Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5449_Библиотеки_им_академика_М_И_Перельмана
.pdf
Chapter 4
Metal complexes and their therapeutic applications
Drug development in recent years has advanced either through new discoveries at the
molecular level or through drug designing strategies using theoretical molecular model-
ing. Another approach is to deliver drugs using a chaperone that complexes with the
drug. This strategy improves both the pharmacokinetics and pharmacodynamics of po-
tent drugs. Thus, with a variety of potential ligands as well as diverse synthetic strate-
gies, metal complexes can be tailored to overcome a number of specific limitations of a
drug. The unique properties of metal complexes, such as environment-responsive li-
gand exchange, various photochemical and photophysical properties, and most impor-
tantly, their ability to interact with biomolecules, make metal complexes candidates for
selective drug delivery.
4.1 Mechanism of action of metal complexes
Chemotherapy is based on the objective of obtaining a selective effect between a nor-
mal host cell and the invading cell, whether bacterial, protozoa or even cancerous.
This selectivity can be achieved by differences in distribution, comparative biochem-
istry or cytology [1]. Further, the damage caused or induced on the attacked cell is
more dependent on the host cell’s defense mechanism. Mechanism-wise, DNA interac-
tion of metal complexes plays an important role in cellular replication as well as the
transmission of genetic information, and as such, the nucleic acids are primary tar-
gets for drug action. Thus, to understand the mechanism of action of a drug, be it
metal complexes, an understanding of action may be considered at this level. A sum-
mary of action of metal complexes as drugs can be outlined as follows:
Precurser molecules
DNA : DNA
DNA
RNA (Amino acid and protein synthesis)
Inhibition
b
y direct bonding
Inhibition
by indirect bonding
However, understandably, metal complexes act by both mechanisms. For direct ac-
tion, the binding of the drug molecule to the polymer is an essential requirement,
whereas for indirect action, the interference with small precursor molecules of the
nucleic acids or cellular biochemistry is a prerequisite. Even for cancer, it has long
https://doi.org/10.1515/9783111426136-004
https://t.me/med1917
been recognized that the reciprocity between anticancer drug molecules and potential
carcinogens as well as their role in DNA modification is unambiguous. Owing to this,
the importance of drug-DNA interaction is of utmost importance.
4.2 DNA binding with metal complexes: a brief account
The basic sites of binding of DNA and any drug, including metal complexes, are
shown in Fig. 4.1. The fundamental modes on the basis of many drugs, as an example,
are through any of the four modes:
1. Intercalation
2. Covalent and noncovalent bonding
3. Covalent and inner sphere biding
4. Strand breakage
4.2.1 Intercalation
The idea of intercalation was proposed by Lerman [2] to explain the binding of aro-
matic planar molecules, e.g., aminoacridines and phenanthridines. This type of interac-
tion involves the insertion of any planar molecule between two neighboring base pairs
of DNA held by van der Waals forces [3]. A concept is also proposed involving a weak
interaction of an electrostatic nature between the phosphate anions and charged
groups of molecules. Further, another nonclassical intercalation model is also proposed
[4], which involves the bending of the helix, whereas in the classical view of intercala-
tion, the helix is extended and locally unwound by the binding reaction fig 4.2.
Fig. 4.1: Modes of interaction of metal complexes with DNA.
52 Chapter 4 Metal complexes and their therapeutic applications
https://t.me/med1917
4.2.2 Outer sphere binding
In this kind of binding, the negatively charged backbone of the DNA helix interacts
with a variety of positively charged molecules in such a way that it involves either
Coulombic interactions or phosphat e-oxygen binding. This results in a reduction of
the overall charge, which subsequently affects stability or conformation. In the case
of a study of the effects of many divalent metal ions on the T
m
(transition melting
temperature) of DNA, the order of perturbation is Mg < Ni < Zn < Cd < Cu. Co(II) and
Ni(II) show an increase in T
m
, and Mn(II) and Zn(II) give a maximal T
m
. Conclusively,
it is amply clear that relative phosphate/base affinities vary among different metal
ions, causing a gradation of properties.
4.2.3 Inner sphere (covalent) binding
Many aqua metal ions bind covalently to the bases of DNA, e.g., mercury and silver. A
review of the literature reveals this [5–7]. In the case of Ag(I), the helix is stabilized
through metal cross-links, and this is inner-sphere covalent binding.
4.2.4 Strand breakage
The fourth kind of DNA binding interaction is through this type. This involves cova-
lent binding and cleavage of the helix backbone, which may be either single or dou-
ble-stranded. This may be induced by cleavage of the phosphate ester-sugar bond or a
C–C break in the sugar skeleton [8].
The role of DNA in drug action is envisaged as the transmission of genetic infor-
mation makes it a primary target; thus, this mechanism sheds light on the design of
more efficient drugs for the future.
Fig. 4.2: Schematic presentation of classical and nonclassical interaction models.
4.2 DNA binding with metal complexes: a brief account 53
https://t.me/med1917
4.3 Transition metal complexes of bioactive ligands: application
for drug delivery
Selective drug delivery platforms are interestingly exploited by transition metal com-
plexes as they have unique properties like envi ronmental-response ligand exchange
kinetics, diverse photochemical and photophysical characteristics, and most impor-
tantly, the ability to have specific interactions with biomolecules. This makes them
extremely suitable for drug delivery roles. On the other hand, enormous development
in drug development and designing at molecular levels for selective inhibition of a
single enzyme has further raised the challenge for the success or failure of any newly
proposed molecule. Out of thousands of molecules designed, only a limited number
meet success. The reasons include poor availability, low efficacy or even severe side
effects of these molecules during trials. Remedy by modification of synthesis is diffi-
cult and cumbersome. To overcome this, an interesting concept of “Chaperones” has
been introduced [9]. Chaperones encapsulate or even complex with the drug and de-
liver it to a specific site. This is thus a simple synthetic strategy that improves both
the pharmacokinetic and pharmacodynamic properties of a parent drug. Thus, metal
complexes with a very wide range of bioactive potential ligands offer versatile scaf-
folds that are easy to mold to overcome specific limitations of a broad spectrum of
drugs.
4.3.1 What are chaperones?
A class of distinct molecules facilitates the intracellular transport of metal ions to dif-
ferent metalloproteins, e.g., enzymes in cells, using specific protein-protein interac-
tions. This way, proteins ensure that the correct cofactor (metal ion) is acquired by its
corresponding metalloenzyme. The metallochaperones are essential to the proper
functioning of cells. Many biological processes, like respiration, photosynthesis and
neurotransmission, are examples of this kind.
4.3.2 What is the role of chaperones?
(a) Enhancement of bioavailability and improvement of drug solubility
It is observed that about 40% of drug candidates resulting from combinatorial
screening programs have poor aqueous solubility. Thus, coordination of a drug to
a metal complex, which has a positively charged center, greatly improves aqueous
solubility in a number of examples. Esomeprazole magnesium is one such exam-
ple,whereawater-solublebis(esomeprazole) magnesium complex is adminis-
tered [10].
54 Chapter 4 Metal complexes and their therapeutic applications
https://t.me/med1917
(b) Decreasing systematic toxicity
Controlled drug release is a real challenge, and transition metal complexes greatly
help in controlling this since the transition metal complexes have highly responsive
bonds with respect to their environment. As such, to facilitate this, prodrug com-
plexes are tailored in such a way that they are inert under normal physiological
conditions but become labile as soon as the environment, like pH, redox status or
even light application, changes. This deactivates the drug before its arrival at the
target, avoiding premature metabolism and leading to undesirable side effects.
(c) Strategy of multimodal action to increase potency
Metal complexes, apart from overcoming the above limitations of an organic mol-
ecule, are themselves bioactive. By this strategy, an active metal complex is pro-
duced from an active molecule of prodru gs and used to act upon a target in
multiple forms. Such dual-action drugs are sometimes more potent than the origi-
nal drug. This may also surpass the problem of drug resistance.
4.4 Classification of metal-based drugs
The field of application of metal complexes or metal-based drugs is undergoing a par-
adigm shift in recent years. Earlier, a drug was discovered and its mechanism of ac-
tion was investigated. Now, even theoretically and with computer-aided design, the
mechanism of action is understood a priori to the discovery process. This hypothesis
or approach of finding specific properties of metal complexes is used to optimize the
drug-likeness of the metal compound in question. A very brief summary is included
to highlight the classification of metal complexes applicable as drug candidates based
on their mechanism of action.
