Sources of leads and drugs

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Originally drugs and leads were derived from natural sources. These natural sources are still important sources of lead compounds and new drugs, however the majority of lead compounds are now discovered in the laboratory using a variety of sources, such as local folk remedies (ethnopharmacology), investigations into the biochemistry of the pathology of disease states and high-throughput screening of compound collections (see Chapter 5), databases and other literature sources of organic compounds.

1.5.1 Ethnopharmaceutical sources

The screening of local folk remedies (ethnopharmacology) has been a fruitful source of lead compounds and many important therapeutic agents. For example, the antimalarial quinine from cinchona bark, the cardiac stimulants from foxgloves (Fig. 1.5) and the antidepressant reserpine isolated from Rauwolfia serpentina.

Chemical Constituent Foxgloves Leaf

Figure 1.5 Digitalis purpurea, the common foxglove. The leaves contain about 30 different cardioactive compounds. The major components of this mixture are glycosides, with aglycones of digitoxigenin, gitox-igenin and gitaloxigenin. Two series of compounds are known, those where R, the carbohydrate residue (glycone) of the glycoside, is either a tetrasaccharide or a trisaccharide chain. Many of the compounds isolated were formed by drying of the leaves prior to extraction. Digitoxin, a trisaccharide derivative of digitoxigenin, is the only compound to be used clinically to treat congestive heart failure and cardiac arrhythmias

Figure 1.5 Digitalis purpurea, the common foxglove. The leaves contain about 30 different cardioactive compounds. The major components of this mixture are glycosides, with aglycones of digitoxigenin, gitox-igenin and gitaloxigenin. Two series of compounds are known, those where R, the carbohydrate residue (glycone) of the glycoside, is either a tetrasaccharide or a trisaccharide chain. Many of the compounds isolated were formed by drying of the leaves prior to extraction. Digitoxin, a trisaccharide derivative of digitoxigenin, is the only compound to be used clinically to treat congestive heart failure and cardiac arrhythmias

1.5.2 Plant sources

In medicinal chemistry, 'plant' includes trees, bushes, grasses, etc., as well as what one normally associates with the term plant. All parts of a plant, from roots to seed heads and flowers, can act as the source of a lead. However, the collecting of plant samples must be carried out with due consideration of its environmental impact. In order to be able to repeat the results of a collection and if necessary cultivate the plant to ensure supplies of the compounds produced by the plant, it is essential that a full botanical record of the plant is made if it does not already exist. This record should contain a description and pictures of the plant and any related species, where it was found (GPS coordinates) and its growing conditions. A detailed record of the collection of the samples taken must also be kept since the chemical constitution of a plant can vary with the seasons, the method used for its collection, its harvest site storage and method of preparation for onward transportation to the investigating laboratory. If the plant material is to be shipped to a distant destination it must be protected from decomposition by exposure to inappropriate environmental conditions, such as a damp atmosphere or contamination by insects, fungi and microorganisms.. The drying of so-called green samples for storage and shipment can give rise to chemical constituent changes because of enzyme action occurring during the drying process. Consequently, extraction of the undried green sample is often preferred, especially as chemical changes due to enzyme action is minimised when the green sample is extracted with aqueous ethanol.

Plant samples are normally extracted and put through screening programmes (see Chapter 6). Once screening shows that a material contains an active compound the problem becomes one of extraction, purification and assessment of the pharmacological activity. However, the isolation of a pure compound of therapeutic value can cause ecological problems. The anticancer agent Taxol (Fig. 1.6), for example, was isolated from the bark of ch, coo.

c6h5conh

C6H5

NCH,

Pilocarpine

Vincristine

Figure 1.6 Examples of some of the drugs in clinical use obtained from plants. Taxol and vincristine are anticancer agents isolated from Taxus breifolia and Vinca rosea Linn, respectively. Pilocarpine is used to treat glaucoma and is obtained from Pilocarpus jaborandi Holmes Rutaceae. Morphine, which is used as an analgesic, is isolated from the opium poppy

Pilocarpine

Vincristine

Figure 1.6 Examples of some of the drugs in clinical use obtained from plants. Taxol and vincristine are anticancer agents isolated from Taxus breifolia and Vinca rosea Linn, respectively. Pilocarpine is used to treat glaucoma and is obtained from Pilocarpus jaborandi Holmes Rutaceae. Morphine, which is used as an analgesic, is isolated from the opium poppy the Pacific Yew tree (see section 6.8). Its isolation from this source requires the destruction of this slow-growing tree. Consequently, the production of large quantities of Taxol from the Pacific Yew could result in the wholesale destruction of the tree, a state of affairs that is ecologically unacceptable.

