Natural Products; Pharmacological Importance of Family Cucurbitaceae: A Brief Review

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Natural Products; Pharmacological Importance of Family Cucurbitaceae: A Brief Review

Syed Shoaib Ahmad Shaha, M. Ijaz Hussainb, M. Kashif Aslamb and Gildardo Riverac*

aDepartment of Chemistry, Quaid-i-Azam University Islamabad, 45320, Pakistan; bDepartment of Chemistry, The Islamia University of Bahawalpur, Pakistan; cCentro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México

Abstract: Compounds derived from nature have played a major role in drug discovery. They became the basis for the development of new pharmaceuticals. In this scope, family Cucurbitaceae is a prominent source of secondary metabolites, mainly triterpenoids. In this paper, we provide a brief review of cucurbitane metabolites that exhibit an extensive range of biological actions specifically antidiabetic, anti-inflammatory, cytotoxic, hepatoprotective, and antiparasitic effects.

Keywords: Antibacterial, antiparasitic, Cucurbitaceae, momordica, natural products, pharmacological activity.

1. INTRODUCTION

Natural products are biologically active compounds that are isolated from plants and animals and have an efficient safety profile against animal and plant pathogens. With regard to the use of natural products in medicine, it has been found that in the beginning of human history, compounds for treating diseases were very limited. Although a lot of research has been done in this field, remedies which were used 6,000 years ago are still in use today [1]. The Sumerians used clay tablets for plant prescriptions and if we go back about 5,000 years in Chinese history, we will find that the use of about 3,000 medicinal plants was recorded by Chinese Emperor Chi’en Nung himself. In the first Century AC, a Roman scholar, Pliny the Elder, in his famous work “Naturalis Historia” recorded the contribution of Greeks and Romans in the field of medicine. Dioscorides, a Greek army surgeon, wrote “De Materia Medica” which commented plants and therapeutically useful animal and mineral products. He was the first systematic western natural scientist and his book contained a description of about 600 medicinal plants. The credit of extracting the “active constituents” from medicinal plants goes to Paracelsus Theophrastus (1493–1541), a Swiss physician. His work in medicine helped lay the foundation for plant-derived drugs and their manufacturing.

Until the early part of the eighteenth century, active ingredients from plants had not been isolated. Among the foremost active compounds isolated were atropine (1), strychnine (2), colchicine (3) and morphine (4) from opium (Fig. 1). Quinine (5) was extracted from the Cinchona plant (Fig. 1) [2, 3]. The first proprietary drugs appeared during the 1890s [4]. In the 19th and 20th centuries, scientists

*Address correspondence to this author at the Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro, s/n, Esq. Elías Piña, 88710, Reynosa, México; Tel: +52 899 9243627; Fax: +52 899 9243628; E-mail: [email protected]

continued their struggle to discover active phytochemicals. They also attempted to find the relationship between phytochemical consumption and human health which ultimately led to the formation of phytochemistry. Approximately 25% of active ingredients in modern drugs have a plant origin [5].

Compounds derived from nature have played a major role in drug discovery and development. Out of fifteen drugs included in the World Health Organization´s (WHO) therapeutic schemes for malaria treatment, eleven were either natural products or related to natural products [5]. A WHO report states that physicians in developing countries such as Sri Lanka, Nepal, Bangladesh and Burma, commonly suggest conventional curing drugs based on a plant source. In underdeveloped as well as developed countries, natural and conventional drugs are being used and comprise more than 50% of the total drugs used in practice. Another WHO survey revealed that about 80% of the world populations rely on plants for their primary health care needs [6].

2. CONTRIBUTION OF NATURAL PRODUCTS TO HUMAN HEALTH

Nature possesses a kind of strong healing power that man has discovered with the passage of time. Humans have learned how to use different kinds of herbs, plants, and flowers to cure diseases. They discovered that naturally available compounds derived from plants and animal sources contain chemicals which play a vital role in human health and physical development. These plants and their derived compounds are still being used as primary sources for the treatment of many human maladies. In developing countries, about 80% of the population prefers to use traditional medicine systems for their healthcare [7]. This system is based mainly on naturally-derived compounds. It has been proven that naturally available plants are a great source of biologically active compounds. These compounds form the

2 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 8 Shah et al.

basis for the development of new pharmaceuticals. New discoveries in the field of natural science have shown that about half a million plant species are present worldwide. Of these species, only 1% has been phytochemically investigated by scientists [8]. This means that there is a lot of potential for discovering new bioactive compounds. Secondary metabolites or phytochemicals are compounds whose actual function has not yet been discovered, but it is widely accepted that these compounds play an important role in the immune system of plants. These plant compounds have been found to be powerful agents against insects and pathogenic microbes. They are used for acquiring a self-defense mechanism that cannot be obtained by combinatorial synthesis [9-11].

