent against
hAChE with IC
50
values in the range of 2 to 8 nM, and analogues
(28, 29 and 31ac) were the most eective inhibitors against
hBChE with IC
50
values 0.420 nM; however, tacrine (27)as
Fig. 5 Structure of acridone alkaloids (2225).
37
Fig. 6 Structure of citrusinine-I (26).
38
15778 | RSC Adv.,2017,7, 1577615804 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review
Open Access Article. Published on 09 March 2017. Downloaded on 8/26/2022 12:29:47 PM.
This article is licensed under a
Creative Commons Attribution 3.0 Unported Licence.
View Article Online

a reference compound showed less activity against hAChE (IC
50
¼ 500 nM) and hBChE (IC
50
¼ 23 nM).
44
Docking models of the
binding of compound (29) into hAChE showed cationp inter-
actions between Tyr341 and Trp286 residues of the peripheral
anionic site and the positively charged acridine ring and
showed cationp interactions between Trp86 and the proton-
ated tacrine ring. Additionally, stabilization of compound ( 29)
may be due to a hydrogen bond between the amino group of
tacrine and the oxygen atom of Tyr337.
44
Furthermore, Janockova et al. studied the interaction of
derivative (30) with ctDNA.
47
The results of UV-Vis absorption
spectroscopy showed that the binding of compound ( 30)
occurred with a binding constant value K ¼ 2.0 10
3
M
1
.
Thus, the results are indicative of a strong interaction between
analogue (30) and ctDNA. Additionally, they demonstrated that
(30) is a dual topo inhibitor, acting both as a topo I inhibitor
and as a topo II catalytic inhibitor.
46
Thiratmatrakul and co-workers synthesized the new tacrine-
carbazole hybrids (36ac) as potential multifunctional agents
for the treatment of AD.
48
The intermediate imines (34ac) were
prepared by reaction of 7-methoxyheptaphylline (32a) or hep-
taphylline (32b) with 1,3-diaminopropane (33a) or 1,5-dia-
minopentane (33b) in MeOH. The reaction of the corresponding
imines (34ac) with 9-chlorotacrine (35) in the presence of
pentanol obtained compounds (36ac) (Scheme 1).
47
Derivative (36a) revealed the most potent activity against
AChE inhibitory and antioxidant action. Additionally, the
molecular modelling study showed that synthesized analogues
demonstrated binding with the catalytic active site (CAS) and
the peripheral anionic site (PAS) of AChE. Furthermore, tacrine-
carbazole hybrids exhibited a neuroprotective eect against
oxidative stress induced by H
2
O
2
and Ab1-42 toxicity. Moreover,
analogue (36a) exhibited an ability to improve short-term and
long-term memory decit in mice induced by scopolamine.
47
Mohammadi-Khanaposhtani et al. presented the synthesis of
triazole derivatives of acridone (44an) (Scheme 2).
49
In the rst
step, 2-arylamino benzoic acids (39) were obtained by the Ull-
mann condensation reaction of 2-bromobenzoic acid (37)and
various aniline derivatives (38) in the presence of potassium
carbonate and copper in EtOH at reux. Subsequent cyclization of
compound (39) by PPA at 100
C obtained acridone derivatives
(40), which by reaction with propargyl bromide (41) using potas-
sium tert-butoxide in DMSO at room temperature yielded 10-
(prop-2-yn-1-yl)acridin-9-one derivatives (42). Then, compounds
(42) were converted to the target triazole analogues (44an)using
CuI and freshly prepared azide derivative (43).
48
Obtained derivatives of acridone (44an) were tested in vitro
for inhibition of acetylcholinesterase (AChE) and butyr-
ylcholinesterase (BChE). The best ability to inhibit AChE was
Fig. 7 Structure of tacrine (27) and tacrine/acridine derivatives (28
30, 31ac).
44
Scheme 1 Synthesis of tacrine-carbazole hybrids (36ac).
48
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 1577615804 | 15779
Review RSC Advances
Open Access Article. Published on 09 March 2017. Downloaded on 8/26/2022 12:29:47 PM.
This article is licensed under a
Creative Commons Attribution 3.0 Unported Licence.
View Article Online

