Medicinal Annonaceae

The evidence currently available strongly suggests that members of the family Annonaceae hold some potential as sources of proapoptotic agents. Of particular interest in this regard is the genus Goniothalamus. The main macroscopically botanical characteristics to look for in field collection of Goniothalamus are treelets or shrubs with smooth, thin, and fibrous bark; aromatic wood; simple, alternate, and exstipulate leaves, with long glossy blades, and without obvious secondary nerves; a triangular thalamus or receptacle; and a perianth, which consists of a calyx, and two series of three greenish petals that are veined and somewhat woody (Fig. 101). Lens examination of the corolla shows that the inner whorl of the petal is smaller than the outer one and is fused in a vault above the androecium. The fruits are one- to two-seeded ripe carpels that are olive green and smooth.

Within the Annonaceae, Goniothalamus species are thought to have evolved from the tribe Uvariae, from which they have possibly inherited the ability to elaborate styryl-lactones and acetogenins, the former possibly being present in several other genera in the tribe Annoneae and known to occur in other Magnoliidae, including the Laurales and Piperales.

Qoniothalamus species. Six Goniothalamus species are used in the traditional medicinal Asian system, and most of these have been used in Malaysia in connection with

abortion and childbirth since very early times. The leaves of Goniothalamus macrophyl-lus Hook. f. & Thoms. are used to abrogate fever, and a decoction of the roots is given as a postpartum remedy and to cause abortion. The roots of Goniothalamus giganteus Hook. f. & Thoms. (Fig. 102) are used to abort and treat colds, and the heated leaves are applied to swellings. A decoction of Goniothalamus scortechinii King is given as a postpartum protective remedy. The roots of Goniothalamus tapis Miq. (Fig. 103) are used as an abortifacient during early months of pregnancy. In Indonesia, an infusion of the roots is used to treat typhoid fever. In Taiwan, the seeds of Goniothalamus amuyon Merr. are used to treat scabies. In the Philippines, the seeds are used to treat rheumatism and tympanites, and the fruit is stomachic. None of the uses mentioned here has been substantiated yet via pharmacological experimentation; however, these species are well-known for their phytochemical constituents, as all six have been phytochemically investigated. Most phytochemical reports found so far on Goniothalamus species deal with the chemical constituents of Goniothalamus giganteus Hook. f. & Thoms. Phytochemical studies on Goniothalamus species have resulted, so far, in the isolation of two major classes of lipophilic secondary metabolites: aceto-genins and styryl-lactones, both possessing complex stereochemistry and existing in different stereoisomeric forms with varying levels of toxicity toward several human tumor cell lines.

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Fig. 103. Goniothalamus tapis. From Flora of Malaya. FRI No 19803. Geographical localization: Le Song F.R. Pahang, low undulating seasonal swamp primary forest, alt: 100 feet. Det: Y. C. Chan.

Irrespective of the presence of a large variety of cytotoxic acetogenins and styryl-lactones in the genus Goniothalamus, only 19 species out of 160, or 12%, of species have been phytochemically investigated to date, namely Goniothalamus amuyon Merr., Goniothalamus andersonii J.Sincl., Goniothalamus arvensis Scheff, Goniothalamus borneensis Mat-Salleh, Goniothalamus cardiopetalus Hook. f. & Thoms., Goniothalamus cheliensis. Hu, Goniothalamus donnaiensis Finet & Gagnep., Goniothalamus gardneri Hook. f. & Thoms., Goniothalamus giganteus Hook. f. & Thoms, Goniothalamus griffithii Hook. f. & Thoms, Goniothalamus leiocarpus (W.T.) Wang P.T.Li, Goniothalamus malayanus Hook. f. & Thoms, Goniothalamus montanus J.Sincl., Goniothalamus scorte-chinii King, Goniothalamus sesquipedalis Hook. f. & Thoms., Goniothalamus tapis Miq., Goniothalamus thwaitesii Hook. f. & Thoms, Goniothalamus uvaroides King., and Gonio-thalamus velutinus Airy Shaw.

Note that both acetogenins and styryl-lactones are cytotoxic for mammalian cells, as the result of distinct biochemical pathways, which, however, have their molecular origin near or in the mitochondrial membrane and/or the mitochondrial respiratory system (61,62). Acetogenins were first characterized as the active principles responsible for

Fig. 104. Examples of cytotoxic acetogenins from Goniothalamus species.

