Constituentes Químicos De Morinda Citrifolia (Noni)

Morinda citrifolia L. (Rubiaceae), commonly called Noni or Indian mulberry, is a small evergreen tree or shrub of Polynesian origin.1 M. citrifolia bears a lumpy, green to yellowish-white fruit, normally 5 to 10 cm in length, with a surface covered in polygonal-shaped sections.1,2 M. cit- rifolia has a long history of use as a medicinal plant in parts of Southeast Asia, Polynesia, and Australia and is considered to be the second most important medicinal plant in the Hawaiian Islands.1,3 The leaves, roots, bark, and fruits have all been used medicinally to treat a wide range of ailments. These include, but are not limited to, diabetes, diarrhea, hypertension, malaria, pain, and topical infec- tions.1,4 The fruits are also eaten as a food, but primarily only in times of famine.4

Today, the use of M. citrifolia in the United States is becoming more widespread and Noni products are com- mercially available in health food stores, chain grocery stores specializing in natural foods, and on the Internet. Both the leaves and the fruits are being sold in tablet, tea, and juice form, although the fruit as a juice is the predominant formulation sold. This growth in popularity in the United States may in part be attributed to claims of Noni being a “cure-all” or aid in relieving symptoms for a host of chronic conditions such as arthritis, cancer, diabe-

effect that was increased when given in conjunction with several chemotherapeutic agents.10 Currently, a freeze- dried Noni fruit extract is in phase I clinical trials at the Cancer Research Center of Hawaii in cancer patients for which there is no other standard treatment available. The aim of this trial is to determine if Noni extract can be useful to cancer patients for antitumor and/or symptom control.11 To date, the major chemical constituents of this plant have been found to be anthraquinones,12 flavonol glyco- sides,13 iridoid glycosides,13,14 lipid glycosides,15 and trit- erpenoids.14 In the present study, the n-BuOH-soluble

partition part of the MeOH extract of M. citrifolia fruits was found to have moderate antioxidant activity in a free- radical (DPPH) scavenging bioassay. This partition was purified by repeated chromatography, which led to the isolation of two new iridoid glucosides, 6R-hydroxyadoxo- side (1) and 6â,7â-epoxy-8-epi-splendoside (2), and 17 known compounds. All isolates obtained in this study were evaluated for their antioxidant activity, and the neolignan, americanin A (3), demonstrated significant antioxidant activity in two antioxidant bioassays.

Compound 1, [R]23D -50.7° (c 0.28, MeOH), was obtained as a colorless gum by repeated chromatography and finally purified by reversed-phased HPLC. A molecular formula

tes, and hypertension.1 A number of in vitro biological

of C H O

was established for 1 on the basis of the

17 26 11

activities have been reported, such as angiogenesis inhibi-

observed sodiated molecular ion peak at m/z 429.1378 [M

tion,5 antioxidant,6 cyclooxygenases-1 and -2 inhibition,7,8

+ Na]+ in its HRESIMS (calcd for C H

O Na, 429.1373).

17 26 11

and tyrosine kinase inhibition.9 Most of these studies have

involved crude extracts or fractions of M. citrifolia, and the compound(s) responsible for the biological activities have not been determined. In addition, an in vivo study using the ethanol-insoluble precipitate of M. citrifolia fruits, given intraperitoneally to mice with Lewis lung carcinoma implanted cells, demonstrated a significant life-prolonging

* To whom correspondence should be addressed. Tel: +1-614-247-8094.

Fax: +1-614-247-8081. E-mail: kinghorn.4@osu.edu.

† Program for Collaborative Research in the Pharmaceutical Sciences.

‡ Present address: The Ohio State University.

§ The Ohio State University.

Nature’s Sunshine Products, Inc.

The IR absorption bands at 3355 and 1692 cm-1, respec- tively, indicated the presence of hydroxyl groups and a carbonyl group in the molecule. The characteristic 1H NMR (in CD3OD) signals at δH 7.46 (1H, d, J ) 1.2 Hz, H-3), 5.15 (1H, d, J ) 6.0 Hz, H-1), and 4.65 (1H, d, J ) 7.9 Hz,

Glc-1) and 13C NMR (in CD3OD) signals at δC 169.5 (C, C-11), 153.1 (CH, C-3), 113.0 (C, C-4), 100.6 (CH, Glc-1),

and 99.1 (CH, C-1) suggested that compound 1 is an iridoid glucoside.16,17 The observed HMBC correlation from the anomeric proton (Glc-1) of glucose to the acetal carbon at δC 99.1 (C-1) indicated that the location of the glucose unit is at C-1 in the molecule of 1. The presence of a methyl

10.1021/np0495985 CCC: $30.25 © 2005 American Chemical Society and American Society of Pharmacognosy Published on Web 03/22/2005

ester group at C-4 was readily assigned on the basis of the chemical shifts of H-3, C-3, C-4, and C-11, as well as the observed correlations from both H-3 (δH 7.46) and the methoxy (δH 3.69) signals to the carbonyl carbon (δC 169.5) in the HMBC spectrum of 1. Generally, the five- and six- membered rings of iridoids are cis-fused,18 although a few trans-fused iridoids also have been reported.16,19 The chemical shifts of C-1 are about 103 ppm and 96-100 ppm for trans- and cis-fused iridoids, respectively.16 Therefore, the rings are cis-fused in the molecule of 1, since the C-1 signal was detected at 99.1 ppm in the 13C NMR spectrum of this isolate. Further analysis of the observed 2D NMR (1H-1H COSY, HMQC, and HMBC) correlations indicated the gross structure of compound 1 to be 6-hydroxyadoxo- side.16,17 A literature survey revealed that 6â-hydroxya- doxoside has been previously isolated from Bessaya plan-

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