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_5691_Библиотеки_им_академика_М_И_Перельмана
.pdf
Ryori-Noyori, for asymmetric synthesis using chiral catalysts for single enantiomeric
drugs or chemicals [4, 5].
1.12 Medicinal inorganic chemistry and transition metal
complexes
Application of inorganic chemistry to medicine is one of the most rapidly developing
fields. This is evident by novel therapeutic and diagnostic metal complexes being used
in medicine and allied branches. There has been vast development in the field of bio-
coordination chemistry, and full-length reviews and books have appeared in the last
few years [6–8].
Although metals have played a very important role in medicine for years, metal
complexes have entered into the fray recently. Unique properties of metal complexes
offer advantages over metals as they are easy to use in combinatorial synthetic meth-
ods owing to their immense diversity. Thus, understanding their action and biological
functions can develop an entirely new area of metallopharmac euticals. A very brief
description of the significan ce and importance of metal-based drugs is given in the
following paragraphs to draw a sketch of how important these are. The summary
here is presented based on their application.
1.12.1 Anticancer drugs
Most common and widely used drugs in chemotherapy are Pt-based drugs. However,
there are drugs based on other metals also showing anticancer effects. Titanocene di-
chloride is one such compound that is active against breast cancer as well as gastrointes-
tinal tumors. Gallium salts too have been shown to exhibit anticancer activity. It is noted
that gallium shows a synergistic effect with cis-platin for the treatment of lung cancer.
Furthermore ruthenium (III) also plays a role in transferrin delivery to tumor cells. Gold
(I) complexes use a different route than cis-platin and are useful in anticancer treatment.
Cobalt complexes, on the other hand, are pH-dependent cell-selective antitumor agents.
Conclusively, many metal complexes are finding anticancer applications.
1.12.2 Anti-inflammatory drugs
Attempts are being made to develop Cu and Zn anti-inflammatory drugs with fewer
side effects and better efficacy than the parent organic drugs currently in use. It is
known that anti-inflammatory drugs may have serious side effects and cause many
deaths worldwide.
1.12 Medicinal inorganic chemistry and transition metal complexes 11
https://t.me/med1917
1.12.3 Antidiabetic drugs
Cr and V antidiabetic drugs are under investigation for their safety, efficacy as well as
mechanism of action. There is active research input for finding safer V-antidiabetic
drugs by understanding their mode of action. Cu metabolism and its effect on insulin
is one area under screening to contain the degenerative side effects of insulin.
1.12.4 Antimicrobials
A number of metal complexes have been finding application as powerful antimicro-
bial drugs. Silver bandages, zinc antiseptic creams, bismuth drugs and metal clusters
are some examples of such compounds.
1.12.5 Metal deficiency diseases
It is well established that diets deficient in metals like Zn, Fe, Cu, and Ca are the cause
of many diseases. Selenium and even other metals create situations that need treat-
ment. A number of studies are underway to effectively find the cause, mechanism
and determinants of drugs to treat such diseases.
1.12.6 Biomineralization
The processes that are essential in the development or formation of bones and teeth
are biomineralization processes. Even the storage of iron in ferritin is one such pro-
cess. These processes have a quite significant role in the lifecycles of diseases like ma-
laria since the parasite causes biomineralization of the heme group, which is toxic to
the invading parasite. A better knowledge of these processes and their genetic control
has opened up a new area for drug development using metals.
1.12.7 Degenerative diseases per se metals
The metals are essential for human health, yet they are involved in many degenera-
tive diseases such as heart diseases and strokes, brain disorders, arthritis or even can-
cer. Although human metabolism effectively controls the distribution, concentration
and metabolism of metals, their role in degenerative diseases is still in its infancy.
Conclusively, metallopharmaceuticals and metal complexes are on the serious agenda
of drug development and design. Exhaustive work is ongoing, and efficient drugs
based on metals are emerging. The unique properties of transition metal complexes,
12 Chapter 1 Introductory concepts: fundamentals of metal complexes – an overview
https://t.me/med1917
their kinetics and their physicochemical properties make them an interesting area of
the drug discovery process and could evolve into a new area of medicinal inorganic
chemistry.
1.13 Metals and related compounds in alternative systems
of medicine
Alternative systems of medicine include major systems that are currently established:
Ayurveda, the traditional Chinese system and Tibetan Zuotai. This section introduces
the concepts underlying these three systems, in particular with the context of metal-
related medicines. Giving details of these systems would neither be desirable nor is it
within the scope of the book. In recent years, a number of books and reviews have
appeared regarding not only the application and medicinal use of metal-related or
metal-based components in these systems but also their therapeutic potential [9, 10].