Gardnerilin B

Fig. 104. Examples of cytotoxic acetogenins from Goniothalamus species.

shrimp lethality from the bark of Goniothalamus giganteus Hook. f. & Thoms. collected from Thailand. Extract of the bark showed toxicity in the brine shrimp test and showed murine cytotoxicity in the 3PS (P388) leukemia bioassay (63).

From the crude ethanol of the bark of Goniothalamus giganteus Hook. f. & Thoms., a series of cytotoxic acetogenins were isolated, including giganin, goniothalamicin, annonacin, gigantriocin, gigantetrocin, gigantrionenin, giganenin and gonionenin, goniodenin, asimilobine, gigantecin, bullatalicin, bullatalicinone cis-giantrionenine, 4-acetylgigantetrocin A and gigantransenins A, B, and C, pyranicin and pyragonicin, goniotrionin, goniotetracin, and 2,4-cis- and trans-gonioneninone (64-71). Gigantransenins A, B, and C showed selective inhibitory effects on the human breast tumor cell line (MCF-7) comparable with the potency of adriamycin (68). Pyranicin and pyragonicin were selectively cytotoxic against the pancreatic cell line (PACA-2) in a panel of six human solid tumor cell lines, with pyranicin showing 10 times the potency of adriamycin, whereas goniotrionin was more potent against MCF-7. Both goniotetracin and 2,4-cis- and trans-gonioneninone are selectively and significantly cytotoxic to the human pancreatic tumor cell line (PACA-2).

Goniodonin and 34-epi-goniodonins were isolated from Goniothalamus donnaiensis Finet & Gagnep. collected from Guangxi Province, China (72). Gardnerilins A and B from Goniothalamus gardneri Hook. f. & Thoms. collected from DiaoLo mountain, Hainan Province, China, gave cytotoxic IC50 values against Bel 7402 human tumor cell lines of 3.6 and 8.5 pg/mL, respectively (Fig. 104; refs. 73-75).

Fig. 105. Examples of cytotoxic styryl-lactones from Goniothalamus species.

In regard to the precise molecular mode of action of acetogenins, there is an expanding body of evidence to suggest that both tetrahydrofuran or tetrahydropyran rings and/or hydroxy groups, which are hydrophilic, and the hydrocarbon chains, which are hydrophobic, moor the molecules by anchoring the mitochondrial membrane outside and inside, respectively. The pharmacophores, i.e., the lactones, are therefore secured and interact with the complex I (nicotinamide adenine dinucleotide [NADH]-ubiquinone oxidoreductase) in the mitochondrial electron transport system and abrogate the survival of cancer cells by asphyxiation (61).

Jewers et al. first reported goniothalamin (Fig. 105) as the active constituent of the bark of Goniothalamus andersonii J. Sincl., Goniothalamus macrophyllus Miq., and Goniothalamus malayanus Hook. f. & Thoms. collected in the peat swamp of Sarawak, Malaysia (75). Styryl-lactones such as goniothalamin have since attracted a great deal of interest on account of their ability to inhibit the mitochondrial respiratory chain and to induce apoptosis (76-83). An additional example of an apoptogenic styryl-lactone is altholactone characterized from Goniothalamus arvensis Scheff. collected in the

National Park of Variant in the central province of Papua New Guinea, and from the Goniothalamus borneensis Mat-Salleh collected in Malaysia (84). An additional example of a cytotoxic styryl-lactone is cardiopetalolactone characterized from the stem bark of Goniothalamus cardiopetalus Hook. f. & Thoms. collected from the Palaruvi forest in Kerala, India, with altholactone, goniopypy-rone, cardiobutanolide, goniothalamin, goniodiol, goniofufurone, and goniofupy-rone (85,86). 8-Acetylgoniofufurone, 7-acetylgonio-pypyrone, 5-acetylgonio-pypyrone, goniofu-furone, goniopypyrone, goniothalamin, goniothalenol, (+ )-isoaltholac-tone, goniodiol, 7-acetylgoniodiol, goniotriol, 8-acetylgoniotriol, and 9-deoxygo-niopypyrone were isolated from the roots of Goniothalamus griffithii Hook. f. & Thoms. (87). An isomer of altholactone, (+ )-isoaltholactone was isolated from stem bark of Goniothalamus malayanus Hook. f. & Thoms, from the leaves of Gonio-thalamus montanus J. Sincl., and the roots of Goniothalamus tapis Miq. (88). Gonio-lactones A through F were identified from the roots of Goniothalamus cheliensis Hu, among which was goniolactone B, exhibiting significant cytotoxicity against A2780, HCT-8, and KB cells with IC50 values of 7.40, 4.43, and 7.23 ^M, respectively (89).

