Zhe-ming Gu

Recent advances in annonaceous acetogenins

Annonaceous acetogenins are waxy substances consisting of C32 or C34 long chain fatty acids which have been combined with a propan-2-ol unit at C-2 to form a gama-lactone. They are only found in several genera of the plant family, Annonaceae. Their diverse bioactivities as antitumour, immunosuppressive, pesticidal, antiprotozoal, antifeedant, anthelmintic and antimicrobial agents have attracted more and more interest worldwide. Recently, we reported that the Annonaceous acetogenins can selectively inhibit the growth of cancerous cells and also inhibit the growth of adriamycin resistant tumour cells. As more acetogenins have been isolated and additional cytotoxicity assays have been conducted, we have noticed that, al(hough most acetogenins have high potencies among several solid human tumour cells lines, some of the derivatives within the different structural types and some positional isomers show remarkable selectivities among certain cell lines, e.g. against prostate cancer (PC-3).

The absolute configuration of trilobacin and trilobin, a novel highly potent acetogenin from the stem bark of Asimina triloba (Annonaceae)

Abstract Trilobacin ( 1 ) is the only previously reported Annonaceous acetogenin with the erythro relative configuration between the adjacent bis-tetrahydrofuran (THF) rings. The relative configuration in the adjacent bis-THF moiety of 1 was corrected to threo/trans/erythro/cis/threo from C-15 to C-24, and the absolute configuration was determined as 4 R , 15 R , 16 R , 19 R , 20 S , 23 R , 24 R and 36 S by advanced Mosher ester methodology and the COSY and NOESY spectral analyses of its 4,24-diacetate ( 1a ). Further investigation of the EtOH extract of the stem bark of the paw paw tree, Asimina triloba , monitoring for bioactivity by brine shrimp lethality, led to a novel acetogenin, trilobin ( 2 ). Spectral and chemical methods identified 2 as a 4-deoxy-10-hydroxy isomer of 1 . The absolute configuration of 2 was determined as 10 R , 15 R , 16 R , 19 R , 20 S , 23 R , 24 R , and 36 S by analyses of its Mosher ester derivatives. 2 was selectively cytotoxic among three human solid tumor cell lines with over a billion times the potency of adriamycin.

Novel cytotoxic annonaceous acetogenins: (2,4-cis and trans)-bulladecinones from annona bullata (annonaceae)

Abstract A mixture of two novel cytotoxic adjacent bis-tetrahydrofuran (THF) ketolactone acetogenins, (2,4- cis and trans )-bulladecinones ( 1 and 2 ), was isolated from the bark of Annona bullata Rich. (Annonaceae). Adjacent bis-THF rings, located at C-12 and C-16 and having only one adjacent hydroxyl group, and the presence of an erythro vicinal diol in 1 and 2 are new features for the Annonaceous acetogenins.

New cytotoxic annonaceous acetogenins: Bullatanocin and cis- and trans-Bullatanocinone, from Annona bullata (Annonaceae)

Abstract Further bioactivity-directed fractionation of the ethanol extract of the bark of Annona bullata Rich. (Annonaceae) has led to the isolation of the new nonadjacent bis-tetrahydrofuran acetogenins, bullatanocin ( 1 ), cis- bullatanocinone ( 2 ) and trans-bullatanocinone ( 3 ). A known adjacent bis-tetrahydrofuran acetogenin, desacetyluvaricin ( 4 ), which is new to this species, was also isolated. Brine shrimp lethality test (BST) data and cytotoxicities against human solid tumor cell lines of 1–4 were compared with those of the diastereoisomers, bullatalicin ( 5 ), cis- and trans-bullatalicinone ( 6 and 7 ) and 4-deoxyasimicin ( 8 ). 1 shows cytotoxic potencies 10,000 times those of adriamycin in the lung and colon cancer cell lines.

THREE NEW BIOACTIVE BIS-ADJACENT THF-RING ACETOGENINS FROM THE BARK OF ANNONA SQUAMOSA

Continuing work on the bioactivity-directed fractionation of the bark of Annona squamosa has resulted in the discovery of three new Annonaceous acetogenins, (2,4-cis and trans)-squamolinone (1), (2,4-cis and trans)-9-oxoasimicinone (2), and bullacin B (3). Compounds 1-3 are all adjacent bis-THF ring acetogenins with 2 representing the first bis-ring acetogenin to contain a carbonyl along its aliphatic chain. Compound 3 was selectively cytotoxic in a panel of six human tumor cell lines with a potency of nearly a million times that of adriamycin against the MCF-7 (human breast adenocarcinoma) cell line.

