Manoyl oxide derivatives

The aerial parts of Conyza steudellii (Asteraceae) have given new labdane xylosides, while from the leaves of Conyza trihecatactis, a xylopyranoside of 13-epi-sclareol has been isolated among other labdanes [104,105]. Havardic acids A-F (as methyl esters), have been isolated from another genus of the Asteraceae family, i.e Grindelia havardii [106]. 11-oxo-manoyl oxide derivatives and coleosol, which is also a manoyl oxide derivative, have been obtained from Coleus forskohlii (Labiateae) [107,108] while from another plant of the Labiatae family, Roylea calycina a tumor inhibitory compound, namely precalyone, as well as calyone have been isolated [109]. 

The study of manoyl oxide derivatives i.e. 7 and 8 in, Fig (7), (i.e ent-hydroxy and en/-acetoxy-3(3-manoyl oxides) isolated from Cistus creticus, by GC-MS resulted in only one peak indicative of the purity of the products [33]. From the H-NMR data it is clear that the 13-epi isomer was present in both derivatives [58,139]. The chromatographic data of the compounds 7 and 8 were recently published [33,63]. Hence, investigations have proven that, apart from the 13-epi isomer, there are more isomers with varying intensities, which correspond to isomers that arise from the different configuration of C-8 chiral center [33]. This isomer showing a different configuration at C-8 has been isolated from the volatile leaf oil of Alaska (yellow) cedar and its structure has been confirmed using spectroscopic methods as well as chemical reactions [150],... 

The most important manoyl oxide derivative is forskolin (9), Fig. (7), (7p-acetoxy-8, 13-epoxy-la, 6p, 9a-trihydroxylabd-14-en-ll-one) [151-153]. It belongs to the labdane series of diterpenes and was isolated from the Indian herb Coleus forskohlii (Willd.) Briq. (Labiatae). Since ancient times it has been used in Hindu and Ayurvedic traditional medicine [154]. The plant Coleus forskohlii (Willd.) Briq. has been extensively studied, and from its extracted roots a group of diterpenoids, with the basic skeleton of 11-oxo-manoyl oxide, have been isolated. The main compound, forskolin, presented remarkable chemical and biological properties [155]. Analogues of forskolin were then prepared by semisynthesis [156] or obtained by microbial transformations [157]. New analogues, more soluble than forskolin have shown activities comparable to and even higher than forskolin [158]. 

Calyone (27) and precalyone (28), the latter showing tumour inhibitory activity, have been isolated from Roylea calycina (Labiatae), and coleosol (29) is a manoyl oxide derivative which has been isolated from another of the Labiatae used in folk medicine. Coleus forskohlii ... 

Sclareolide 31, a minor constituent of some plant extracts, can be prepared by oxidation of sclareol or manoyl oxide derivatives. The microbial oxidation of sclareolide by M. plumbeus ATCC 4740 was less productive than the oxidation of sclareol, but afforded, beside 3 (3-hydroxy and 3-keto derivatives, a small amount of l 3-hydroxy sclareolide [18]. Similar results and, in addition, the formation of 1,3-dihydroxylated derivatives have been obtained by incubation with Curvularia lunata, in higher conversion yields [35]. Cephal-osporium aphidicola, a fiingus producing the hydroxylated diterpenoid aphidicolin, was shown to hydroxylate sclareohde at the 3 position and, in addition, to afford a 33,6p-dihydroxylated derivative in substantial yields [36]. 

Some new diterpenoid oxides have been obtained from Eupatorium jhanii. They are jhanol (12) and its 18-acetate together with jhanidiol (13) and its 18-monoacetate and diacetate. Their structures were established by correlation with manoyl oxide and by an examination of their C n.m.r. spectra. 11/3-Hydro-xymanoyl oxide (14) has been isolated from Juniperus oxycedrus ° A group of new 11-oxomanoyl oxide derivatives (15a—e) has been obtained from Coleus forskohlii (Labiatae). Their oxygenation pattern is reminiscent of that of the tricyclic diterpenoids which have beemobtained from other Coleus species. 

Ent -3p-hydroxy 13-epi-manoyl oxide (7) (ribenol), Fig. (7), has been used as starting material for a biotransformation process by Curvularia lunata. The in vitro micropropagation of the Sideritis foe tens species has been described and several entananoyl oxide derivatives, as well as other labdanes, have been isolated from micropropagated plants. Recently, biotransformation by Curvularia lunata of some en/-l 3-e/n-manoyl oxides functionalized at C-3 or C-3 and C-12 produced derivatives, which inhibited the growth of the pathogenic protozoa, Leishmania donovani [130],... 

Apart from forskolin, a number of other manoyl oxides have been shown to interact with the AC enzyme system. Biotransformation of certain ent- 3-epi-manoy oxides by Curvularia lunata resulted in compounds functionalized in C-3 or in C-3 and C-12, which exhibited an AC stimulatory effect, although milder than that of forskolin (about 30 times less) [173]. The same activity was also ascribed to some synthetic derivatives of en/-8a-hydroxy-13 (16), 14 dien-18-oic acid methyl ester [178,179], The biotransformation of ent-manoyl oxide-16-hydroxy 18-oic acid methyl ester with Rhizopus nigricans, however, resulted in carbomanoyl oxide which showed a selective inhibitory action on the activity of adenylate cyclase depending on the material initially used to stimulate the enzyme. This manoyl oxide inhibited the activity of the enzyme previously stimulated by forskolin but not by glucagon. A manoyl oxide ent-3fi, 6/ -dihydroxy-13-e/ z-manoyl oxide) which also inhibited the activity of AC, was produced from the biotransformation of... 

Data submitted for publication. The study concerns the effect of the thiomidazolide derivative of enf-3p-hydroxy manoyl oxide and of sclareol on the expression of the two oncogenes in two leukemic cell lines, where an apoptotic effect was also observed... 

X0-14-norlabdanes derived from the ozonolysis of methyl communate have been clarified. Copaifera multijuga contains copaiferolic acid and a new labdane acid, ll-hydroxylabda-8(17),13-dien-15-oic acid. The leaf oil of Chamaecyparis nootkatensis contains two new manoyl oxides. They have been assigned the... 

The cyclization reactions of manool derivatives have continued to attract attention. A synthesis of the strobane skeleton based on oxymercuration reactions of 13-epimanool has been described. The oxidation of sclareol by chromium salts has been re-examined in a series of papers. The circular dichroism curves of manoyl oxide and its 13-epimers have been examined. Some further 11-oxomanoyl oxide derivatives, coleonol E and F, (13) and (14),... 

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