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2.3 Important Means in Biotechnology


47


2.3.1 Recombinant DNA (rDNA)





47


2.3.2 Restriction Enzymes






47


2.3.4 DNA
-
Ligase







48


2.3.5 Hybridization Probes




49


2.3.6 Cloning Process



50


2.4 Recombinant Proteins




50


2.4.1 Bacterial Systems



58


2.4.2 Glycosylation




59


2.4.3 Mammalian Tissue Culture Expressio
n Systems


60

2.5 Biotechnology Vs Modern Pharmacy Practice


60


2.5.1 Human
Proteins as Drugs


61


2.5.2 New Drug Classes



63



2.2.3 Vaccines




64


2.5.4 New Immunodiagnos
ticcAgents


66


2.5.5 DNA Probs and RELP Analysis


68


2.5.6 Enzyme Linked Immunosorbant Assay(ELISA)


69

2.6 Biotechnology Based Pharmaceuticals for the Millennium



71


2.6.1 Genetically Engineered Vaccine


73


2.6.3 Antibodies in Biotechnology



75

2.6.4 Gene Therapy





77

2.6.5 3D Picture of the ‘Lock’ And ‘Keys’


78

2.7 Biotechnolgy and Modern Drug Discovery



79

2.7.1 Approved Medicines



79

2.7.2
Medicines Under Develo
pment


80



2.7.3 Human Clone



80


2.8 Biotechnology Some Thought Provoking Newer Ideas


82


2.8.1 Potato Vaccine



82

2.8.2 Functional Food Revolution


82

3. Carbo
hydrates



84

3.1 Introduction



84

3.2 Classification



86

3.
2.1 Homoglycans



86

3.2.2 Heteroglycans



100

3.3 Carbohydrate Biogenesis



119

4.Glycosides




122

4.1 Introduction



122

4.1.1 O
-
Glycosides



125


4.1.2 S
-
Gl
ycosides


125

4.1.3 N
-
Glycosides



125

4.2 Classification



127

4.2.1 Ant
hracene Glycosides(or Anthraquinone Glycosides)


127

4.2.2 Phenol Glycosides



139

4.2.3 Steroid Glycosides



144

4.2.4 Flavonoid Glycosides



157

4.2.5 Coumarin and Furanocoumarin Glycosides


168

4.2
.6 Cyanogenetic Glycosides



173

4.2.7 Thiglycosides



179

4.2.8 Saponin Glycosides



182

4.2.9 Aldehyde Glyco
sides



195

4.2.10 Bitter Glycosides



196

4.2.11 Biosynthesis of Glycosides


200

4.3 Biosynthesis of Glycosides



202

4.3.1 Biosynthesis of Anthrancene Glycosides




203

4.3.2 Biosynthesis of Phenol Glycosides


204

4.3.3 Biosynthesis of Steroid Glycosides



204

4.3.4 Biosynthesis of Flavonoid Glycosides


204

4.3.5 Biosynthesis of C
oumarin and Furanoc
oumarin Glycosides


205

4.3.6 Biosynthesis of Cyanogenetic Glycosides


207


4.3.7 Biosynthesis

of Thioglycosides


209

4.3.8 Biosynthesis of Saponin Glycosides



209

4.3.9 Biosynthesis of Aldechyde Glycosides


210

4.4 fProfile of Glycosides in Natural Plant Sources



210

5. Terpenoids



215

5.1 I
ntroduction



215

5.2 Classification



218

5.2.1 Monoterpenoids



218

5.2.2 S
esquiterpenoids



228

5.2.3 Diterpenoids



233

5.2.4 Triterpenoids



236

5.2.5 Tetrate
rpenoids and Carotenoids


238

5.2.6 Volatile Oils (or Essential Oils)


240

5.2.7 Resins and Resin Combinations


306

5.2.8 Oleoresins



323

5.2.9 Oleo
-
Gum
-
Resins



328

6.Phenylpropanoids



340

6.1 Introduction



340

6.2 Classification




340

6.2.1 Hydroxycinnamic Acids



341

6.2.2 Phenylpropenes




344

6.2.3 Coumarins





345

6.2.5 Biphenylpropanoid Derivatives

361

6.2.6 High Molecular Weight Phenylpropanoids


366

6.3 Biosynthesis of Phenylpropanoids

369

7. Alkaloids


372

7.1 Introduction


372

7.1.1

Nomenclature


374


7.1.2
Occurrence and Distribution in Differen
t Organ’s of Plant
s


374