Digoniodiol, deoxygoniopypyrone A, goniofupyrone, goniothalamin, deoxygoniopypy-rone A, gonodiol-8-monoacetate, and gonotriol were characterized from the aerial parts of Goniothalamus amuyon Merr. collected in the southern part of Taiwan near the coastal regions (90,91). The petroleum ether extract of the stem bark of Goniothalamus sesquipedalis Hook. f. & Thoms. collected in Bangladesh afforded goniothalamin, isogonio-thalamine oxide, 5-acetoxygoniothalamine, and 5-acetoxygoniothalamine oxide (92). 5-Acetyl goniothalamin was characterized from Goniothalamus uvaroides King collected in Bangladesh (93).

Altholactone is apoptogenic in HL-60 promyelocytic leukemia cells via oxidative stress (94). Goniothalamin is cytotoxic against the HepG2 cancer cell line, with IC50 values in the range of 0.19 to 0.64 (ig/mL, and abrogates the survival of cancerous (HGC-27, MCF-7, PANC-1, HeLa) and non-cancerous (3T3) cell lines time-and dose-dependently (82,95). Goniothalamin induces apoptosis in Jurkat T-cells by the activation of the enzymatic activities of effector caspases-3 and -7 (82). Current paradigms of apoptosis suggest that the loss of mitochondrial transmembrane potential occurs earlier in the commitment phase of apoptosis, which results in the release of mitochondrial apoptogenic proteins—and possibly inhibition of the respiratory chain—including cytochrome c, which in the presence of ATP, interacts with Apaf-1, resulting in the activation of caspases 9 (a cysteine pro-teinase). This, in turn, activates effector caspases such as caspases-3 or -6, hence cell death. Note that styryl-lactones inhibit the mitochondrial respiratory chain in mammalian cells.

A critical factor for Goniothalamus use as a medicinal herb is its content of styryl-lactones, which promote apoptosis in mammalian cells. One might set the hypothesis that the abortifacient and/or postnatal and anti-inflammatory traditional uses of Goniothalamus

Fig. 106. Pseudouvaria setosa. Herb Hort. Bot. Sing. Geographical localization: Raub Pahang. Date: 4/19/1932. Field collector: Osman. Det: J. Sinclair 2/8/1949.

species might involve styryl-lactones because apoptosis is known to play a crucial role in trophoblasts of patients with recurrent spontaneous abortion of unidentified cause, and in T-cells in the human decidua as defense mechanism against rejection of fetal allograft by the maternal immune system (96,97).

Pseudouvaria setosa (King) J. Sinclair (Orophea setosa King) is a small tree that grows wild in the primary rainforests of Thailand and the northern part of peninsular Malaysia. The young stems, petioles, leaf margin, lower midrib, and secondary nerves are covered with irritating hairs. The leaves are simple, exstipulate, and alternate and membranaceous, 11-16 cm X 4.5-7 cm. The blade is oblong to oblong-oblance-olate and shows 12-13 pairs of secondary nerves prominent beneath. The flowers are solitary on a 1.8-2-cm-long pedicel. The sepals are minute and suborbicular. The corolla consists of two series of petals which are white with pink bases, ovate, and pubescent. The inner petals are 6 mm long, and united iat apex into a vault. The fruits are one to six globose, ripe carpels that are grayish-yellow and tomentose and up to 2 cm in diameter (Fig. 106).

The roots are chewed by Malays to treat cough. The roots are boiled then reduce into a powder form, which is applied externally to reduce fever. The leaves are part of a mixture eaten with sireh to promote libido. The pharmacological properties of Pseudouvaria setosa (King) J. Sincl., and of the genus.

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Pseudouvaria in general, is unknown. Note that the Pseudouvaria species, and Uvariae in general, have the interesting tendency to elaborate C-benzylated chalcones, which induce apoptosis. Examples of such flavonoids are triuvaretin and isotri-uvaretin, uvaretin, isouvaretin, diuvaretin, and angoluvarin from Uvaria leptocladon and Uvaria angolensis (98-100). Uvaretin and diuvaretin from Uvaria acuminata abrogated the survival of human promyelocytic leukemia HL-60 cells cultured in vitro with chromatin degradation and condensation arrest of cells in G1 phase and activation of caspase-3 (101,102).

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