HASRAT J. A. ⁽¹⁾; DE BRUYNE T. ⁽¹⁾ ; DE BACKER J.-P. ⁽²⁾ ; VAUQUELIN G. ⁽²⁾ ; VLIETINCK A. ⁽¹⁾ ;
 

The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [3H]rauwolscine to 5-HTergic 5-HT1A receptors in calf hippocampus, and three alkaloids, annonaine (1), nomuciferine (2) and asimilobine (3), isolated from the fruit have been shown to have IC50 values of 3 µM, 9 µM and 5 µM, respectively, although in ligand-binding studies it was not possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the results of functional assays of the alkaloids. The inhibition of cAMP accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A receptor from man. None of the alkaloids showed antagonistic properties towards the 5-HT1A receptors because in the antagonistic tests no influence on the forskolin-stimulated increase of cAMP level was detected. Full agonistic properties were measured for all three compounds; the inhibition constants (Ki) for 1, 2 and 3 were < 10 µM. Inhibition of the binding of the radioligand to the 5-HT1A receptor was observed in every ligand-binding assay performed with the alkaloids; the Ki values for 1, 2 and 3 were in the µM range. These results imply that the fruit of Annona muricata possesses anti-depressive effects, possibly induced by compounds 1, 2 and 3, and that in the past potent leads for the development of anti-depressive therapeutics have not been used.
 

Geum-Soog Kim¹, ^fn1, Lu Zeng¹, Feras Alali¹, Lingling L Rogers¹, Feng-E Wu¹, Soelaksono Sastrodihardjo² and Jerry L McLaughlin¹,
¹ Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47906, U.S.A
² Department of Education and Culture, Center of Interuniversities, Biology Division, Bandung Institute of Technology, 10 Yanesba St., Bandung 40132, Indonesia

Abstract
Bioactivity-directed fractionation of the leaves of Annona muricata L. (Annonaceae) resulted in the isolation of two new Annonaceous acetogenins, muricoreacin (1) and murihexocin C (2). Compounds 1 and 2 showed significant cytotoxicities among six human tumor cell lines with selectivities to the prostate adenocarinoma (PC-3) and pancreatic carcinoma (PACA-2) cell lines.
 

Hwa-Woei Chih^a, ^d, Hui-Fen Chiu, ^b, ^c, Kung-Sung Tang^a, Fang-Rong Chang^c, ^d and Yang-Chang Wu^c, ^d
 

Abstract
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).