HETEROCYCLES

Review | Regular issue | Vol. 78, No. 6, 2009, pp. 1413-1426
Received, 28th November, 2008, Accepted, 26th January, 2009, Published online, 28th January, 2009.
DOI: 10.3987/REV-08-651

■ The Diterpenoids from the Genus Hyptis (Lamiaceae)

Franco Piozzi,* Maurizio Bruno, Sergio Rosselli, and Antonella Maggio

Department of Organic Chemistry, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy

Abstract

The genus Hyptis (family Lamiaceae) is known mainly for the essential oils isolated from the aerial parts of several species. Less known are the diterpenoids, extracted from a limited number of species. In consideration of the interest for the structures of this class of compounds, largely occurring in the whole Lamiaceae family, the present paper means to review and update their chemistry. Also the use of many species of Hyptis in folk-medicine is reported.

INTRODUCTION
The genus Hyptis, family Lamiaceae (Labiatae) comprises about 400 species, and is one of the largest genera of the family. It is native of Central and South America, including the southern part of United States.1,2 Now several species were introduced in Western and Central Africa (for instance Cameroon, Nigeria, Burkina Faso, Ivory Coast), and even in India, China, Thailand and Fiji Islands, where they are cultivated specially for the production of essential oils. Moreover, they are important for the ethnopharmacologic point of view.
For this reason, a large number of species was investigated for their content of essential oils, and minor attention was given to other constituents. For instance, the occurrence of diterpenoids was reported only in nine species.

CHEMICAL INVESTIGATIONS
The present paper means to review the isolation and the structures of these products. A total of 66 diterpenoids occurs in the genus, and 26 of them show heterocyclic structures.
The first paper concerning this investigation was published in 1974 and reported the isolation of two novel diterpenoids with the abietane skeleton from the aerial parts of Hyptis suaveolens collected in Trinidad3: suaveolic acid 1 and suavelol 2.
Two years later, three diterpenoids were isolated from the root extract of Hyptis fructicosa harvested in Brazil.4 The first one was identified with the already known horminone 3;5 the second product was new, and was attributed the structure 4 of 14-methoxy-taxodione. The structure of the third product was elucidated the following year6 as 5: it is a new natural compound and was given the name hyptol. All these three diterpenoids have the abietane skeleton, and hyptol 5 show an α,β-unsaturated furanic ring fused with the C-ring of the abietane skeleton.

A diterpenoid with a different skeleton was isolated in 1990 from the leaves of Hyptis salzmanii, growing in Brasil.7 It was given the name salzol and the structure 6 of 6,7,8-trihydroxy-20-benzoyloxy-isopimarane.
In the same year the roots of Hyptis umbrosa from Brazil8 yielded an unusual product, with a rearranged abietane skeleton, named umbrosone. The elucidation of the structure 7 rested on deep NMR investigations.
The aerial parts of Hyptis dilatata, collected in Panama,9 proved to be very rich in diterpenoids. The paper published in 1998, based on extensive chromatographic fractioning, reported the isolation of three known abietane compounds from the first fraction: carnosol 8,10 rosmanol 9,11,12 methylrosmanol 10.13,14 The treatment of the following fractions required acetylation and diazomethane treatment: many known abietane derivatives were isolated: diacetyl-carnosol 11,10,11 triacetyl-rosmanol 12,11,13 diacetyl-methylrosmanol 13,13 diacetyl-ethylrosmanol 14,14 triacetyl-isorosmanol 15,15 triacetyl-epirosmanol 16,12 diacetyl-carnosic acid 17,14,16 diacetyl-carnosic acid methylester 18,17 acetyl-pisiferic acid methylester 19.16,18 Two not previously described derivatives were identified: diacetyl-epimethylrosmanol 20 and diacetyl-epiethylrosmanol 21.
It must be evidenced that the nine abietane 11-21 are not authentic natural products, but derivatives originating from the acetylation/diazomethane treatment: the diterpenes originally occurring before the treatment are carnosol 8, rosmanol 9, methylrosmanol 10, but evidently also ethylrosmanol 22, isorosmanol 23, epirosmanol 24, epimethylrosmanol 25, epiethylrosmanol 26, carnosic acid 27, pisiferic acid 28, all not acetylated or partially acetylated products. These true natural products 22-28 were not isolated.