7.1.3 Site of Formation of Alkaloids in Plants

377


7.1.5
Isomeris
m


378

7.1.6 General Characteristics of Alkaloids



389

7.1.7 General Methods of Extraction and Isolation of Alkaloids 389

7.2 Classification of Alkaloids 395

7.2.1 Alkaloids Derived from Amination Reactions 401

7.2.2 Alkaloids Derived from Anthranilic Acid

427

7.2.3 Alkaloids Derived from Histridine
436

7.2.4 Alkaloids Derived from Lysine 441

7.2.5 Alkaloids Derived from Nicotimic Acid

7.2.6 Alkaloids Derived from Tyrosine 475

7.2.7 Alkaloids Derived from Tryptophan 495

7.3 Alkaloids in Tissue Cultures

542

7.4 Alkaloids in Chemosystematics 543

8. Bitter Principles 547

8.1 Introduction 547

8.2 Classification of Bitter Principles 547


8.2.1 Phenolic Bitter Principles 548

8.2.2 Lactone Bitter Principles 550

8.2.3 Chromone Bi
tter Principles 553

8.2.4 Coumarin Bitter Principles 556

8.2.5 Coumarone Bitter Principles 559

8.2.6 Miscellaneous Bitter Principles 561

9.Antribiotics 568

9.1 Introduction 568

9.2 Antibiotic Development 569

9.2.1 Quest for New Antibiotics 569

9.2.2 Larg
e
-
scale Production 571

9.3 Classification of Antibiotics 579

9.3.1 Aminoglycosides 579

9.3.2 Anthracvclines 590

9.3.5 Lincosamides 616

9.3.6 Macrolides 618

9.3.7 Penicilins 625

9.3.8 Polypeptide Antibiuotics 641

9.3.9 Tetracylines 649

9.3.10 Misscell
aneous Antibiotics 657

10. Drug Molecules of Marine Organisms 695

10.1 Introduction 695

10.2 Classification of Drug Molecules of Marine Organisms
696

10.2.1 Cytotoxic /Antineoplastic Agents 696

10.2.2 Cardiovascular Active Drugs 701

10.2.3 Marine Toxi
ns 709

10.2.4 Antimicrobial Drugs 716

10.2.5 Antibiotic Substances 718

10.2.6 Antiinflammatory and Antispasmodic Agents 720

10.2.7 Miscellaneous Pharmacologically Active Substances 721

10.3 Marine Natural Products: An Upgradation Profile 726

10.3.1 Microb
ial Transformations 726

10.3.2 Puuphenone: Semisyntheic Analogues 729

10.4 Summary 733

11. Nutraceuticals 735

11.1 Introduction 735

11.2 Phytochemicals as Nutraaceuticals 737

11.2.1 Terpenoids (of Isoprenoids) 738

11.2.2 Non
-
Carotenoid Terpenoids 742

11.2.
3 Polyphenolics [ or Polyphenol Extracts] 744

11.2.4 Phenolic Acids 751

11.2.5 Non
-
Flavonoid Polyphenolics 753

11.2.6 Glucosinolates [ or Thioglucosides ] 755

11.2.7 Thiosulphimates [ or Cysteine Sulphoxides ] 759

11.2.8 Phytosterols 760

11.
2.9 Anthraquinones 761

11.2.10 Glucosamine [ Synonym: Chitosamine; ] 763

11.2.11 Octacosanol [ Synonym : Octacosyl Alcohol ] 764

11.2.12 Carnitine [ Synonym: g
-
Trimethyl
-
b
-
hydroxybutyrobetaine; ] 765

11.2.13 Capsaic
in[ Synonym: Axsain; Mioton; Zacin; Zos
trix; ] 767

11.2.14 Piperine 768

11.2.15 Chlorophyll 768

11.2.16 Pectin 770

11.2.17 Dominant Phytochemical Pigments 770

11.2.18 Toctotrienols and Tocopherols 770

11.3 Contemporary Nutraceuticals 772

11.3.1 Spiruline 773

11.3.2 Broccoli 773

11.3.3 Al
oe Vera Gel and Aloe Juice 774

11.3.4 Soyfoods 776

11.3.5 Omega
-
3 Fatty Acids 776

11.3.6 Pomegranate Juice 777

11.3.7 Walnuts 777

11.3.8 Certified Organic Mushroom Nutrace 777

12. Enzyme and Protein Drug Substances 779

12.1 Introduction 779

12.2 Enzyme Var
iants 782

12.3 Enzymes of Pharmaceutical Relevance and Unity 783

12.4 Brief Description of Enzymes Use as Drugs 784

12.4.1 Bromelain 784

12.4.2 Chymonypsin 784

12.4.3 Collagense 784

12.4.4 Deoxyribonuclease [ DNase] 785