In view of this, a preliminary description is being included.
1.13.1 Ayurveda
This system of medicine has sustained four to five millennia and is time-tested on the
basis of preparation, application as well as activity through research. The system uses
drugsofdifferentoriginssuchasherbs,metalsoranimals.Theuseofmetallicprepara-
tion in medicines is a unique concept of this system. It has been practiced using metals
like mercury, silver, gold, copper and iron. The standard text of this system is Charak
Samhita, which is one of the scheduled books of the Ayurvedic system. The use of metal-
lic medicine came into practice with the advent of Rasashastra, which is an integral part
of Ayurveda dealing with drugs of mineral origin. It describes techniques of preparation,
therapeutic application, as well as toxic effects, if any, and their management. The devel-
opment of this branch is recorded around the eighth century AD since Charak Samhita
and Sushruta Samhita mention the description of metallic components and their thera-
peutic application. Although the discussion is just introductory to apprise readers of the
terminology of this system, a fundamental understanding of this system is desirable to
screen the very application and therapeutic aspects of the system. In view of this, a basic
outline and conceptual discussion of the Ayurvedic system is being given.
To date, Ayurveda is one of the most renowned systems of medicine, having sur-
vived for millennia. It was historically founded by the Hindu philosophical school,
Vaisheshika and the school of logic named Nyaya. It is mentioned that the Vaisheshika
school taught about inferences that should be obtained regarding the pathological
conditions of a patient for treatment. On the other hand, the Nyaya school believed
that one should have extensive knowledge of the patient’s conditions. This means that
treatment should be done by first thoroughly diagnosing the symptoms. In the years
1.13 Metals and related compounds in alternative systems of medicine 13
https://t.me/med1917
to come, the Nyaya and Vaisheshika schools merged to propagate knowledge about
Ayurveda [11, 12]. The recorded history establishes Charak Samhita as the most re-
spected of all records [13, 14].
As per Ayurveda, the entire universe is composed of five elements: Air (Vayu),
Water (Jala), Space (Akash), Earth (Prithvi) and Fire (Teja). These five elements are
called Panch Mahabhoota in Ayurveda. The three basic humors of the human body
have varying combinations of these five Panch Mahabhoota. They form the three basic
humors of the human body, which are Vata dosha, Pitta dosha and Kapha dosha. They
are called Tridosh as (three humors). These Tridoshas control the fundamental physio-
logical functions of the body. Apart from these three, there are subcategories for each
of these three main doshas. A chart along with control is given in Fig. 1.13.
To conclude, there has to be a balance between the three doshas and a slight imbal-
ance between these causes disease. Thus, for a healthy living, this balance should be
maintained [15, 16].
Ayurveda explains the superiority of mineral drugs compared to treatments
based on vegetable drugs or even surgical procedures. These therapies or medicines
are more effective even in small doses compared to vegetable-based products since
mineral products are effective instantaneously and do not have to pass through diges-
tive or metabolic pathways before they are active.
1.14 Quantum logic in Ayurveda
Quantum physics and the Vedic hypothesis of interrelatedness provide a practical un-
derstanding in Ayurveda for integrating its theory and practice. An entire chapter on
quantum logic has been included in the book for an integrated view of health and well-
Fig. 1.13: Chart of functions and control.
14 Chapter 1 Introductory concepts: fundamentals of metal complexes – an overview
https://t.me/med1917
being [17]. Interestingly, in brief, the concept states that everything in the universe is
integrated and interrelated so any change in one part of a system will be reflected in
the other part as well. Ayurveda, having its roots in the Vedas, has integrated this con-
cept of interconnection for understanding the two states of health and disease. Consid-
ering the human body as an indivisible whole with a network of functions that ar e
related to each other, mind and consciousness, as a whole, are interrelated. Disturbance
in either part will have an impact on the other part. Thus, disease is a perturbation in
this network. As mentioned earlier, there has to be a balance between the two to main-
tain this network. Ayurveda is based on this concept. There has to be an approach that
studies the fundamental and applied aspects of Ayurveda or Ayurvedic biology in
depth, with an interface of Ayurveda with modern science today [18]. A complete chap-
ter is dedicated to alternative systems of medicine in this book.