Many of the diterpenoids isolated from Hyptis dilatata show heterocyclic rings of 20,6- and 20,7-lactones.
Also the known19 heterocyclic 20,11-lactone 29 was isolated. All the 8-29 products show the abietane skeleton. Another known compound, diacetyl-esquirolin B 3020 was also isolated, but it has an isopimarane skeleton (not pimarane, as written in the original paper). Probably, also in this case, the plant contained the non-acetylated esquirolin B 31.
Seven new products have been isolated from the aerial parts of Hyptis spicigera occurring in Mexico,21 and popularly known as “hierba del burro”. It is remarkable that these compounds show a different skeleton, as they are labdane derivatives. They were not given trivial names. On the basis of spectroscopic determinations and functional groups chemical modifications they were attributed the following structures. The first product has the structure 32 of 19-acetoxy-2α,7α,15-trihydroxy-labda-8(17),(13Z)-diene. The other new products are 15,19-diacetoxy-2α,7α-dihydroxy-labda-8(17),(13Z)-diene 33; 7a,15,19-triacetoxy-2α-hydroxy-labda-8(17),(13Z)-diene 34; 19-acetoxy-2α,7α-dihydroxy-labda- 8(17),(13Z)-dien-15-al 35; 19-acetoxy-7α,15-dihydroxy-labda-8(17),(13Z)-dien-2-one 36; 19-acetoxy-2α,7α-dihydroxy-labda-14,15-dinor-labd-8(17)-en-13-one 37; 2α,7α,15,19-tetrahydroxy-ent-labda-8(17),(13Z)-diene 38. It is remarkable that product 38 has the ent-labdane skeleton, whereas the 33-37 products have the normal labdane backbone.

Three diterpenoids, also in this case with the labdane skeleton, have been found in the aerial parts of Hyptis fasciculata collected in Brazil.22 The first product was identified as the known23 methoxynepetaefolin 39, showing four oxigenated rings, whilst the others are new natural products, 15β-methoxyfasciculatin 40 and 15α-methoxyfasciculatin 41, both also rich in oxigenated rings.
A recent paper24 reports on the investigation of the roots of Hyptis platanifolia, again from Brasil. Five abietane derivatives were isolated: two of them are the known inuroyleanol 4225 and coulterone 43,25 whilst new products are 19-oxo-inuroyleanol 44, 11,14-dihydroxy-12-methoxy-7-oxo-8,11,13-abietatrien-19,20β-olide 45 and 19,20-epoxy-12-methoxy-11,14,19-trihydroxy-7-oxo-8,11,13-abietatriene 46, the last as a diastereoisomeric mixture at the 19-hydroxy group. No trivial names were given to these new products. Both products 45 and 46 have a lactone or lactol 20,19-ring.

Another species from Northeastern Brazil is Hyptis martiusii, popularly known as “cidreira-do-mato”, whose roots were investigated. A paper26 reported the isolation of two known diterpenoids: carnosol 810 and 11,14-dihydroxy-8,11,13-abietatrien-7-one 47.27 In a second paper28 some new diterpenes were described: 12-O-methyl-carnosic acid 48, the structurally interesting 7-seco-7(20),11(20)-diepoxy-7,14- dihydroxy-abieta-8,11,13-triene 49, and a product 50 with a rearranged abietane skeleton, designated as martiusane. In continuation29 two more abietane diterpenes were found: the known 7α-acetoxy-royleanone 5130 and the new 7β-hydroxy-11,14-dioxo-abieta-8,12-diene 52.

An abietane diterpenoid with high antiplasmodial activity was isolated31 from the leaves of Hyptis suaveolens collected in Nigeria. It has the structure 53 of 9α,13α-epi-dioxiabiet-8(14)-en-18-ol. The same product had been isolated from Cedrus atlantica.32
The 1-53 diterpenoids here listed were isolated from the aerial parts or from the roots or from the whole plant. A large number of investigations on the essential oils of this genus was performed for the identification of their components, almost exclusively mono- and sesquiterpenes. However in one case also the occurrence of minor amounts of some diterpenes was detected.
This the case of the oil from Hyptis suaveolens, largely studied. A first paper33 on material collected in Venezuela quoted the presence of three unidentified diterpenes. In a sample of the oil from Malaysia the GC analysis indicated the occurrence of six unidentified diterpenes.34 In a sample of oil from Nigeria35 the occurrence of a diterpene hydrocarbon was reported, indicated as 5βH,8βH,9βH,10α-labd-14-ene 54 but no structural formula was given. Two diterpenes, 8,11,13-abietatriene 55 and 8,11,13-abietatrien-18-ol 56 (syn. dehydroabietol, dehydroabietinol) were identified in the oil from Kumaon, India.36 Particularly rich in diterpenoids was the oil from Cameroon:37 biformene 57, atisirene 58, rimuene 59, abietatriene 55, phyllocladene 60, abietinol 61 (syn. abietol), dehydroabietol 56 and the linear diterpene phytol 62 were identified. The oil from North India38 contained abietadiene 63, abietatriene 55 and dehydroabietol 56. Many products occurred in the oil from Alfenas (Brazil):39,40 abietatriene 55, abietadiene 63, abieta-7,13-dien-3-one 64, abietinol 61, 4-epi-abietinol 65,41,42 dehydroabietol 56, manoyloxide 66. Remarkable differences were observed in the content of diterpenes (and also of monoterpenes and sesquiterpenes) depending on the geographical origin of the oil and on the season of harvesting.