The interest in medicinal plant research has increased globally because of the promising potential of medicinal plants used in various traditional, complementary and

alternate treatments of human disease. Another fact is that these compounds are important for human health and have a commercial value. In fact, the fascination of man with natural products has driven many important world events [12, 13].

Large varieties of natural products are being used as anti-inflammatory, antioxidant, antimicrobial and anticancer agents. Aspirin (6), a compound with anti-inflammatory activity, is derived from natural sources and is used in medical practice (Fig. 2) [14]. Different varieties of drugs have been isolated from natural sources. For example, Curcumin (7) [15-17] from Curcuma longa, ternatin (8) [18], a tetramethoxy flavone from Egletes viscose, and anthocyane flavonoids (9) [19] in the natural juice from Aronia melanocarpa have been used as anti-inflammatory drugs (Fig. 2).

O

O

N

OH

N

OOH

NH

H

HO

HO

O N

N

N

H

H

OHH

O

1 2 3

4 5

O O

O

O

HN

O

O

Fig. (1). Structure of active ingredients from plants.

OHO

O

O

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O

O O

O

OH

O

O

OH

O

O

O

OH

OO+

OH

OH

OH

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6 7

8 9 Fig. (2). Natural products used as anti-inflammatory agents.

Natural Products; Pharmacological Importance of Family Cucurbitaceae Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 8 3

Manoalide (10) [20] from the sponge Luffariella variabilis, diterpene lactones andrographolide (11) [21, 22] and 14-deoxy-11,12-didehydroandrographolide (12) from A. paniculata are considered to possess anti-inflammatory and analgesic activity (Fig. 3). Pdophyllotoxin (13), vinblastine (14) and vincristine (15), [23] from Podophyllum peltatum

[24-26], Madagascan periwinkle and Catharanthus roseus respectively, are used in the treatment of childhood leukemia and have antimitotic activity (Fig. 3) [27]. Taxol (16) from the bark of the Pacific or American yew tree Taxus brevifolia and epothilone (17) from myxobacteria, are used as anticancer drugs, while it is reported that 17 is more potent

than taxol (Fig. 3) [28, 29]. Camptothecin (18) [30] was isolated from the Chinese tree Camptotheca acuminate, and is currently being developed as an anticancer agent (Fig. 3). Cephalotaxine (19), an alkaloid, is obtained from Cephalotaxus harringtonia and possesses antineoplastic activity against murine lymphocytic leukemia (Fig. 3) [31, 32].

Metabolites are compounds that are synthesized by plants for the maintenance and survival of plants and animals. They are naturally produced by biochemical degradation and are classified into the following main categories:

OHO

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O O

O

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O

O

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OH

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HOH

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H

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HO OCOCH3

COOCH3

OH

C2H5

C2H5

HO COOCH3

N

N

H

N

N

HO OCOCH3

COOCH3

OH

C2H5

C2H5

HO COOCH3OHC

NHO

OH

O

O

O

O

HOH

HO

OAc

AcOO

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OHO O

OH

S

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OOH

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ON

HOO

H

10

11 12

13 14

15 16

17 18 19 Fig. (3). Natural products used as anticancer agents.


Alkaloids

Alkaloids are one of the largest classes of secondary metabolites with more than 12,000 different compounds. These are basic in nature and possess a variety of pharmacological activities. Piperine (20), cocaine (21), atropine (1), vinblastine (14), ephedrine (22), codeine (23) and barberine (24) are a CNS depressant, local anesthetic, myotic, antileukemic, cardiac stimulant, analgesic, narcotic, and antipyretic, respectively (Fig. 4) [33].

Coumarins

Coumarins occur in more than seventy different plant families such as grasses and fodder crops. More than 1,200 different types of coumarins are reported from higher plants.

Mammein (25), present in Mammea americana, is a well-known insecticide (Fig. 5) [33].