12.4.5 Fibrinolysin 785

12.4.6 Hya
luronidase 785

12.4.7 Muramidase 785

12.4.8 Papain 786

12.4.9 Pancreatin 786

12.4.10 Pancrealipase 786

12.4.11 Pepsin [ Greek: Pepsis=digestion] 787

12.4.12 Rennin[or Chymosin] 787

12.4.13 Seratiopeptidase 787

12.4.14 Streptokinase 787

12.4.15 Urokinase 7
88

12.4.16 L
-
Asparaginase 789

B. Protein as Drug Substances

12.5 Introduction 789

12.6 Protein Variants 790

12.7 Brief Description of Proteins Used as Drugs 791

12.7.1 Complement Protein (Complement Factor C
-
3) [Latin;


Complere=to Complete]

791

12.7.2 Gelatin[Latin: Gelatina=Gelatin] 792

12.7.3 Collagen [Synonym: Ossien]:


(Greek: Kolla=glue,+gennan=to produce) 792

12.7.4 Casein [Latin: caseus=cheese] 793

12.7.6 Yeast 794

12.7.7 Thaumatin [Synonym: Talin;]

795

13. Biomedicinals From Plant
-
Tissue Cultures 797

13.1 Introduction 797

13.2 Profile of Plant
-
Tissue Cultures 800

13.2.1 Type of Cultures 800

13.2.2 Composition of Culture Medium 801

13.2.3 Surface Sterilization of Explants

803

13.2.4 Preparation of Tissue Cultures 804

13.3 Biomedicinals in Plant
-
Tissue Cultures 805

13.3.1 Secondary Metabolites 806

13.3.2 Usefulness of Secondary Metabolites 808

13.3.3 Secondary Metabolites in Chemosystematics 809

13.3.4 Newer
Products Developed 810

13.4 Bioproduction of Commendable Secondary Metabolites 811

14. Hi
-
Tech Products from Plant Sources 814

14.1 Introduction 814

14.2 High Throughput Screening (HTS) 815

14.2.1 HTS and Bioassays 816

14.2.2 Access t
o Plants vis
-
à
-
vis Natural Source Material 817

14.2.3 HTS and Selection for Plant Materials 818

14.2.4 Identification Process of Plants for Targeted Sets 819

14.2.5 Dereplication and Isolation of Active Compounds 820

14.3 Suc
cess of HTS of Plant Source Materials for New Lead Chemical Entities 820

14.3.1 Use of MS for Identification of Potent Biologically


Active and Important Drug Molecules 821

14.
4 Hi
-
Tech Products 822

14.4.1 Genistein [ Sy
n:

Genisteol; Prunetol;] 822

14.4.2 Camptothecin 823


14.4.
3 Rhein [Syn: Monorthein : Rheic Acid; Cassic Acid ; Parietic


Acid; Rhubarb yellow] 823

14.4.5 Homoharringtonine (HHT) 824

15. Indian Traditional Herbal Drugs 827

15.1 Introduction 827

15.2 Indian Traditional Herbal Drugs 828

15.2.1 Cardiovascular Drugs 828

15.2.2 Immunmodulators and Adaptogens 830

15.2.3 Antidiabetic Drugs 830

15.2.4 Antineoplastic Drugs 831

15.2.5 Antiviral Drugs 832













1

Introduction

Pharmacognosy
-
ABrief History Phytochermistry

Importance of Natural Drug Substances Further Reading References

Natural Drugs Substances Cultivation

And Production


1.1 PHARMA
COGNOSY
-
A BRIEF HISTORY





`Pharmacognosy’
-
has been coined by the merger of two Greek words
Pharmakon

(drug) and
Gnosis(knowledge) i.e., the knowledge of drugs. The nomenclature
-
`Pharmacognosy’ was used first and
formost by C.A.Seydler, a medical student in Halle
/Salle, Germany, who emphatically employed
Analetica Pharmacognostica as the main title of his thesis in the year 1815. Besides, further
investigations have revealed that. Schmidt has made use of the terminology `Pharmacognosis’ in the
monograph entitled L
ehrubuch der Materia (i.e., Lecture Notes on Medical Matter) which dates back to
1811, in Vienna. This compilation exclusively deals with the medical plants and their corresponding
characterstics.


It is indeed quite interesting to
observe that our
ancients were duly equipped with a vast, in
-
depth
and elaborated knowledge of plethora of drugs from the vegetable origin but unfortunately they
possessed a scanty knowledge with regard to the pressure of chemically pure compounds in most of
them.


C
amphor found its enormous use in the treatment and cure of many ailments, for instance:
internally as
-

a stimulant and carminative; externally as
-
an antipruritic, countererirritant and antiseptic
by the ancient Egyptians, Chinese, Indians, Greeks and Roman
s.


Earlier it was obtained by mere cooling of volatile oils from
-
sassafras, rosemary, lavender, sage;
while the Ancient Greeks and Romans derived it as a byproduct in the manufacture of wine. Nowadays,
camphor is obtained on a large
-
scale synthetic
ally ( racemic mixture

) from the α
-
pinene present in the
turpentine oil ( Chapter 5 ).


African natives used plant extracts in their ritual ceremonies whereby the subject would lose his/her
complete body movements but shall remain mentally alert for 2 or 3 days. Later on
, the earlier
civilization also discovered of time they also recognized certain plant products exclusively used for
poisoning their spears and arrows in killing their preys and enemies as well. Interestingly, they found
that some plant extracts have the un
ique property of keeping the new meat fresh and also to mask its
unpleasant taste and flavor.


The human beings belonging to the ancient era in different parts of the globe independently discovered
the inherent stimulating characteristics of a

wide variety

of drinks exclusively prepared from the
vegetative source as stated below in Table 1.1.


Table 1.1 Stimulating Characteristics from Vegetative Sources

S.No.

Common
Name

Biological origin
(Family)


Part
Used

Active Ingredient

Distributio
n

1.

Guarana

Paulliuia clipanna
(Sablindacoal)

Seed

Caffeine

(2.5
-
5.0%)

Tahnin

(Catheochutannia
acid) 25%

Brazil,
Uruguay

2.

Paraguay
Tea or
Mate

Ilex paraguanensis
St. Hill
(Aquifollaceae)

Leave

Caffeine

South
America

3.

Coffee
Bean Of
Coffee
Seed

Coff
ee Arabica
Linne or G.liberica
(Rubiacease)

Seed

Caffeine (1.2%)
Trigonelling
(0.25%) Tannin
(3.5%) Glucose &
Dextrin
(
15%)Eatty Oil
(trioleoglyceerol)
and
palmitoglycerot
(10
-
13%)
Pritein(13%)

Ethiopia,
Indonasia,

Srilanka,Brazil

4.

Coca Kola
or Kolahuts

Coca nitida
(Ventenat) Schott
et Endlicher
(Stersulliacease)

Seed

Caffeine
anhydrous (<=1%)

Slerra Legone,
Congo,
Nigeria, Sri
Lanka, Ghana,
Brazil,
Indonesia,
Jammaica

5.

Tea or Thea

Camella Sinerists
Linne s O.
Kuntze(Theacease)

Leave or
Leaf Bud

Caffe
ine (
1
-
4%)
Gallotaphic acid
(15%) volatile oil
(yellow) 0.75%

China, Japan,
India,
Indonesia, Sri
Lanka

6.

Cacao
Beans

Theobrome cacao
Linne
(Sterculiacease)

Seed

Fixed Oil (35
-
50%)
Starch (15%)
Protein (15%)
Theo bromine (1
-
5%), Caffeine
Ecu
ador,
Columbia,
Malasia,
Curacao,
Maxico,
(0.07
-
0.36%)

Trinidad,
Brazil, Nigeria,
Camrrons,
Ghana,
Philliphines,
Sri Lanka





Fig.1.1
the

Xanthine and Purine Structures


Figure 1.2, illustrates the mode of synthesis of caffeine essentially from the same precursors
present in

Coffea

Arabica
as the

three
purine alkaloids (see Fig 1.1) found in order biological systems which have
been studied so far at length, either from a compound which may afford an active 1
-
carbon fragment
(e.g., serine, methanol, glycine and forma
lin) or from formic acid.