A different approach to identifying useful sources is that used by Hostettmann and Marston, who deduced that owing to the climate African plants must be resistant to constant fungal attack because they contain biologically active constituents. This line of reasoning led them to discover a variety of active compounds (Fig. 1.7).

Figure 1.7 Examples of the antifungal compounds discovered by Hostettmann and Marston

A number of the drugs in clinical use today have been obtained from plant extracts (see Fig. 1.6). Consequently, it is vitally important that plant, shrub and tree sources of the world are protected from further erosion as there is no doubt that they will yield further useful therapeutic agents in the future.

1.5.3 Marine sources

Prior to the mid-twentieth century little use was made of marine products in either folk or ordinary medicine. In the last 40 years these sources have yielded a multitude of active compounds and drugs (Fig. 1.8) with potential medical use. These compounds exhibit a range of biological activities and are an important source of new lead compounds and drugs. However, care must be taken so that exploitation of a drug does not endanger its marine sources, such as marine microorganisms, fungi, shellfish, sponges, plants and sea snakes. Marine microorganisms and fungi may be grown in fermentation tanks on a commercial scale. Microbial fermentation is a batch process, the required compound being extracted from the mature organisms by methods based on those outlined in Chapter 6. As well as drugs, microbial fermentation is also used to produce a wide range of chemicals for use in industry.

Marine sources also yield the most toxic compounds known to man. Some of these toxins, such as tetrodotoxin and saxitoxin (Fig. 1.8), are used as tools in neurochemical research work, investigating the molecular nature of action potentials and Na+ channels

Figure 1.7 Examples of the antifungal compounds discovered by Hostettmann and Marston

A naphthoxirene derivative

Key: R = P-D-glucopyaranosyl Uncinatone

A chromene

A naphthoxirene derivative

Key: R = P-D-glucopyaranosyl Uncinatone

A chromene

COOH

COOH

CH2OCOMe nh2

CH2OCOMe

HOOCCH(CH2)3CONH s

Cephalosporin C

Me Avarol

Me Avarol hoch2 o nh2

hoch2 o nn ho nn ho

Ara-A

H OH

Tetrodotoxin

Saxitoxin o hn^nVNH2

Saxitoxin

COOH Me

Domoic acid r

Cys-Lys-Gly-Lys-Gly-AIa-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-CysArg-Ser-Gly-Lys-Cys-amide

Ziconotide

Figure 1.8 Examples of active compounds isolated from marine sources (Me represents a methyl group). Avarol is reported to be an immunodeficiency virus inhibitor. It is extracted from the sponge Disidea avara. The antibiotic cephalosporin C was isolated from the fungus Acremonium chrysogenium (Cephalosporin acremonium). It was the lead for a wide range of active compounds, a number of which are used as drugs (see section 7.5.2). Domoic acid, which has anthelmintic properties, is obtained from Chondria armata. Tetrodotoxin and saxitoxin exhibit local anaesthetic activity but are highly toxic to humans. Tetrodotoxin is found in fish of the order Tetraodontiformis and saxitoxin is isolated from some marine dinoflagellates. Ara-A is an FDA - approved antiviral isolated from the sponge Tethya crypta. Ziconotide is the active ingredient of Prialt, which is used to treat chronic pain. It is an analogue of the m-conopeptide MVIIA, which occurs in the marine snail Conus magnus.

(see sections 7.2.2 and 7.4.3). Although tetrodotoxin and saxitoxin are structurally different they are both believed to block the external opening of these channels.

1.5.4 Microorganisms

The inhibitory effect of microorganisms was observed as long ago as 1877 by Louis Pasteur, who showed that microbes could inhibit the growth of anthrax bacilli in urine. Later in 1920 Fleming demonstrated that Penicillin notatum inhibited staphylococcus

C—Yal-Gly-Ala-Leu-Ala-Val-Val-Val-Trp-Leu-Trp-Leu-Trp-Leu-Trp —NHCH 2 CH 2 OH

Gramicidin A

Benzylpenicillin

COOH

L-Thr L-Thr

Dactinomycin

Dactinomycin h2n.

NH NH

NHCH3

Streptomycin

NHCH3

Streptomycin

HOCH.