1.15 Chinese alternative system of medicine or traditional
Chinese medicinal methods (TCMM)
Chen et al. [19] have published a comprehensive consolidated review on metals in tra-
ditional Chinese medicinal materials (TCMM). TCM, or the traditional Chinese medi-
cine system, is a complete natural medicinal system that has originated and been
practiced for thousands of years. It is a system maintaining the health of Chinese peo-
ple and is a vehicle of traditional knowledge [20, 21]. Since the system uses herbal
medicines as alternative medication, it has been accepted worldwide in recent years
[22]. On account of this, China has signedTCMcooperationagreements with more
than 40 countries, regions and organizations and has built a TCM group of centers
using the Belt and Road initiative, opening hundreds of TCM institutes in many coun-
tries, including this great network initiative for TCM [23, 24]. Since Chinese medicines
include a wide variety of herbs and botanical materials, they are susceptible to metal
content and pollution. This warrants a logical understanding of the distribution and
differentiating rules of TCMM to interpret rises in residual metals. TCM centers on
health maintenance and the treatment of diseases. It emphasizes on improving the
body’s resistance to disease. To improve health, TCM uses many natural therapeutic
methods. The mechanism of therapy inTCMworksonenhancingthebody’sresis-
tance to disease, which is improved by the interconnection among self-controlled sys-
tems. It uses different therapeutic methods like mind-spiritual methods, e.g., Qigong,
Taiji-boxing and natural methods, e.g., acupuncture, moxibustion and herbal medi-
cines. These methods, being natural, are claimed to be safer with fewer side effects. It
further compares results by comparing symptoms pre- and post-treatment. It differs
from the mechanism of modern medicine that seeks from molecular and cellular lev-
els. However, the mechanism in TCM works on activating the system, improving sys-
tem connection and enhancing human resistance. TCM is based on a basic concept of
Zheng (syndrome), which is the outcome of the analysis of all symptoms like pulse
1.15 Chinese alternative system of medicine or traditional Chinese medicinal methods 15
https://t.me/med1917
and tongue appearance. Further , there are many Zhengs such as simple and com-
bined ones. So, to some extent, diagnosis is based on Zheng. As per the Zheng, the
treatment is decided. A detailed descriptionisnotpossiblehere,sointhechapter
dealing with the system, further discussion would be ascribed.
1.16 Zuotai: Tibetan medicine
Commonly, minerals and metallic preparations are used in both Ayurveda and Tibetan
medicine. The underlying principles of Tibetan medicine somehow relate to Ayurvedic
basics. Tibetan medicine was historically founded by doctors from India, China, Persia
and Roman areas of Central Asia. Buddha’s teachings on medicine went from India to
Tibet. Thus, the Tibetan medicinal system is a combination of native Tibetan medicine
and Buddhist teachings on medicine. Since this book is focused on metallic preparations
or Zuotai, only a brief description of the principles of the system is included here, and
details will be described in the chapter dedicated to alternative systems.
The chief characteristic of Tibetan medicine is that it is fundamentally a Buddhist
system of medicine. It is more or less deeply related to the Indian Ayurvedic system
and has three humors: bile, phlegm and wind (Pitta, Kapha and Vata as in Ayurveda).
In this system, every disease is related to these three principles. In the Buddhist sys-
tem, people who are characterized by the bile element have a lot of negative emo-
tions. People whose bodies have a lot of phlegm or mucus are having delusions about
their existence and role. Thus, as per this system, diseases are divided according to
humors. In sum, we can briefly classify them in Fig. 1.14.
1.16.1 Treatment
The greatest number of treatments is based on her bal medicine in this system. This
system uses a mixture of many plant ingredients and thus is called polypharmacy.
Zuotai, or mineral-based medicine, is also part of this system. However, the details of
the system using Zuotai will be included in a subsequent chapter.
Fig. 1.14: Humors.
16 Chapter 1 Introductory concepts: fundamentals of metal complexes – an overview
https://t.me/med1917
1.17 Metal chelates in biological systems
Metal ion toxicity is the first and foremost challenge for people involved in any de-
signing or biological application in general. All metal ions that have gained access to
the circulation in reasonable quantities and are not rapidly excreted are considered
to be toxic. The metal individually deranges electrolytic balance, causes irritation to
individual organs, affects the CNS or can even interfere in enzymatic processes. There
can be a variation in the level of toxicity depending on the concentration levels. How-
ever, it is amply evident that no organism is tolerant to high concentrations of metal
ions, which serve any useful purpose.