Saponins

Many higher plants contain different kinds of saponins with strong pharmacological activity. Currently, it has been found that they are present in approximately 3,000 different plant species and in over 70 plant families [33].

Steroids

Steroids are chemical compounds which are widely present in animals but their existence in more than 300 higher plants is also reported. Cholesterol and hormones such as estrone (26) and ecdysone (27) are animal sterols but

N

O

O

ON

OO

O

OOH

HN

O

O

H

N

H

N+

OO

O

O

20 21 22

23 24 Fig. (4). Alkaloid derivatives from natural products with pharmacological activity.

O O

OH

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HO O

H H

H

HO

OH

O

HO

HO

OH

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H

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HH

H

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H

25 26 27

28 29 30 Fig. (5). Chemical structure of coumarins and steroids derivatives.


are also isolated from plants. The reason for their presence in plants is still unclear (Fig. 5). Sitosterol (28), campasterol (29) and stigmasterol (30) are extracted from a wide variety of plants (Fig. 5) [33].

Terpenoids

Terpenoids, derived from mevalonic acid, are one of the largest classes of phytochemicals and about 15,000 terpenoids have been reported to date. The reason behind the presence of such a large number is because of the linkage of isoprene units, which is their building block, head to tail, tail to tail, head to head, and in an irregular manner. They also constitute a link with rings and different functional groups. Allamandin (31) isolated from Allamanda cathartica possesses anti-leukemic activity while oleuropin (32) from Olive is found to possess hypotensive and sedative activities (Fig. 6) [33].

3. PHARMACOLOGICAL AND ECONOMIC IMPORTANCE OF FAMILY CUCURBITACEAE

Cucurbits are a prominent source of secondary metabolites. It is reported that the bitter flavor of cucurbits is due to tetracyclic triterpenoids [38]. The plants in Cucurbitaceae family are either annual or perennial climbing or prostrate herbs. The family contains 120 genera with 825 species, which are widely distributed mainly in tropical areas and poorly in temperate regions [34]. In Pakistan 17 genera and 32 species of Cucurbitaceae are present [35]. The leaves

are alternate, petiolated, palmated, having a paniculated inflorescence. Flowers are solitary and yellow or white in colour. They are either unisexual or rarely bisexual and about half are monoecious, while remaining species are dioecious [36, 37]. In female flowers, five sepals are outside the ovary, with five open or imbricated lobes. Five petals are bell-shaped. Stamens are also five. Carpels are united with the ovary that is inferior to semi-inferior and are 2 to 3 or 5 in number. It is often unilocular and sometimes multi-locular. Ovules are numerous and inverted. Style is simple and free. Fruits are elongated, globose berry or pepo, rarely with a capsule. Seeds are habitually flattened and sometimes are winged with a straight embryo. Various phytochemicals such as alkaloids from Momordica and saponins from Momordica, Citrullus, Cucurbita and Lagenaria were reported by Schultes and co-workers [6]. The family proved itself as a strong source of food and medicine. The hard woody pericarp of Lagenaria ualgaris is used in the manufacture of excellent flasks, primitive vessels, utensils, snake blow pipes, drum for tambura, soraja, and in the construction of other musical instruments. Legenaria ulgaris, Cucurbita pepo, Cucuribita maxima, C. moschata, Luffa aegyptiaca and Momordica charantia are used as common vegetables. Cucumis melo, C. sativus and Citrulus vulgaris are the source of fruit. The vines of this family are used for ornamental purposes. The pulp of Citrullus colocynthesis is used as a purgative and for intestinal disorders, such as dropsy. The fruit pulp of Trichosanthers dioica mixed with

OO

O

OH

O

OO

HO

HO

O

O O

COOCH3

OGlu

31 32 Fig. (6). Terpenoid derivatives with biological activity.

H

HO

H

O

O

H

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H

OH

HO

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OH

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33 34 35

36 37 Fig. (7). Cucurbitane-type triterpenoids.


coconut oil cures ear itch, while roots are used to prevent lung inflammation in animals. Bryonia dioica is used for the treatment of atrophic arthritis and bronchial asthma, and as a powerful remedy for snake bite.

