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Bullatacin, isolated from the fruit of Annona atemoya, is one of the most potentially effective antitumor annonaceous acetogenins. Bullatacin was studied here for its ability to inhibit the proliferation of 2.2.15 cells, hepatitis B virus (HBV) DNA transfected human hepatocarcinoma cell line. It was found that bullatacin induced cytotoxicity of 2.2.15 cells in a time- and dose-dependent manner. Fifty percent effective dose (ED50) on day 1 of exposure to bullatacin were 7.8 +/- 2.5 nM for 2.2.15 cells. [3H]-Thymidine incorporation assays showed almost the same results. Bullatacin-treatment also reduced concentrations of hepatitis B surface antigen (HBsAg) in the cultured medium released from 2.2.15 cells, coincident with the decrease in the cell proliferation. Analysis of mophological changes of bullatacin-treated 2.2.15 by inverted phase-contrast microscope and eletron microscopy revealed a possible model of action for bullatacin to inhibit proliferation of 2.2.15 cells by inducing apoptosis. Most of the bullatacin-induced cell death was found to be due to apoptosis, as determined by double staining with fluorescein-isothiocyanate (FITC)-labeled annexin V and propidium iodide (PI).

Seven new annonaceous acetogenins, muricins A-G (1-7), as well as five known compounds, a mixture of muricatetrocin A (8) and muricatetrocin B (9), longifolicin (10), corossolin (11), and corossolone (12), were isolated from the seeds of Annona muricata. The structures of all isolates were elucidated and characterized by spectral and chemical methods. These acetogenins showed significantly selective in vitro cytotoxicities toward the human hepatoma cell lines Hep G(2) and 2,2,15.

A new guaipyridine sesquiterpene alkaloid, cananodine (1), and two new eudesmane sesquiterpenes, cryptomeridiol 11-alpha-L-rhamnoside (2) and gamma-eudesmol 11-alpha-L-rhamnoside (3), along with gamma-eudesmol (4), were isolated from the fruits of Cananga odorata. The structures of compounds 1-3 were established on the basis of NMR and MS methods. In addition, compounds 1-4 and four previously reported alkaloids, cleistopholine (5), N-trans-feruloyltyramine (6), (+)-ushinsunine-beta-N-oxide (7), and lyscamine (8), were evaluated for cytotoxicity against two human hepatocarcinoma cell lines.

A new halimane diterpene, 3beta,5beta, 16alpha-trihydroxyhalima-13(14)-en-15,16-olide (1), and a new oxoprotoberberine alkaloid, (-)-8-oxopolyalthiaine (2), along with 20 known compounds, were isolated from a methanolic extract of Polyalthia longifolia var. pendula. The structures of compounds 1 and 2 were established by spectroscopic analysis. Several of these compounds were evaluated for cytotoxicity toward a small panel of human cell lines.

Four new compounds, a mixture of 20,23-cis-2,4-trans-bullatalicinone (1) and 20,23-cis-2,4-cis-bullatalicinone (2), rollimusin (3), and rolliacocin (4), along with eight known acetogenins, were isolated from an ethyl acetate extract of the unripe fruits of Rollinia mucosa. The structures and stereochemistry of 1-4 were determined on the basis of spectral data and chemical evidence.

Chromatographic fractionation of a MeOH extract from the stems of Annona cherimola led to the isolation of a new non-adjacent, bis-THF ring acetogenin (one THF ring being at C-4 and the other at C-16), aromin-A (1) along with the known cytotoxic acetogenin squamocin (2). The structures of these isolates were established by means of mass spectrometry and spectroscopic techniques.

Chromatography of an ethyl acetate extract of seeds of Annona reticulata led to the isolation of a new cytotoxic gamma-lactone acetogenin, cis-/trans-isomurisolenin, along with six known cytotoxic acetogenins, annoreticuin, annoreticuin-9-one, bullatacin, squamocin, cis-/trans-bullatacinone and cis-/trans-murisolinone. Structures of these compounds were established by means of mass and related spectral experiments. Some of the compounds isolated, showed potent cytotoxicities against Hep. 2,2,15, Hep. G2, KB and CCM2, four cancer cell-lines.

A new naturally occurring alkaloid, acetylcamptothecin, together with 17 known compounds, (+)-1-hydroxypinoresinol, omega-hydroxypropioguaiacone, p-hydroxybenzaldehyde, scopoletin, uracil, thymine, sitosterol, sitosteryl-beta-D-glucoside, 3 beta-hydroxy-stigmast-5-en-7-one, stigmast-5-en-3 beta,7 alpha-diol, 6 beta-hydroxystigmast-4-en-3-one, sitost-4-en-3-one, linoleic acid, trigonelline, camptothecin, 9-O-methoxycamptothecin and pumiloside were isolated and characterized from the stem of Nothapodytes foetida. Among them, scopoletin, camptothecin, 9-O-methoxycamptothecin and O-acetylcamptothecin showed significant cytotoxic activity.

Three structurally related acid amides, N-trans-feruloyltyramine (1), N-p-coumaroyltyramine (2), and N-trans-caffeoyltyramine (3), one lignan, (-)-syringaresinol (4), one aromatic aldehyde, syringaldehyde (5), and two steroids, beta-sitosterol and beta-sitosterol-beta-D-glucoside were isolated from the stem parts of Annona montana (Annonaceae). N-trans-Caffeoyltyramine (3) is a new natural compound. These compounds and their acetate derivatives were subjected to the antiplatelet aggregation and cytotoxicity bioassay where some of them showed significant activities.

1. The antimuscarinic properties of liriodenine, isolated from Fissistigma glaucescens, were compared with methoctramine (cardioselective M2 antagonist) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, smooth muscle selective M3 antagonist) by radioligand binding tests, functional tests and measurements of second messenger generation in canine cultured tracheal smooth muscle cells. 2. Liriodenine, pirenzepine, methoctramine and 4-DAMP displaced [3H]-N-methyl scopolamine ([3H]-NMS) binding in a concentration-dependent manner with Ki values of 2.2 +/- 0.4 x 10(-6), 3.3 +/- 0.7 x 10(-7), 8.9 +/- 2.3 x 10(-8) and 2.3 +/- 0.6 x 10(-9) M, respectively. The curves for competitive inhibition of [3H]-NMS with liriodenine, methoctramine and 4-DAMP were best fitted according to a two site model of binding, but pirenzepine was best fitted according to a model with one site. 3. Liriodenine and 4-DAMP displayed a high affinity for blocking tracheal contraction (pKB = 5.9 and 9.1, respectively) and inositol phosphate formation (pKB = 6.0 and 8.9, respectively), but a low affinity for antagonism of cyclic AMP inhibition (pKB = 4.7 and 7.8, respectively). 4. Methoctramine blocked cyclic AMP inhibition with a high affinity (pKB = 7.4), but it antagonized tracheal contraction and inositol phosphate formation with a low affinity (pKB = 6.1 and 6.0, respectively). 5. In conclusion, both M2 and M3 muscarinic receptor subtypes coexist in canine tracheal smooth muscle and are coupled to the inhibition of cyclic AMP formation and phosphoinositide breakdown, respectively. The antimuscarinic characteristics of liriodenine are similar to those of 4-DAMP. It may act as a selective M3 receptor antagonist in canine tracheal smooth muscle.

Using cytotoxicity as a guide to fractionation, one novel acetogenin, annoreticuin-9-one [3], and four known cytotoxic acetogenins, squamone [4], solamin [5], annomonicin [6] and rolliniastatin 2 [7], were isolated from active extracts of the leaves of the Formosan plant Annona reticulata. Their structures were elucidated on the basis of uv, ir, 1H- and 13C-nmr, and ms data of the natural compounds and their derivatives.

The styrylpyrone, goniodiol-7-monoacetate [1] [6R-(7R,8R-dihydro-7-acetoxy-8-hydroxystyryl)-5, 6-dihydro-2-pyrone], has been isolated from Goniothalamus amuyon, and its detailed molecular structure has been determined by X-ray crystallographic analysis. Goniodiol-7-monoacetate showed potent (ED50 values less than 0.1 microgram/ml) cytotoxicities against KB, P-388, RPMI, and TE671 tumor cells.

Bioactivity-guided fractionation of a CHCl3 extract of the leaves of Piper aborescens afforded a new cytotoxic pyridone alkaloid, N-(3-methoxy-4,5-methylenedioxydihydrocinnamoyl)-delta 3-pyridin-2-one [1], as well as three known cytotoxic pyridone alkaloids, N-(3-methoxy-4,5-methylenedioxycinnamoyl)-delta 3-pyridin-2-one [2], piplartine [3], and piplartine dimer A [4].

The stem and stem bark of Polyalthia longifolia afforded the cytotoxic aporphine alkaloid liriodenine [1], as well as two aporphine alkaloids, noroliveroline [2] and oliveroline-beta-N-oxide [3] and three azafluorene alkaloids, darienine [4], polyfothine [6], and isooncodine [7], which are not bioactive. Polyfothine [6] and isooncodine [7] are new natural compounds.

A number of benzylisoquinoline alkaloids of plants indigenous to Taiwan were isolated and purified and their chemical structures were determined. These compounds, namely benzyltetrahydroisoquinolines or their N-oxides, aporphines, oxoaporphines and 1-N, N-dimethylaminoethylphenanthrenes or their N-oxides, were studied for their potency in inhibiting precursor incorporation into DNA, RNA and protein. Inhibition of murine leukemic L1210 and human leukemic CCRF-CEM and HL-60 cell growth was also examined. Of the compounds evaluated for cell growth inhibition, (+-)-N-methylcoclaurine(3), (-)-norannuradhapurine HBr(19), oxoglaucine (23), dicentrine methine (27) and 1-(N-methyl-N-hydroxyaminoethyl)-3, 4-methylenedioxy-7-methoxyphenanthrene (28) showed an IC50 less than 10 microM.

Two cytotoxic isoquinoline alkaloids, liriodenine and palmatine, were isolated from the Xanthorhiza simplicissima Marsh. Liriodenine, isolated for the second time from the family of Ranunculaceae, demonstrated potent cytotoxicity against KB, A-549, HCT-8, P-388, and L-1210 tumor cells, while palmatine showed marginal cytotoxicity against KB cells.

A series of 53 isoquinoline alkaloids and their N-oxides have been tested for their cytotoxicity against A-549, HCT-8, KB, P-388, and L-1210 cells. These alkaloids include two tetrahydroprotoberberines, two protoberberines, six aporphines, one morphinandienone, five oxoaporphines, seven phenanthrenes, one spirobenzylisoquinoline N-oxide, nine aporphine N-oxides, seven benzyltetrahydroisoquinoline N-oxides, one benzylisoquinoline N-oxide, one protopine N-oxide, three tetrahydroprotoberberine N-oxides, four pavine N-oxides, and four phenanthrene N-oxides. The results are discussed on the basis of structure-activity relationships.