The relationship between toxic action and metal coordination was proposed by
Voegtlin et al. [25]. It is explained that specific interactions are related to the magni-
tude of ionic changes and the hydrated ion sizes. Further, it is implied that most metal
ions can form complexes with many of the available donor atoms of proteins. How-
ever, strongly complexing ions may even displace the weaker ones from their com-
plexing sites. To summarize, metal ion toxicity is related to the chelation mechanism;
there should be an obvious correlation between the stability of the metal chelate and
its toxic potency. An order has been proposed [26] between the stability of transition
metal complexes and the cation toxicity, which is Mn < Fe (II) < Co (II) < NI (II) < Cu (II)
> Zn, which also applies to groups of enzymes like urease and diastase.
1.18 Quantitative structure-activity relationship (QSAR)
An approach designed to find the relationship between chemical structure (or struc-
ture-related properties) and the biological activity of the studied compound is termed
a structure-activity relationship (SAR). There are two types: qualitative and quantita-
tive relationships. Qualitative relationships are derived from noncontinuous data,
such as yes or no data, whereas quantitative relationships are derived from continu-
ous data, such as toxic potential. The concept follows that the activity of a molecule is
governed by its properties. It ascribes to the fact that molecules can be represente d
by one or more descriptors, one being the 2D structure. The biological activity of any
substance is controlled by its structure. Thus, the objective of SAR is the first to know
the limits of variation in the structure of a chemical consistent with the production of
a specified effect. Secondly, it aims to define how alterations in structure influence
the overall properties of a compound and its endpoint potency.
1.19 Sustainable medicine
Sustainable medicine is an important matter in the present scenario of challenges in
the healthcare system. With deteriorating environmental factors, people’s health is
1.19 Sustainable medicine 17
https://t.me/med1917
going to be negatively affected. Thus, sustainable medicine is an emerging field
which, in one fold, attempts to address healthcare’s socioenvironmental and eco-
nomic impacts. We are to create an environmentally equitable and affordable health-
care system including medicines. Drug discovery also has to be sustainable since the
expanding population and aging have enhanced the importance of medicine and its
use; this would create a serious impac t on our health and ecosystem. Although the
concept of sustainability is growing slowly and just being felt in the pharmaceutical
industry, a consolidated approach has to be strategized to make it more important.
1.20 AI in drug discovery and development
Artificial intelligence has recently started gaining much attention in all aspects of life,
and the pharmaceutical industry is no exception. Although it has started emerging
and gaining importance as well as impacting areas of all pha rmaceutical industries,
drug discovery will certainly be a big beneficiary. AI would work functionally in the
discovery and development of drugs, its growth and sustainability and would be an
important tool in this sector. It will help in the designing of applicable molecules and
greener routes to improve the overall life cycle of the p roduct. This means that AI
would play an important role starting from drug discovery to product manageme nt
and challenges. It can also play a major role in the incorporation of the developed
drugs in the correct dosage, optimization, faster manufacturing, and quality assur-
ance to ensure batch-to-batch consistency. Thus, it would become an important tool in
the pharma sector and drug designing.
There has been a drastic increase in digitalization and data in the pharmaceutical
industry. When it comes to using this data, it becomes a complex problem in terms of
scrutinizing and applying it to solve difficult clinical problems. Here, AI is an extremely
helpful tool. This is a technology-based system using different tools and networks that
mimic human intelligence without threatening human presence [27, 28]. It uses soft-
ware for interpretation and learns from input data to make decisions regarding specific
tasks. It has thus accelerated the growth of the pharmaceutical sector and is becoming
an inevitable part of drug designing, manufacturing and clinical application.
1.21 Computer-aided drug designing (CADD)
In recent years, computer-aided drug designing (CADD) has become an important tool
that assists at various stages of drug development. It not only reduces the cost of drug
research but also saves ample time compared to the old synthesize-screen-valida te
strategy. A priori, a synthetic chemist can develop and screen theoretical molecules
with information such as probable activities they will have, their mechanisms of ac-
tion and even ADMET (absorption, distribution, metabolism, excretion and toxicity)
18 Chapter 1 Introductory concepts: fundamentals of metal complexes – an overview
https://t.me/med1917
for the newly proposed drug molecules. Thus, CADD has expedited the process of
drug discovery.