It is important to note that metal-based drugs and imaging agents have found a
prominent place in the treatment and medical diagnosis of diseases. Rational drug de-
sign, theoretical drug design, AI or computer-aided drug design are new frontiers of
drug design based on the mechanism of action. The possibility of developing a new
drug armed with an understanding of its toxicity, mechanism of action or even phar-
macokinetics and dynamics has opened up new challenges yet has extremely helped
in rational drug design. An excellent review [11] has highlighted the role of metals in
medicine. Base d on the mechanism, a brief summary of the classification of metal-
based drugs is given in the following paragraphs. The classification can be repre-
sented by the following graphical figure 4.3.
4.4 Classification of metal-based drugs 55
https://t.me/med1917
4.4.1 Covalent binding of metal-based drugs to biomolecules
Based on extensive ligand exchange chemistry of metal complexes, which is a charac-
teristic property, most of the approved drugs are anticancer Pt(II) complexes, viz., cis-
platin, oxaliplatin and carboplatin. Gold-based auranofin is another example of such
drugs used for its antiarthritic application. In these drugs, the metal ion and nonlabile
coligands bind through covalent binding with essential biomolecules such as DNA and
proteins and inhibit their function, leading to apoptosis and necrosis. Structures are
given in Fig. 4.4 for platinum complexes.
Fig. 4.3: Classification based on mechanism.
Pt
NH
2
Cl
NH
3
Cl
Cis platin
Pt
NH
3
NH
3
O
O
O
O
Carbplatin
Pt
NH
O
NH
O
O
O
Oxaliplatin
Fig. 4.4: Structure of Pt(II) complexes.
56 Chapter 4 Metal complexes and their therapeutic applications
https://t.me/med1917
Cisplatin, after administration as an intravenous injection, stays largely intact as chlo-
ride is in high concentration in the blood. As soon as it enters the cell, this complex
undergoes aquation, where one or two of the chloride ligands are exchanged by
water molecules since the chloride concentration in the cell is much lower compared
to blood. The newly formed Pt(II) species are now activated and subsequently bind to
nuclear DNA, preferably at the N7 position of guanine, resulting in intrastrand cross-
links. These cross-links finally block replication and cell division by interfering with
DNA processing [12, 13].
4.4.2 Inhibition of enzymes
There are certain metal-based drugs that inhibit enzymes by mimicking substrates
and metabolites, without forming any covalent bonds between the central metal and
enzyme; vanadium-oxo species are such examples. Oxovanadate (V) has long been
identified as a potent antidiabetic agent.
4.4.3 Redox-active drugs
The exchange kinetics of a ligand is strongly influenced by the oxidation state of any
metal ion [14]. This consequently gives the idea that in one oxidation state, the metal
will be less reactive, and in another, it will be more reactive, thus bioactive in differ-
ent oxidation states. This difference in activity in different oxidation states provides
an activation mechanism as redox change suitable for a biologically accessible range.
Thus, in practice, a less active, less toxic drug is administered to a patient, and when
activated (oxidation/reduction mechanism), the drug exerts its activity. This benefit is
attuned with metal complexes being used for cancer therapy [15, 16]. Activation by
reduction can be exemplified by Ru(III) and Pt(IV) complexes, which are reduced to
more cytotoxic Ru(II) and Pt(II) species in situ. Thus, by careful selection of both the
ligands as well as leaving groups of Ru(II) and Pt(IV) complexes, this potential of
redox couples Ru(III)/Ru(II) and Pt(IV)/Pt(II) is matched with the reducing environ-
ment mostly in the tumor environment.
Another type of redox activation of metal complexes relies on the excessive pres-
ence of reactive oxygen species (ROS), e.g., IO
2
,O
2
–
,HOorH
2
O
2
, present in tumors or
parasites. For example, it was evidenced that the activity of ferrocene-containing anti-
cancer and antimicrobial drug candidates is activated by ROS, as shown in Fig. 4.5.
4.4 Classification of metal-based drugs 57
https://t.me/med1917
4.4.4 Photodynamic and photoactivated chemotherapy
Diseases like fungal, microbial, cancer and different skin conditions are some of the dis-
eases treated through “Photodynamic therapy.” This therapy utilizes photosensitizers,
activated by light, to generate ROS and/or radicals. The oxidative stress thus ensued re-
sults in cell death. It is advantageous that it has low systemic toxicity and is activated
only when light is irradiated. Metal complexes have favorable physicochemical proper-
ties [17], making them useful candidates for DDT and PSS since metal-based PSS absorb
light efficiently in the visible region. An example of this category is the palladium-based
B
OO
O
O
N
H
Fe
O
O
N
H
Fe
OH
-H
+
+H
+
O
O
N
H
Fe
OO
Reaction with nuclotide
Fig. 4.5: Mechanism of prodrug activation by ROS.
58 Chapter 4 Metal complexes and their therapeutic applications
https://t.me/med1917
complex Tookad Soluble (Fig. 4.6) which has been recently approved in Mexico for the
treatment of prostate cancer and is in phase II and III clinical trials in 45 countries [18].
4.4.5 Metal complexes for delivery and release of pharmacologically active ligands
In certain generally accepted metal-based drugs, the metal ion is supposed to be a carrier
that delivers and finally releases a biologically active ligand. Simple examples of this type
are cyanide and carbon monoxide in low doses, where their role may not be the same as
seen at high levels. Further, the metal ions used for delivery purposes may themselves be
bioactive molecules. This is common when nonessential metal ions are used to release
NO
–
and CN
–
from a molecule. NO has a critical role as a vasorelaxant and inhibitor of
platelet aggregation. They also have roles in applications such as cardiovascular indica-
tions and sexual dysfunction [19]. Since NO plays a versatile role as a ligand, a number of
metal-NO complexes have been used for their therapeutic effect. For example, sodium
nitroprusside (Fig. 4.7) is used to rapidly lower blood pressure in hypertensive crises. CO
is another example, which is a key signaling molecule at low concentrations. CO can pro-
vide protection during ischemia-reperfusion/inflammation-inducedinjury[20].Optimiz-
ing the dose of CO gas is challenging although carboxyhemoglobin has been evaluated in
Fig. 4.6: Structure of Tookad soluble.
Fe
C
CC
C
C
N
O
N
N
N
N
N
2Na
+
2-
Fig. 4.7: Structure of sodium nitroprusside.
4.4 Classification of metal-based drugs 59
https://t.me/med1917
clinical trials [21]. Additionally, metal complexes have been used to sensitize certain bio-
active molecules for pharmacological applications, facilitating their delivery to diseased
tissue [22]. Examples include curcumin-based compounds. Since curcumin has anti-
inflammatory, antioxidant, antitumor and antihistaminic properties, its clinical applica-
tion is limited owing to its high metabolism rate, sensitivity to light and bioavailability.
These issues are overcome by coordinating curcumin to biologically essential metal ions
as well as nonessential metal ions [25]. This facilitates the controlled release of the bioac-
tive compound when and where it is needed.
4.4.6 Catalytic drugs
Catalytic potential of metals is well established, and in certain metal complexes, it has
been fruitfully exploited in medicines. Instead of undergoing a reaction with a biomo-
lecular target, in some cases, catalysis via metal potentially transforms a large molec-
ular excess of a biomolecular substrate. When the turnover number of any catalyst is
high, even a minute quantity of such a catalytic drug has a substantial impact. This
means a very low dose of the drug can give the desired therapeutic effect.
Metal-based catalytic drugs are of two major types:
(1) Those mimicking the catalytic processes.
(2) Those containing nonessential metals and/or those that catalyze abiotic processes
have no enzymatic counterparts.
In cancer combination therapies, oxidative damage is a frequently observed side ef-
fect. An antioxidant, SOD mimetic, has been successful with this treatment. In oropha-
ryngeal cancer treatment, a combination of radiation and cisplatin is administered.
This treatment has a serious side effect of severe oral mucositis. To address this, SOD
mimetic GC 4419 (Fig. 4.8) has been evaluated in a phase I clinical trial and has shown
an acceptable safety profile if administered daily over 7 weeks.
NH
N
NH
N
Mn
Cl
N
Cl
Fig. 4.8: Structure of GC 4419.
60 Chapter 4 Metal complexes and their therapeutic applications
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана