25

Chapter-1

Introduction

26

INTRODUCTION TO ANACARDIC ACID AND ITS

DERIVATIVES

Anacardium occidentale L. (Family: Anacardiaceous), commonly

known as cashew is a medium sized evergreen tree with sprawling branches.

The leaves are alternate, oval blunt, and widely notched at the tips. The

flowers are small with greenish-white petals, which become pinkish and

have distinct red strips. They are grouped in terminal bunches. The fruit

consists of two parts; a soft, swollen, pear-shaped edible stalk called the

cashew apple and a hard kidney shaped nut, which is attached to the

cashew fruit. The cashew tree (Anacardium occidentale), a species originally

native to Brazil where it is still cultivated, is also grown in a large number in

other tropical and sub-tropical countries, represents one of the major and

cheapest sources of this class of compounds.1 It is now commonly found

along the coastal regions of India. Anacardic acids are chemical compounds

found in the shell of the cashew nut (Anacardium occidentale).

Anacardic acid (Figure 1.1) is a yellow liquid. It is miscible partially in

alcohol and ether, but nearly immiscible in water. Chemically, anacardic

acid is a mixture of several closely related organic compounds. Each one

consists of a salicylic acid substituted with an alkyl chain that has 15

carbon atoms. The exact mixture depends on the species of the plant2 of

which the 15 carbon unsaturated side chain found in the cashew plant is

very lethal to Gram positive bacteria.

27

Figure 1.1: 2-hydroxy-6-(pentadeca-8, 11, 14-trienyl)benzoic acid

Cashew nut shell liquid (CNSL) is a by-product of cashew nut industry

and anacardic acid ene mixture (Figure 1.2) isolated from CNSL

constituents (Figure 1.3) which are salicylic acid derivatives with a

nonisoprenoid alk(en)yl side chain.3

Figure 1.2: Anacardic acid ene mixture

Cashew nut shell liquid (CNSL) is obtained as a by-product from

mechanical processing for edible use of cashew kernel (Anacardium

occidentale .L) and is a mixture of anacardic acid 2, cardanol 3 and smaller

amounts of cardol 4 and 2-methylcardol 5.4 Due to the easy thermal

decarboxylation of anacardic acid 2, the main component of distilled CNSL

is cardanol 3 (yield up to 70–80 % and purity up to 90 %) as a mixture of

saturated (3-n-pentadecylphenol), monoolefinic [3-(n-pentadeca-8-

enyl)phenol], diolefinic [3-(n-pentadeca- 8, 11-dienyl)phenol], and triolefinic

[3-(n-pentadeca-8, 11, 14- trienyl)phenol] long-chain phenols, with an

28

average value of two double bonds per molecule. Cardol 4 and methylcardol

5 are present in smaller percentages (Figure 1.3).5

Figure 1.3: Major Components of CNSL.

World-wide cashew nut production is presently estimated to be

1,200,000 tons per annum and the availability of CNSL is 300,000–360,000

tons per annum. Cardanol, upon catalytic hydrogenation, yields 3-n-

pentadecylphenol (hydrogenated cardanol) and this unique alkyl phenol

derivative is produced commercially in high purity. Owing to the difficulty of

synthesizing long-chain alkyl phenols with an aliphatic chain in the meta

position, hydrogenated cardanol represents a simple and easily available

entry to various derivatives useful for different purposes (e.g., flame-

retardants, waterproofing agents, antioxidants, gum inhibitors for gasoline).

In recent years the cashew, Anacardium occidentale L. (Anacardiaceae)

apple, has increased in value, especially in the countries where it is grown,

such as Brazil. There is no doubt that the nut (true fruit) is the most

important product of the cashew tree. However, this tree also yields the

29

pearshaped ‘‘apple’’ (pseudo fruit) to which the nut is attached. A number of

processes have now been developed for converting the cashew apple into

various products, such as juice, jam, syrup, chutney and beverage. Cashew

apple juice is, in fact, one of the most popular juices in Brazil today.

Anacardic acids Fig. 1.4; 6[8’(Z)-pentadecenyl] salicylic acid (C15:1) (6), 6

[8’(Z), 11’(Z)-pentadecadienyl] salicylic acid (C15:2) (7) and 6[8’ (Z), 11’ (Z),14’-

pentadecatrienyl] salicylic acid (C15:3) (8) were previously characterized from

the cashew apple and their diverse biological activities have been described.

Figure 1.4: Anacardic acid ene mixture.

The reports include their potent antibacterial activity,6 moderate

cytotoxic activity against several tumor cell lines,7 and tyrosinase,8

lipoxygenase9 and prostaglandin endoperoxidase synthase inhibitory

activities.10

Primarily used for tooth abscesses, it is also active against acne, some

insects, tuberculosis, and MRSA. It is primarily found in foods such as

cashew nuts, cashew apples, and cashew nutshell oil, but also in mangos

and Pelargonium geraniums.11 The first chemical analysis of the oil of the

cashew nut shell from the Anacardium occidental was published in 1847.12

30

It was later found to be a mixture rather than one chemical, sometimes the

plural anacardic acids is used.

Biological Evaluation of Anacardic Acid and its Derivatives

A variety of synthetic methods for the preparation of anacardic

acids,13-20 as well as for converting these materials to other useful

compounds, has been reported.20,21 Several natural products and synthetic

compounds have been evaluated against T. cruzi GAPDH using a standard

biochemical assay22-25 Among these, a mixture of anacardic acids, isolated

from the Brazilian cashew-nut shell liquid, presented promising results.26

Chemically, anacardic acids feature a convenient salicylic acid system and a

long side chain at the 6-position, in which a double bond is found at C-8 in

the monoene, diene at C-8, C-11 and triene at C-8, C-11, C14 components.

These compounds exhibit a wide range of biological activities (e.g.,

insecticide, antifungal, antimicrobial, molluscicide, antitumoral)6,27-30

stimulating the search for new derivatives with improved properties.31-38

Anacardic acid and its derivatives have been tested for various

biological activities (Table 1.1) viz., soybean lipoxygenase-1 inhibitory

activity,9,39 and antimicrobial activity.6, 40

31

Table 1.1: Some of the biological activities of anacardic acid derivatives

S.No Structure Biological activity references

1

Soybean

lipoxygenase-1 & anti

bacterial activity

against S.mutans

9, 41

2

Bacterial histidine

protein kinase (HAK)-

Mediated two-

component regulatory

systems

42

3

Potent

phosphodiesterase-5

32

4.

Cyclooxygenase

Inhibitors

31

5.

Metgicillin resistant

staphylococcus

aureus

43, 44

32

6.

Mycobacterium

smegmatis

45

7.

Cytotoxic activity 46

8.

Cytotoxic activity 47

It has been proved that anacardic acid has a unique function of

mediating changes in membrane potential and pH gradient across liposomal

membranes.48 Anacardic acid was found to form highly lipophilic metal

derivatives with selectivity towards the first row transition metals such as

Fe+2, Cu+2 and Zn+2 having selective ionophoric properties.49 An amide

derivative of anacardic acid 9 (Figure 1.5) has been reported to be the first

specific activator of histone acetyltransferase (HAT) activity of p30050 while

anacardic acid (Figure 1.2) showed to be HAT inhibitor.

Figure 1.5

33

A few anacardic acid derivatives such as 9 (Figure 1.5) were reported

and elucidated their mechanism of HAT activation and suggested that, 9

(Figure 1.5) and its derivatives binds to p300 predominantly to the amide

group of -helix and β-sheets and affect the structure of the enzyme.51 But

all the reported compounds were not cell permeable and showed inhibition

at higher concentrations of the compound. More recently, it has been shown

that anacardic acid is a specific activator of kinase activity of Aurora Kinase

A,52 suppresses expression of nuclear factor-kB regulated gene products

leading to potentiation of apoptosis53 and inhibitor of the HAT activity of

recombinant Plasmodium falciparum GCN5.54 Sbardella et al. recently

showed that long chain alkylidenemalonates which are structurally related

to anacardic acid as modulators of histone acetyltransferases.55

Non-isoprenoid phenolic lipids exist in plants from a number of

different families, notably the anacardiaceae shrub, many small plants, and

certain bacterial sources. As the main component of natural cashew nut-

shellliquid (CNSL), anacardic acids (1) (Figure 1.2) are the most widely

distributed phenolic lipids.