shown by compound (44g)(IC
50
¼ 7.31 mM), with a 4-substituted
chlorine on the pendant benzyl group.
48
In turn, derivatives (44e
and 44j) with strong electron-withdrawing nitro groups into the
pendant benzyl group showed decreased activity. Additionally,
the presence of groups in the order of OMe > Me $ Cl > Br
instead of hydrogen on the 2-substituted acridone moieties
provided an increase in inhibitory activity. Thus, the presence of
methoxy and chlorine groups contributes to good interactions
with the active sites of enzymes and plays an important role in
the inhibitory activity. Docking studies of compound (44g)
showed pp interactions between Phe330 and the 1,2,3-triazole
moiety and between Trp84 and the acridone moiety. Addition-
ally, derivative (44g) forms hydrogen bonds between the oxygen
of OMe and Ser122. Furthermore, a weak interaction between
chlorine and the backbone carbonyl group of amino acid is
benecial.
48
The Mohammadi-Khanaposhtani group also demonstrated
acridone-1,2,4-oxadiazole-1,2,3-triazole hybrids as inhibitors of
AChE and BChE.
50
In this research, a series of new acridone-
1,2,4-oxadiazole-1,2,3-triazoles (47ap) were obtained accord-
ing to the synthetic pathway given in Scheme 3. The target
compounds (47ap) were synthesized by the reaction of 10-
(prop-2-yn-1-yl)acridin-9-one derivatives (45) in the presence of
CuI and the freshly prepared azide derivative (46).
50
Among these compounds, (47ad, 47k and 47n) showed an
inhibitory eect against AChE with IC
50
values ranging between
11.55 and 77.79 mM. The most activity was shown by compound
(47b) containing an unsubstituted acridone ring and 4-
methoxyphenyl-1,2,4-oxadiazole moieties, while derivatives
(47cj, 47lm, and 47op) containing acridone moieties 2 or 4-
substituted by methoxy, chlorine or bromine groups demon-
strated no observable activity. Additionally, it may be that
a methoxy group into the pendant benzyl group imparted
a higher activity than chlorine, methyl, and bromine substitu-
ents. Docking studies showed that the orientation of analogue
(47b) in the active site of AChE was the same as donepezil.
Namely, compound (47b) forms pp interaction between the
acridone moiety and Phe331 and Trp84 in the catalytic anionic
site (CAS). Additionally, compound (47b) is proposed to interact
with the hydroxyl group of Ser200 in the catalytic triad site
through hydrogen bonds involving the carbonyl group of acri-
done. Further, the 1,2,4-oxadiazole moiety exhibited pp
interaction with a phenyl group of Tyr121 in the peripheral
anionic site (PAS).
50
Scheme 2 Synthesis of triazole derivatives of acridone (44an).
49
Scheme 3 Synthesis of acridone-1,2,4-oxadiazole-1,2,3-triazole derivatives (47ap).
50
15780 | RSC Adv.,2017,7, 1577615804 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review
Open Access Article. Published on 09 March 2017. Downloaded on 8/26/2022 12:29:47 PM.
This article is licensed under a
Creative Commons Attribution 3.0 Unported Licence.
View Article Online

Citations
More filters
Journal ArticleDOI
TL;DR: In this review, a detailed picture covering the important therapeutic aspects of the acridone nucleus and its functional analogues is discussed.
Abstract: 'Acridine' along with its functional analogue 'Acridone' is the most privileged pharmacophore in medicinal chemistry with diverse applications ranging from DNA intercalators, endonuclease mimics, ratiometric selective ion sensors, and P-glycoprotein inhibitors in countering the multi-drug resistance, enzyme inhibitors, and reversals of neurodegenerative disorders. Their interaction with DNA and ability of selectively identifying numerous biologically useful ions has cemented exploitability of the acridone nucleus in modern day therapeutics. Additionally, most derivatives and salts of acridine are planar, crystalline, and stable displaying a strong fluorescence which, when coupled with their marked bio selectivity and low cytotoxicity, enables the studying and monitoring of several biochemical, metabolic, and pharmacological processes. In this review, a detailed picture covering the important therapeutic aspects of the acridone nucleus and its functional analogues is discussed.