1.22 Prediction of activity spectra of substance (PASS)
Prediction of activity spectra for substances (PASS) predicts, on the basis of the struc-
ture of any compound, over 4,000 types of biological activities such as pharmacologi-
cal effects, transportation, action of the molecule (drug), its toxic or adverse effects,
and even influence on gene expression. The PASS online software makes these predic-
tions available based on the structural formula of any molecule. The prediction of
spectra reflects the results of the interaction of the chemical compound with different
biological entities. It is expressed in yes/no as a form of qualitative expression. This
may be a gross generalization, yet it provides the possibility of combining information
from many sources in a common training set. A very brief introduction to this tool
and the terms used is given here just to appraise the reader before the actual data for
examples using this tool is provided in a subsequent chapter.
PASS is a software designed as a tool for evaluating the general biological poten-
tial of an organic drug-like molecule (no prediction is possible for metal complexes). It
is used to estimate the biological activity profile of a virtual molecule before chemical
synthesis and biological testing.
Pa (probability to be active) estimates the probability or chance that the studied
compound belongs to the subclass of active compounds (similar to the structures of mol-
ecules, which are most typical in a subset of active compounds in the PASS training set).
Pi (probability of being inactive) estimates the chance that the studied compound
belongs to the subclass of inactive compounds.
IEP (invariant error of prediction) is the average error of predicted results. It fol-
lows a leave-one-out cross-validation process.
Leave-one-out cross-validation procedure is performed using the whole PASS
training set for validation of prediction quality or results.
MOL file: It is the file format created by MDL (Accelrys) for holding information
about atoms, bond connectivity and coordinates of a molecule.
SD file is a group of chemical data file formats developed by MDL for structural
information. SDF stands for structural data file wrapping the MOL file format.
1.23 Absorption, distributions, metabolism, excretion (ADME)
and toxicity profiling
An important part of the assessment of the pharmacological properties of small mole-
cules is significant to the initial selection of a chemical lead. This helps in identification
and lead optimization in order to elucidate SAR. This is done to select investigational
1.23 Absorption, distributions, metabolism, excretion (ADME) and toxicity profiling 19
https://t.me/med1917
New Drug-enabling studies. ADME (absorption, distribution, metabolism and excretion),
in fact, helps in understanding the PK of any identical molecule. An excellent review
[29] addresses ADME and in silico modeling of molecules. After 1990, poor PK and toxic-
ity were the main reasons for failure in drug development. This led to the conclusion
that these two areas were of prime consideration in the early stages of drug develop-
ment studies. Combinatorial chemistry with high-throughput screens helped in develop-
ing a large number of compounds for which data were needed a priori. This increased
the importance of ADMET in the strategy of drug design. A very precise strategy is now
developed. The testing of any drug before evaluation at the clinical stage is performed
well in advance. Drug metabolism, as well as PK and toxicity, are tested in advance too.
It facilitates synthesizing a large number of closely related libraries of chemicals. These
libraries are run through high-throughput screenings to find new hits. Thus, more fo-
cused and meaningful series are then designed and synthesized. This strategy has called
for an increased demand for ADMET data.
1.24 Molecular docking
In the area of computer-aided drug design, molecular modeling docking has become
an important tool. This is a method that can predict the preferred orientations of one
molecule to a second one when we want to know which ligand is going to bind with a
target to form a stable complex [30–32]. It helps in determining the preferred docking
assessment (DA). A docking protocol is quantified in terms of predictive capability,
and it is called DA.
1.25 Nanomedicine and metal-based nanomedicines
Application of nanotechnology has emerged as a new area in every field of life. Nano-
technology in medicinal applications is no exception, particularly in cancer diagnosis
and treatment. Since nanotechnology has the ability to detect a wide range of molecu-
lar signals and biomarkers in real time, it has opened new vistas in early detection,
diagnosis, prognostics, as well as therapeutic planning. Conventional cancer therapeu-
tics have several disadvantages that can be overcome by using nanotherapeutics.
Metal nanoparticles (NPs) are gaining specific attention since they have great poten-
tial to work as multipurpose agents. To mention some, gold, iron/iron oxide, zinc, tita-
nium,ceriumoxide,silver,nickelandcopper N Ps have been found useful for the
treatment of cancer. Among all, gold NPs are the most useful nanomaterial for cancer
treatment. Alternative systems of medicine, particularly Ayurveda, have been using
this concept for centuries [33]. The application of nanoparticles, particularly in the
form of Bhasma, is an accurate application showing safer usage of metal NPs [34–35].
The application of metal nanoparticles has been a common concept in organometallic
20 Chapter 1 Introductory concepts: fundamentals of metal complexes – an overview
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана