Introduction Mammea americana L. (Clusiaceae) is a tree native to the West Indies and northern South America. Known commonly as ma- meyormammeeapple,theroundfruitoftheplantis4±8cmin diameter,withalight-brownskin.Thereare1±4ovoidseedsper fruit. The fruit is generallyconsidered edible, and is enjoyed raw, cooked, or processed into a wine. However, there are concerns in some Caribbean cultures that the fruits and seeds are poisonous [1]. For example, in Puerto Rico the fruits are widely consumed, butpeoplearegenerallyawarenottoeatmuchduetogastricdis- tress [2]. The seeds of M. americana are known to have insectici- dal activity [1]. Antioxidant and Cytotoxic Isoprenylated Coumarins from Mammea americana Hui Yang 1 Petr Protiva 2 Roberto R. Gil 3 Bei Jiang 2 Scott Baggett 1 Margaret J. Basile 4 Kurt A. Reynertson 1 I. Bernard Weinstein 2 Edward J. Kennelly 1 Affiliation 1 Department of Biological Sciences, Lehman College and The Graduate Center, The City University of New York, Bronx, NY, USA 2 Department of Medicine, Columbia University Medical Center, New York, NY, USA 3 Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA 4 Department of Neurology, University of Miami School of Medicine, Miami, FL, USA Correspondence Dr. Edward J. Kennelly ´ Department of Biological Sciences ´ Lehman College and The Graduate Center ´ The City University of New York ´ 250 Bedford Park Boulevard West ´ Bronx ´ NY 10468 ´ USA ´ Phone: +1-718-960-1105 ´ Fax: +1-718-960-8236 ´ E-mail: edward.kennelly@lehman.cuny.edu Received November 3, 2004 ´ Accepted March 30, 2005 Bibliography Planta Med 2005; 71: 852±860 ´  Georg Thieme Verlag KG Stuttgart ´ New York DOI 10.1055/s-2005-871257 ´ Published online September 19, 2005 ISSN 0032-0943 Abstract Antioxidant-guided fractionation of Mammeaamericana L. seeds resultedintheidentificationofthreenewisoprenylatedcoumar- ins, mammea B/BA hydroxycyclo F (1), mammea E/BC (2), and mammeaE/BD(3).Inaddition,twelveknownisoprenylatedcou- marins, mammea A/AA (4), mammea A/AA cyclo D (5), mammea A/AAcycloF(6),mammeaA/ACcycloD(7),mammeaA/ADcyclo D(8),mammeaB/BA(9),mammeaB/BAcycloF(10),mammeaB/ BB(11), mammea B/BC (12), mammea B/BD (13), mammea E/BA (14), and mammea E/BB (15), as well as two known flavanols, (+)-catechin (16) and (-)-epicatechin (17) were identified. The fifteen isoprenylated coumarins were screened for their cyto- toxicity in the SW-480, HT-29, and HCT-116 human colon cancer celllinesandantioxidantcapacitiesintheDPPH(1,1-diphenyl-2- picrylhydrazyl) free-radical assay. Compounds 1 ± 15 exhibited significant cytotoxic activities in the SW-480, HT-29, and HCT- 116 human colon cancer cell lines (IC 50 ranges 13.9±88.1, 11.2± 85.3, and 10.7±76.7 mM, in the three cell lines, respectively) at concentrations comparable to 5-fluorouracil (IC 50 = 53.0, 46.1, and 45.1 mM), a drug frequently used for human colon cancer treatment. Compounds 2 ± 4, 9, and 11 ± 15 displayed high anti- oxidantactivityintheDPPHassay(IC 50 range86±135 mM),com- pounds 1 , 5 ± 8,and 10,however,hadnoantioxidantactivity(IC 50 >200 mg/mL) in the DPPH assay. The results of these assays were used to study the structure-activity relationships for this class of compounds. In the SW-480 cell line, the three new coumarins, 1 ± 3, also exhibited dose-dependent increases in sub-diploid cells by flowcytometry, indicating that they induce apoptosis. Key words Clusiaceae ´ Mammea americana ´ mamey ´ isoprenylated cou- marin ´ cytotoxicity ´ antioxidant activity ´ SAR studies Original Paper 852