Sesquiterpene peroxides

A further support to the antimalarial potential of peroxides may be derived from yingzhaosu A. (39), a sesquiterpene peroxide isolated from Artabotrys undnatus [76]. The structure-activity relationship in the analogues of yingzhaosu has also been studied. The promising members of this class are Ro-40-6772, Ro-41-3823 and Ro-42-1611, which are under detailed biological evaluations [62]. 

Quinghaosu Sesquiterpene peroxide Blood schizontocidal falciparum ... 

Sesquiterpene peroxides, such as yingzhaosu A and C (isolated from roots of Artabotrys uncinatus), have been also shown to have antiparasitic activity against F. berghei [175] (Fig. 20). 

The first examples of linear sesquiterpenic peroxides were isolated in 2006 from an undetermined spedes of genus Sinularia collected in Taiwan. None of these derivatives is cytotoxic (Chao et al., 2006b). 

Chemistry and biological activity of artemisinin (sesquiterpene y-lactone with oxepane fragment and transannular peroxide bridge) and related antimalari-als 99H(51)1681. 

Artemisinin (8) doperoxide sesquiterpene lactone Arterolane (RBX11160, OZ-277) (64) Antiparasitic (antimalarial) Under study (on interation of peroxide moiety with parasite targets) Phase III Ranbaxy 561-565... 

More recently, the sesquiterpene A -isonakafuran-9-hydroperoxide (76) (P2j, O— O = 1.458 A, H—O—O—C = 63.3°, Figure 30) has been isolated from the dichlorometh-ane/methanol extract of the marine sponge Dysidea sp. nov . The peroxide is inhibitory to the marine fungus Trichophyton mentagrophytes and to murine leukemia cells. In view... 

Semen, reactive oxygen species, 612 Sensorial quaUty appreciation, oxidation stabihty, 664 Semm protein oxidative damage, 614 see also Human seram Sesquiterpenes, stractural chemistry, 133-6 SET see Single electron transfer Sharpless epoxidation, allylic alcohols, 789 Shelf durability, peroxide value, 656 Ship-in-the-bottle strategy, chiral dioxetane synthesis, 1176-7... 

Fig. 1.9. Effects of sesquiterpene lactones on European corn borer, (a) Glutathione levels (b) lipid peroxidation synergistic effects of-terthienyl (c) with sesquiterpene lactones from the Asteraceae on larval mortality. Means followed by the same letter are not significantly different in Tukey s test (P < 0.05).

Artemisinin 1, a naturally occurring sesquiterpene peroxy-lactone, has been isolated in up to 0.25% yield from the dry leaves of Artemisia annua L.1 Interest in artemisinin is based on its phytomedicinal properties. In 168 b.c. China, as described in a Treatment of 52 Sicknesses, the leaves of A. annua (Qinghao) were used for the treatment of chills and fever.2 It was not until 1972 that the active antimalarial agent qinghaosu was isolated in pure form. This allowed for the unequivocal elucidation of its structure through the use of x-ray crystallography. This complex tetracyclic peroxide is now referred to as artemisinin in various sources such as Chemical Abstracts or the Merck Index. 

Erickson KL, Beutler JA, Gray GN, Cardellina II JH, Boyd MR (1995) Majapolene A, a Cytotoxic Peroxide, and Related Sesquiterpenes from the Red Alga Laurencia majuscula. J Nat Prod 58 1848... 

More than 11,000 Sesquiterpenes have been isolated from natural sources [3]. Feverfew (Tanacetum parthenium (L.) Sch. Bip.,. Compositae) is a common herb utilized for fever, arthritis and migraine. The leaves of feverfew contain large amounts of sesquiterpene lactones. The chloroform extracts of fresh leaves and a commercial leaf product show dose-dependent inhibiting the production of throboxane B2 (TXB2) and leukotriene B4 (LTB4) in rat and human leukocytes. Sesquiterpene lactones isolated from the leaves of feverfew, such as parthenolide and tanaparthin-a-peroxide, demonstrate potent dual inhibitions of COX and LOX pathways with IC50 for COX at 6 17 pg/ml, and for LOX at 12 17 pg/ml, respectively [135],... 

On the basis of this palladium-mediated three-component coupling reaction, Morimoto and co-workers developed a methodology for the synthesis of two novel modified furanoeremophilane-type sesquiterpenes isolated from Trichilia cuneata, the 13-hydroxy-14-nordehydrocacalohastine 72 and 13-acetoxy-14-nordehydrocacalohastine 73 [75]. These two natural products showed inhibitory activities for membrane lipid peroxidation in mitochon-... 

Artemisinin is used here as an example of a plant sesquiterpenoid with both traditional value as well as with medicinal and social value in the twenty-first century. Research on artemisinin has also established new benchmarks for biochemical engineering and functional genomics of plant terpenoids. Artemisinin is a functionalized sesquiterpene with a unique peroxide linkage from the sweet wormwood Artemisia annua). Chinese herbalists have used it since ancient times, and it is now used for its unique efficacy to treat multidrug-resistant strains of the malaria parasite Plasmodium falciparum. Its medicinal importance has prompted studies into its biosynthesis and its biochemical engineering so that cost-effective methods for producing it in large scale and in consistent quality may be realized. 

Artemisinin (152) is a sesquiterpene lactone with an unusual peroxide bridge. One of the earliest modifications involved catalytic reduction of the peroxide, resulting in loss of one oxygen and total loss of antimalarial activity (196) in the adduct (153). The role of the peroxide bridge in producing antimalarial effects was not fully understood, but it appeared essential for activity, so much of the early work on analogs conserved this structural feature as an empirical finding. The mechanism... 

Qinghao (Artemisia annua L.) is an important medicinal herb, which has h>een used in the Chinese traditional system of medicine for many centuries. In 1972, Chinese scientists isolated (+)-artemisinin (7, qinghaosu) from the above plant, which is indigenous to China [27-30]. Artemisinin is a sesquiterpene lactone peroxide, whose structure and synthesis have been worked out [27,28]. It has marked activity against both chloroquine-sensitive and resistant strains of Plasmodium falciparum and is particularly suitable for treating cerebral malaria as it is very fast acting [29-31]. 

Qinghaosu is a sesquiterpene 1,2,4-trioxane simulating the peroxide linkage, which is an important structural requirement for antimalarial activity. Further, qinghaosu and its synthetic derivatives suffer from various limitations such as high rate of recrudescence, poor oral absorption, short half-life and embiyo-toxicity [65]. These facts led to an intense search for better antimalarials derived from simple 1,2,4-triox-anes (38). This class of compounds have been extensively studied by Jefford et al. [66-69] and others [70-75] some of them show marked in vitro and in vivo antimalarial activities [62,65]. 

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