A=Active 1
-
carbon fragment [ serine, methanol, glycine


and formalin];

B=α
-
Amino acetic acid(H2N.CH2COOH) or glycine

C=Amide nitrogen of Glutamine


[HOOC.CH2.CH2CH.NH2.COOH];

D=Carbon dioxide;

E=Nitrogen from Aspartic Acid


[HOO
C
-
CH2CH(NH2).COOH].


Fig.1.2 Mode of Synthesis of Caffeine




Methionine along with the said four compounds act as active precursors of the three `Methy1
Groups’ at N1,N3 and N7 positions respectively.



Glycine is responsible for the contribution of C
-
4,C
-
5 a
nd C
-
7,



Carbon doxide contributes C
-
6,



N
-
1 is provided from aspoartate, and



N
-
3 and N
-
9 are derived from the amide nitrogen of glutamate.


Such elaborated and intensive studies of chemical constituents present in ‘
Natural Products’

could
only be feasi
ble with the advent of various advancement in the field of `
Phytochemistry’
.


However, it is pertinent to mention here that the scientific reasoning for the various age
-
old
established characteristic medicinal properties have been adequately ascertain
ed and determined in the
past two centuries. A critical survey of literatures would reveal that a few chemical entities were not
only identified but also known to the therapeutic armamentarium between the said
eras
.


Table 1.2 Examples of Pla
nt Constituents in use from 1627 to 1830

S.No.

Period

Researcher

Chemical Entity

Remarks

1.

1627
-
1691

R.Boyle

Alkalold(s)
(probably)

Present in Opium

2.

1645
-
1715

N.Lemery (French
Apothecary)

Alcohol

As a solvent in
extraction
processes

3.

1709
-
1780

A.
S.Marggraf
(German
Apothecary)

Sugar

Isolated from
many plant
sources including
sugar
-
Beet

4.

1742
-
1786

K.W Scheels

Organic acids
oxalic, tarfaric and
prussic (HCN)

Isolated from
natural sources

5.

1805

Sertuner (German
Chemist)

Meconic acid

Present in
Opium

6.

1811

Gomeriz
(Portugese
Chemist)

Cinchonine

Isolated from
Ginchona Banks

7.

1812

Sertuner(German
Chemist)

Morphine

An alkaloid
present in Opium

8.

1817

Pellettier and
Gayenlou (French
Chemist)

Strychine

An alkaloid from
Strychos Nux
Vomica

9.

1819

do

Brucline

Do

10.

1820

Meissner

Veratramine

An alkamine from
Green Helibore

11.

1830


Amvgdalin

A cyanophore
glycoside from
Bitter Almond


Considerable progress has been made in the nineteenth century when chemists seriously took up the
chall
enge
of synthesizing a plethora
of o
rganic compounds based or `
biologically
-
active
-
prototypes’
.
Some of these purely `synthesized compounds’ essentially possessed structures of ever increasing
complexity; and later on, after systematic pharmacological and micro
biological evaluations proved to be
yielding excellent useful therapeutic indices were found to be existing beyond the realm of
`pharmacognosy’

or more specifically
`
phytochemistry’
-

an altogether new discipline under the banner
of
`medicinal chemistry’

ca
me into existence. However, this particular discipline almost remained
dormant since the era of Paracelsus. But now, the
`medicinal chemistry’

has acclaimed deserving wide
recognition across the globe due to its own legitimate merit and advantages.


In short,
three

major basic disciplines became largely prevalent with regard to the development of
drugs, namely:



Pharmacognosy:
emb
racing relevant information(s) with regard to medicines exclusively
derived from natural sources, for instance: plants, animals and microorganisms,



Medicinal Chemistry:

covering entirely the specific knowledge not only confined to the science
of `synthenti
c drugs’ but also the basic fundamentals of
`drug
-
design’
, and



Pharmacology:

dealing particularly the actions of
`drugs’

and their respective effects on the.