64 citations

Journal ArticleDOI
TL;DR: The weakly coordinating, ketone-directed, regioselective monoamidation of aromatic ketones, chalcone, carbazole, and benzophenones was achieved by employing high-valent cobalt and rhodium catalysis to access numerous biologically important molecular building blocks.
Abstract: The weakly coordinating, ketone-directed, regioselective monoamidation of aromatic ketones, chalcone, carbazole, and benzophenones was achieved by employing high-valent cobalt and rhodium catalysis to access numerous biologically important molecular building blocks. This amidation proceeded smoothly with a variety of ketones and several amidating partners. The application of the products in the synthesis of various heterocycles, including acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines, was also explored. The total synthesis of acridone-based alkaloids, namely, toddaliopsin A, toddaliopsin D, and arborinine, and the formal synthesis of acronycine and noracronycin were also accomplished by applying this method. A mechanistic study revealed this amidation reaction follows a base-assisted intermolecular electrophilic substitution pathway.

52 citations

Journal ArticleDOI
TL;DR: It is suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for cancer therapy and 11l represented a potential lead compound for development of antitumor agents.

43 citations

Journal ArticleDOI
TL;DR: Five design concepts are identified and explored and their application to half-sandwich organoruthenium anticancer compounds in which the bioactive ligand is coordinated to the Ru center through a bidentate chelating motif are explored.

31 citations

Journal ArticleDOI
TL;DR: In this paper, a dual-channel fluorescence chemosensor comprised of acridine-diphenylacetyl moieties (NDA) was used for detecting Sn4+ and Cr2O72- ions in water and biological medium.

30 citations

References
More filters
Journal ArticleDOI
TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.
Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

3,320 citations

Journal ArticleDOI
TL;DR: The biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases is discussed, and progress in the development of specific modulators of the relevant CA isoforms is highlighted, some of which are now being evaluated in clinical trials.
Abstract: Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.

2,649 citations

Journal ArticleDOI
19 Mar 2011
TL;DR: An overview of recent evidence regarding the epidemiology, pathogenesis, diagnosis, and treatment of Alzheimer's disease is provided, and potential ways to reduce the risk of developing the disease are discussed.
Abstract: An estimated 24 million people worldwide have dementia, the majority of whom are thought to have Alzheimer's disease. Thus, Alzheimer's disease represents a major public health concern and has been identified as a research priority. Although there are licensed treatments that can alleviate symptoms of Alzheimer's disease, there is a pressing need to improve our understanding of pathogenesis to enable development of disease-modifying treatments. Methods for improving diagnosis are also moving forward, but a better consensus is needed for development of a panel of biological and neuroimaging biomarkers that support clinical diagnosis. There is now strong evidence of potential risk and protective factors for Alzheimer's disease, dementia, and cognitive decline, but further work is needed to understand these better and to establish whether interventions can substantially lower these risks. In this Seminar, we provide an overview of recent evidence regarding the epidemiology, pathogenesis, diagnosis, and treatment of Alzheimer's disease, and discuss potential ways to reduce the risk of developing the disease.

1,703 citations

Journal ArticleDOI
TL;DR: Several important physiological and physio-pathological functions are played by CAs present in organisms all over the phylogenetic tree, related to respiration and transport of carbon dioxide to bicarbonate between metabolizing tissues and the lungs, pH and CO(2) homeostasis, electrolyte secretion in a variety of tissues/organs, biosynthetic reactions, such as the gluconeogenesis and ureagenesis among others.

498 citations

Journal ArticleDOI
TL;DR: Results provide proof of principle that small molecules can inhibit dimerization of HIF-1 and have potent inhibitory effects on tumor growth and vascularization.
Abstract: HIF-1 is a heterodimeric transcription factor that mediates adaptive responses to hypoxia and plays critical roles in cancer progression. Using a cell-based screening assay we have identified acriflavine as a drug that binds directly to HIF-1α and HIF-2α and inhibits HIF-1 dimerization and transcriptional activity. Pretreatment of mice bearing prostate cancer xenografts with acriflavine prevented tumor growth and treatment of mice bearing established tumors resulted in growth arrest. Acriflavine treatment inhibited intratumoral expression of angiogenic cytokines, mobilization of angiogenic cells into peripheral blood, and tumor vascularization. These results provide proof of principle that small molecules can inhibit dimerization of HIF-1 and have potent inhibitory effects on tumor growth and vascularization.

438 citations