The particular structural behavior and abundance of anacardic acids

have prompted researcher for a strategy to convert these materials into

analogues of an emerging family of antitumor natural products, for example:

oximidines I, II, and III,56-58 apicularens A and B,59-63 and salicylhalamides A

and B64-69 (Figure 1.6), which present a benzofused macrolactone bearing

an unusual N-acylated enamide side-chain. Related to the fact that these

benzolactone enamides do not display any significant structural correlations

to the profiles of known anti-cancer drugs, they constitute a very attractive

34

new class of lead compounds in the search for antineoplastic agents and

have therefore shown considerable interest concerning to isolation, chemical

synthesis and mechanistic studies of the biochemical mode of action.70

Figure 1.6: Oximidines I, II, and III

Other macrolactones structurally related to the above macrolides

include lasiodiplodin,71-72 cis- and transresorcylide,73-74 and curvularin.75-77

These orsellinic acid type macrolides also have attracted the attention of

many synthetic chemists regarding both chemical and physiological

activities.78-81 For instance, methyldehydrolasiodiplodin, a mixture of

geometrical isomers used as a precursor for the synthesis of lasiodiplodin,

exhibits a rather uniform in vitro activity against human tumors e.g. breast,

prostate, renal, ovarian, melanoma, colon, lung and leukemia.82

Crude cashew nut shell liquid represents one of the major and

cheapest sources of naturally occurring non-isoprenoid phenolic lipids

(Figure 1.3) such as anacardic acids (2), cardols (3), cardanols (4),

methylcardols (5) and polymeric materials. CNSL has found important

commercial usage as the phenolic raw material for the manufacture of

certain resins and plastics having unusual electric and frictional

properties.83-86 The interesting chemical characteristics of cardols, such as

the presence of a double bond at the 8-position of the long-chain in the

35

monoene, diene and triene components and a convenient aromatic orcinol

system led to the discovery of these materials into lasiodiplodin (Figure 1.7).

The latter compound is a naturally occurring 12-membered orsellinic acid

type macrolide, isolated from the culture broth of the fungus Botrydiplodia

theobromae (formally Lasiodiplodia theobromae), and exhibits plant growth

regulating properties.87 This macrolide has also been found in the stems and

leaves of Euphorbia splendens and shows antileukemic activity.81 Several

total synthesis of racemic lasiodiplodin have been carried out during the last

20 years,88-93 while some asymmetric synthesis of the R-lasiodiplodin have

been recently published.94-97

Figure 1.7

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43

AIM AND OBJECTIVES

Natural products continue to be a fertile ground for chemical and

biochemical inquiry and serve as an invaluable source to some of the most

widely used agents in human medicine, such as antibiotics, anticancer,

anti-inflammatory, antiviral and antitumor agents. Vincristine, Vinblistine,

Camphothecin, Taxol and Podophylotoxin derivatives are exclusively used in

the treatment of cancer. In addition to these crude extracts of herbs, fruits,

cereals and vegetables are rich in polyphenolics and are good anti-oxidants.

Cashew (Anacardium occidentale L.) is a tropical plant, which belongs to

the family of anacardiacea. The kernel of cashew nut is a rich nutrient and

dietary supplement. Cashew testa contains biflavonoids (-) epiafzelchin and

(-) epicatechin which exhibits anti-inflammatory property. The cashew nut

shell is a rich source of long chain alkyl phenols and phenolic acid. The

biological activity of anacardic acid and the industrial application of

cardanol are attributed to its long alkyl chain. Although a large amount of

CNSL is being produced all over the world, only about 10% CNSL is used for

industrial application while the remaining is unutilised. To make use of this

abundantly available anacardic acid in CNSL, its separation and utilisation

in pharmaceuticals was attempted. Thus the present investigation was

undertaken to study the following points.

Synthesis of a new class of amino anacardic acid derivatives using

anacardic acid ene mixture as synthon and evaluation for their

antibacterial studies (Chapter-2).

44

Synthesis of sulphonamido analogues of anacardic acid derivatives,

using anacardic acid ene mixture as synthon and evaluation for their

antibacterial activity (Chapter-3)

Synthesis of urea analogues of anacardic acid derivatives, using

anacardic acid ene mixture as synthon and evaluation for their

antibacterial activity (Chapter-4)

Synthesis of thiourea analogues of anacardic acid derivatives, using

anacardic acid ene mixture as synthon and evaluation for their

antibacterial activity (Chapter-5)