Pharmacological Action of Genus Momordica

The genus Momordica comprises 12 species commonly found in Asia and Australia and three species are present in Pakistan. The plants that belong to this genus are climbing annual or perennial herbs. Leaves are simple, palmately lobed, margin mucronate-dentate or remotely denticulate. Flowers are yellow or infrequently white. Male and female flowers are solitary and unisexual while male flowers are racemose or umbellate. Calyx tube is closed at the bottom and covered entirely by 2-3 oblong scales. Corolla rotate or broadly campanulate, obovate or oblong or petals are free. Stamens are free and are inserted at the orifice of the calyx tube, anthers coherent at start, ultimately free, pistillode is absent. The ovary is oblong or fusiform, rostrate, or minutely apiculate-excrescent. There are many ovules, usually horizontal. Fruits are cylindric, baccate, indehiscent or

dehiscent. Seeds are turgid or flattened, smooth or sculptured, and grooved at the margins [40]. The aqueous extract of M. cymbalaria showed significant antidiabetic activity when tested in rats [41]. The constituents of the roots of M. dioica showed anticancer, antioxidant, antimicrobial, hepatotoxic, antiallergic, and analgesic activities [42, 43]. The daily use of the juice M. charantia increases body stamina and prevents chronic fatigue [44, 45]. The juice also minimizes the effect of pyorrhea, improves the human digestive system and is used to cure dyspepsia. According to Ayurvedic medicine it can be used for curing diarrhea caused by cholera [46, 47]. The freshly prepared bitter juice controls blood sugar and insulin levels by enhancing insulin-secreting beta cells in the pancreas and also strengthens the liver during hepatitis. Respiratory maladies such as, bronchitis, sore throat, common cold, and asthma have been cured using the paste of bitter melon leaves [48]. The plant Momordica charantia produces a variety of phytochemicals such as alkaloids, proteins, saponins, steroids and triterpenoids [49]. The cucurbitane-type triterpenoids (19R,23E)-5β,19-epoxy-19-methoxycucurbita-6,23,25-trien-3β-ol (33), (23E)-3β-

H

GlcO

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H

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38 39 40

O

O O

OH

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41

O

H

GlcO

H

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H

AllO

H

O

H

GlcO

H

O

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AllO

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O

OOH

GlcO

H

O

HOH

AllO

H

O

HNO NH2

NH2

O

OOH

HOHO

HO

42 43

44 45 46

47 48 Fig. (8). Cucurbitane-type triterpene glycosides and vicine.


hydroxy-7β-methoxycucurbita-5,23,25-trien-19-al (34), (23E)-3β-hydroxy-7β,25-dimethoxycucurbita-5,23-dien-19-al (35) (19R,23E)-5β,19-epoxy-19,25-dimethoxycucurbita-6,23-dien-3β-ol (36) and (19R,23E)-5β,19-epoxy-19-methoxycucurbita-6,23-diene-3β,25-diol (37) were isolated from the alcoholic extract of the fruit of Momordica charantia (Fig. 7) [50].

Ten cucurbitane-type triterpene glycosides (38-47) were isolated from the fruit extract of M. charantia (Fig. 8) [51]. Vicine (48) isolated from seeds of bitter gourd, has been shown to possess hypoglycemic activity in fasting rats (Fig. 8) [52].

The leave extract of M. charantia produces kuguacin J (49), an active component that increases the sensitivity of vinblastine and paclitaxel in KB-V1 cells by inhibiting the transport function of P-gp (Fig. 9). Triterpenes (50-56) have been isolated from the methanolic extract of the stems of M. charantia (Fig. 9) [53].

The ethanolic extract of the fruit of M. grosvenori contains five oxygenated triterpenes (57-61) and triterpene glycosides (62-71) (Fig. 10). All these compounds (57-71) showed potent inhibitory activity against Epstein-Barr virus-early antigen (EBV-EA) induction (70-100% inhibition at 1 × 103 mol ratio/TPA) [54].

Phytochemical survey of Momordica balsamina

Momordica balsamina is a climbing herb of the family Cucurbitaceae, which is commonly known as African pumpkin and Balsam apple. It is locally known as “Garahuni” [55]. The herb is a monoecious annual plant with unbranched glabrous tendrils. The stem is pubescent to

glabrescent, bearing orbicular leaves 1.5-5.0 cm long. They are cordate, glabrous, sinuate-dentate or acutely lobulate. Flowers of this plant are yellow in color ranging in size from 2.5 to 3.0 cm. Calyx tube size ranges from 5-6 mm long and 3-3.5 mm wide while that of Corolla is 10-15 mm long and 8-10 mm wide. The ovary is fusiform, beaked, puberulous, and longitudinally tuberculate. The fruit is orange-red in colour with a size ranging from 2-7 cm long and 1-2.5 cm wide. Seeds are egg-shaped, 1-1.2 cm long, and 6-7 mm wide.