Goniocin from Goniothalamus giganteus: The first tri-THF annonaceous acetogenin

A novel cytotoxic Annonaceous acetogenin, the first member of this class of compounds having a tri-tetrahydrofuran (THF) moiety, has been isolated from Goniothalamus giganteus. The structure was elucidated by spectral data, and the absolute configuration was determined by advanced Moshers methodology.

Applying Mosher's method to acetogenins bearing vicinal diols. The absolute configurations of muricatetrocin C and rollidecins A and B, new bioactive acetogenins from Rollinia mucosa

Muricatetrocin C (1), rollidecin A (2), and rollidecin B (3), three new bioactive annonaceous acetogenins bearing vicinal diols, were isolated from the leaves of Rollinia mucosa (Annonaceae) using activity-directed fractionation. The total structural elucidations of 1-3, including the absolute stereochemistries of the vicinal diols, were achieved by analyzing their per-Mosher ester derivatives. All three compounds showed potent and selective inhibitory effects against several human cancer cell lines.

Quantitative evaluation of Annonaceous acetogenins in monthly samples of paw paw (Asimina triloba) twigs by liquid chromatography/electrospray ionization/tandem mass spectrometry

A quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was established for the quality control of the Annonaceous acetogenins in the extracts of the paw paw tree, Asimina triloba (L.) Dunal. (Annonaceae). A new calibration method was developed by (a) using the diastereoisomers of analytes present in the same extract as internal standards, and (b) adding five different levels of pure analytes to the extract solutions to construct a calibration curve. These modifications completely eliminate the matrix and instrument variations and, thus, provide high accuracy. As an example, concentrations of the three major and most active Annonaceous acetogenins, bullatacin (1), asimicin (2) and trilobacin (3), were directly evaluated, without any further sample preparation, in crude dichloromethane extracts of twigs collected monthly from a single paw paw tree. The results showed that the contents of 1 and the mixture of 2 and 3 increased significantly in May and June, with 1 at 12.94 and 14.55 ppm, respectively, and the mixture of 2 and 3 at 47.05 and 51.26 ppm, respectively. The quantified contents of these potent acetogenins showed a good correlation with potencies observed in the brine shrimp test (BST), which demonstrated the highest activities with extracts from the May and June samples. These results suggest that May and June are the best time to collect paw paw twigs for maximizing pesticidal and other bioactivities. In addition, the results obtained from both methods, BST and LC/MS/MS, also verify the accuracy of each other, This well-defined LC/MS/MS method can be widely applied in the quantitative analysis of other natural components in crude extracts. Copyright

Mono-THF ring annonaceous acetogenins from Annona squamosa

Continuing work on the bark of Annona squamosa Rich. (Annonaceae), directed by the brine shrimp lethality test (BST), has resulted in the isolation of three new Annonaceous acetogenins, 4-deoxyannoreticuin, cis-4-deoxyannoreticuin, and (2,4-cis and trans)-squamoxinone. The first two are additional examples of acetogenins isolated from this plant species which contain the unusual feature of an oxygen functionality at the C-9 position. They have a hydroxylated mono-THF ring with respective threo/trans/threo and threo/cis/threo relative stereochemistries. The latter compound is a ketolactone mixture which has the same relative stereochemistry around the THF ring and the same spatial relationship between the THF ring and the hydroxyl group along the aliphatic chain as 4-deoxyannoreticuin, but is two methylene units longer. Additionally, the isolated hydroxyl group is at C-11, while the THF ring starts at C-17, instead of at C-9 and C-15, respectively, as for the first two compounds. All three compounds showed moderate, but significant, cytotoxicities against a panel of six human tumor cell lines with (2,4 cis and trans)-squamoxinone showing promising selectivity against the pancreatic cell line (PACA-2).

Isolation of new bioactive annonaceous acetogenins from Rollinia mucosa guided by liquid chromatography/mass spectrometry

Reversed-phase high-performance liquid chromatography (RP-HPLC) fractionation, monitored by liquid chromatography/electrospray mass spectrometry (LC/ESI-MS), led to the isolation of two new bioactive annonaceous acetogenins, rollidecin C (1) and rollidecin D (2), from the bioactive aqueous methanol fraction of the leaves of Rollinia mucosa (Annonaceae). The structures were confirmed by analyses of the 1H and 13C NMR data. In addition, a known adjacent bis-tetrahydrofuran (THF) acetogenin, desacetyluvaricin (3), was isolated from this plant for the first time utilizing the LC/ESI-MS monitoring approach. Compound 1 exhibited selective cytotoxicity toward the colon tumor cell line (HT-29), while 2 showed only borderline cytotoxicity in a panel of six human tumor cell lines.