H aoh

HH HH OH H

Pentostatin

Figure 1.9 Examples of drugs produced by microbial fermentation. Gramicidin A, benzylpenicillin (penicillin G) and streptomycin are antibiotics isolated from Bacillus brevis, Penicillin notatum and Streptomyces griseus, respectively. The anticancer agents dactinomycin and pentostatin are obtained from Streptomyces parvulus and Streptomyces antibioticus, respectively

CH2CONH

cultures, which resulted in the isolation of penicillin (Fig. 1.9) by Chain and Florey in 1940. In 1941 Dubos isolated a pharmacologically active protein extract from Bacillus brevis that was shown to contain the antibiotic gramicidin. This was concurrent with Waksman who postulated that soil bacteria should produce antibiotics as the soil contains few pathogenic bacteria from animal excreta. His work on soil samples eventually led Schatz et al. to the discovery and isolation in 1944 of the antibiotic streptomycin from the actinomycete Streptomyces griseus. This discovery triggered the current worldwide search for drugs produced by microorganisms. To date several thousand active compounds have been discovered from this source, for example the antibiotic chloramphenicol (Streptomyces venezuelae), the immunosuppressant cyclosporin A (Tolypocladium inflatum Gams) and antifungal griseofulvin (Penicillium griseofulvum) (Fig. 1.9). An important advantage of using microorganisms as a source is that, unlike many of the marine and plant sources, they are easily collected, transported and grown in fermentation tanks for use in industry.

Animal sources

N-terminal chain ends

Phe I

Val I

Asg I

His I

Leu I

Cys_

Gly I

Ilue

Val I

Adrenaline

Thyroxine

Adrenaline

Thyroxine

C-terminal chain ends

S-S-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asg-Tyr-Cys-Asn

Thr-Ser-Ileu

Gln-Ser — His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Arg-Gly-

Lys I

Pro I

Phe_Phe

Insulin

Animal-derived products have been used since ancient times. However, it was not until the late nineteenth century that thyroid and adrenal medullary extracts were used to treat patients. Investigation of adrenal medullary extracts resulted in the isolation of the pure hormone adrenaline (epinephrine) in 1901. However, it was not until 1914 that pure thyroxine was isolated. This was followed in 1921 by the isolation of insulin from pancreatic extracts by Banting and Best. This enabled insulin to be produced commercially from bovine and porcine sources. Some insulin is still produced from these sources. However, in the later part of the twentieth century insulin was produced from bacteria using recombinant genetic engineering (see section 10.15.2). Animal sources are still used for hormone research but are seldom used to commercially produce drugs.

1.5.6 Compound collections, data bases and synthesis

All large pharmaceutical companies maintain extensive collections of compounds known as libraries. Smaller libraries are held by certain universities. An important approach to lead discovery is to put the members of these libraries through an appropriate high-throughput screening (HTS) (see section 5.6). Screening of large numbers of compounds can be very expensive so pharmaceutical companies tend to test groups of compounds that are selected using criteria specified by the company. These criteria may consist of similar chemical structures, chemical and physical properties, classes of compound and the structure of the target.

Pharmaceutical companies also maintain databases of compounds and their properties where known. Leads are found by searching these data bases for compounds that meet the companies' criteria. These compounds, known as hits, are synthesised, if necessary, before being tested for biological activity by HTS.

The pharmaceutical industry makes extensive use of combinatorial chemistry (see Chapter 5) to synthesise compounds for testing in high-throughput screens. Molecular modelling techniques (see Chapter 4) may be used to support this selection by matching the structures of potential leads to either the structures of compounds with similar activities or the target domain. The latter requires a detailed knowledge of both the three-dimensional structures of the ligand and target site.

1.5.7 The pathology of the diseased state

An important approach to lead compound selection is to use the biochemistry of the pathology of the target disease. The team select a point in a critical pathway in the biochemistry where intervention may lead to the desired result. This enables the medicinal chemist to either suggest possible lead compounds or to carry out a comprehensive literature and database search to identify compounds found in the organism (endogenous compounds) and compounds that are not found in the organism (exogenous compounds or xenobiotics) that may be biologically active at the intervention site. Once the team have decided what compounds might be active, the compounds are synthesised so that their pharmaceutical action may be evaluated.

1.5.8 Market forces and 'me-too drugs'

The cost of introducing a new drug to the market is extremely high and continues to escalate. One has to be very sure that a new drug is going to be profitable before it is placed on the market. Consequently, the board of directors' decision to market a drug or not depends largely on information supplied by the accountancy department rather than ethical and medical considerations. One way of cutting costs is for companies to produce drugs with similar activities and molecular structures to those of their competitors. These drugs are known as the 'me-too drugs'. They serve a useful purpose in that they give the practitioner a choice of medication with similar modes of action. This choice is useful in a number of situations, for example when a patient suffers an adverse reaction to a prescribed drug or on the rare occasion that a drug is withdrawn from the market.

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  • STEPHANIE FRUEH
    What are the sources of lead compounds?
    2 years ago
  • haben
    What is a lead compound in medicinal chemistry?
    1 year ago
  • Rafael
    What is microbial source lead identification?
    1 year ago
  • Samuel
    What are the some of the places medicinal chemists look for drug leads?
    11 months ago
  • Tommy
    What is meant by a lead compound in medicinal chemistry?
    7 months ago
  • bilbo
    What is opth protect group in medicinal chemistry?
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    What pharmaceutical drugs contain lead?
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