As far as we know, no occurrence of diterpenoids in other oils is reported in the literature.
Concerning the structure of these diterpenoids, it can be remarked that they show the abietane or the labdane skeleton prevalently; only few have different skeleta.

BIOLOGICAL ACTIVITY AND PHARMACOLOGY
The most diffused utilization of species belonging to the Hyptis genus is related to their essential oils, obtained, also in industrial scale, from several species. Such oils are largely used in cosmetics and flavouring and as insecticides and insect repellents. Dried whole plants are used for pest control. Oils, parts of plants and extracts find diffused application in ethnopharmacology of tropical countries.
About the biological activities and related pharmacology, wide information is reported in a review2 and references therein. Rarely such activities were attributed to single diterpenoids2,21,26,29 or to the whole mixtures of terpenoids, but usually to the oils or to the extracts in different solvents. In the case of H. martiusii, the cytotoxic and antimitotic activity was tested on the pure diterpenoids.26,29 The diterpenoids from H. spicigera inhibit the larval growth of the European corn borer.21
Therefore, many reports are concerned with activities as expectorant, antihelmintic, antibacteric, antimicrobic, antiviral, antibiotic, antimicotic, antiseptic, antimalaric, antidolorific, anticonvulsive, antioxidant, cytotoxic, anti-tumour. Preparations are used against gastrointestinal disorders, fevers, grippe, cough, asthma, cramps, conjunctivitis, depression, and the most various ailments.
The extract of H. spicigera shows antimicrobic, phytotoxic and antifungine properties, and cytotoxic activity on KB cells 45.21 The powdered plant is used as insecticide in Africa.43
The ethanolic extract of H. umbrosa has a significant antimicrobic activity.8 Also the methanolic extract of H. salzmanii is active against Staphylococcus aureus, Bacillus subtilis, Candica albicans and Mycobacterium smegmatis.7 The methanolic extract of H. albida is active against C. albicans and other Gram-positive and Gram-negative bacteria,44 and used in Mexico against gastroenteric diseases.45
Some Hyptis species are active against schistosomiasi.46
The essential oil of H. mutabilis has antiulcerogenic activity,47 and the essential oil of H. lanceolata shows antifungine properties.48 Extracts of leaves of H. mutabilis are used in Mexico and Brazil against malaria and numberless ailments.47,49
The oil from H. pectinata has insecticide50 and antiseptic51 activity. Extracts of H. pectinata have antimicrobic, antibacteric activity44,51 and are cytotoxic against various cancer cells;51 the aqueous extract is antinociceptive and antiedematogenic.52 It is widely used in Mexico and West Africa.53
The methanolic extract of the roots of H. fructicosa shows antibacteric and anti-tumour activity.4,54
Terpenoids from H. emoryi have been investigated as antifertilizing agents55 and tumour-inhibitors.56 A triterpene from H. romboides is cytotoxic in vitro against cells of human hepatome HS-G2.57
Extracts of the whole plant of H. capitata are reported to be active against HIV, leucemia, many species of cancer, and to have anti-inflammatory, anti-arthritic, anti-diabetic, anti-ulcera, anti-artheriosclerosy properties.58
H. verticillata has various activities: insecticide, acaricide,59 anticancer,60 anti-inflammatory, cytotoxic, antimitotic,61 antimicrobic.44
The most investigated species is certainly H. suaveolens, largely employed in ethnomedicine of Mexico, Brazil, Central and South America, West Africa, India. Roots, leaves, flowers are commonly used. The oil is active as antimicrobic,35,62,63 antibacteric,64 fungicide,35,48,65 larvicide against Aedes aegypti, and also against Vibrio cholerae.66 A tea prepared from the roots is used as stomachic67 in India. The aqueous extract has antinociceptive activity.68
A recent paper69 reported the anti-inflammatory activity of suaveolic acid (1) and suavelol (2) occurring in Hyptis suaveolens collected in El Salvador; these diterpenoids had been isolated previously3 from the same species.

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