Different amino acids such as alanine, arginine, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, threonine, tyrosine, serine and valine have been isolated from this plant [56]. Cucurbitane-type triterpenoids, karavilagenin C (72) and cucurbalsaminol C (73) were isolated from M. balsamina and showed moderate activity against chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum (Fig. 11) [57].

These Cucurbitane triterpenoids exhibit an extensive range of biological actions specifically antidiabetic, anti-inflammatory, cytotoxic, hepatoprotective, cardiovascular, and antiparasitic effects [58]. Ramalhetea et al., isolated balsaminol A (74), balsaminol F (75), balsaminagenin A (76), balsaminagenin B (77), balsaminoside A (78) and karavilagenin C (79) (Fig. 12) from M. balsamina [59-61] possessing weak activity against methicillin-resistant Staphylococcus aureus (MRSA) COLOXA with a MIC value of 24 µM; to evaluate their efflux pump activity against Gram-positive and Gram-negative strains at 3 µM were 75 and 79 yielding a slope of 0.88 and 0.90, respectively.

OH

HO OH

HOH

AcO O

H

OH

HO O

H

O

HO O

HOH

HO O O

O

OH

HO OH

HO O

HO OH

HO

49 50 51

52 53 54

55 56 Fig. (9). Triterpene derivatives.


HPhOCO

HO

HHO

HHO

H

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H

HO

OH

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OH

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OGlc

OH

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GlcO

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OH

OH

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OH

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OH

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OH

OGlc-(6-1)-Glc

Glc

H

Glc-(1 -6)-GlcO

HO

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OH

OGlc-(6-1)-Glc

H

Glc-(1 -6)-GlcO

HO

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OH

OGlc-(2-1)-Glc

H

Glc-(1 -6)-GlcO

HO

O

OH

OGlc-(6-1)-Glc

Glc

H

Glc-(1 -6)-GlcO

HO

OH

OH

O

H

HO

O

OGlc

OH

57 58 59

60 61 62

63 64 65

66 67

68 69

70 71

Fig. (10). Triterpenes and triterpene glycosides with antivirus activity.


HO

HO

H

H

H

HO

HO

H

O

OH

H

72 73 Fig. (11). Karavilagenin C and cucurbalsaminol C; Cucurbitane triterpenoids with anti-parasitic activity.

HO

HO

H

OH

H

HO

HO

H

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H

74 76

OH

HO

HO

H

OH

H

HO

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O

H

OH

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OH

O

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H

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OHOH

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HO

75

77 78 79 Fig. (12). Cucurbitane triterpenoids with bactericidal activity.

Balsaminols C–E (80-82) along with cucurbitacins (83-92) isolated from M. balsamina displayed antimalarial activity with IC50 values of 4.6-7.4 µM for 3D7 and 4.0-8.2 µM for Dd2, respectively (Fig. 13) [62].

4. CONCLUSION

In summary, cucurbitaceae is a plant family with great value in the pharmaceutical industry. Different plants show

secondary metabolites such as triterpernoids, alkaloids, and others, which are responsible for biological activity as antidiabetic, antitumoral, antiparasitic, antibacterial, and anti-inflammatory compounds, therefore some substances would be considered useful scaffolds for developing new drugs.


HO

OH

H H

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HO

OH

H H

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OH

H H

O

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OH

H H

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OH

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OH

H H

OH HO

OH

H H

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H H

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H H

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H H

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80 81 82

83 84 85

86 8788

89 90 91

92 Fig. (13). Cucurbitane triterpenoids with antimalarial activity.

Natural Products; Pharmacological Importance of Family Cucurbitaceae Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 8 11 CONFLICT OF INTERESTS

All authors confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

Gildardo Rivera holds a scholarship from the Comisión de Operación y Fomento de Actividades Académicas (COFAA-IPN) and the Programa de Estímulos al Desempeño de los Investigadores (EDI-IPN).

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Received: May 30, 2014 Revised: July 07, 2014 Accepted: July 07, 2014

Natural Products; Pharmacological Importance of Family Cucurbitaceae: A Brief Review

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Transcript of Natural Products; Pharmacological Importance of Family Cucurbitaceae: A Brief Review