Historic Perspectives on Annonaceous Acetogenins from the Chemical Bench to Preclinical Trials

Abstract

Studies on the Annonaceous acetogenins began after the first cytotoxic acetogenin, uvaricin, was isolated in 1982. This attractive finding made many medicinal and natural product chemists direct their efforts on the isolation and identification of these classes of compounds. As more Annonaceous acetogenins were isolated, more information about them was uncovered. From their structural identification to the total synthesis of natural product analogues and from cell-based screening and molecular-based targeting to animal testing, the mechanisms of action of the Annonaceous acetogenins became clearer. The purpose of this review is to give an account of recent studies on this class of compounds and their analogues, which will aid us not only in clarifying how the Annonaceous acetogenins act but also in establishing principles for the further development of this class of compounds

Anti-cancer efficacy of ethanolic extracts from various parts of Annona Squamosa on MCF-7 cell line

“…Previous studies reported identification and quantification of 2 main compounds of annonaceous acetogenins by HPLC analysis: 12, 15-cis-squamostatin-A and bullatacin from the extract of A. squamosa seeds. Bullatacin, a bistetrahydrofuran annonaceous acetogenin high degree inhibitory action (300 times more effective than taxol) of the mitochondrial respiratory chain complex I, as tested in vivo (Jerry, 2008;Liaw et al, 2010). 12, 15-cissquamostatin-A and bullatacin also showed anti-cancer property against various tumor cell lines (Yang et al, 2009;Chen et al, 2011).…”

Folate-modified Annonaceous acetogenins nanosuspensions and their improved antitumor efficacy

“…[5][6][7] Several studies have reported significant antiproliferative effects of different compounds isolated from ACGs toward various cancer cell lines. 1,4,[8][9][10] For example, cytotoxic effects comparable to fluorouracil were obtained for annosquacin-I, annosquatin-I, uvarigrandin A, and bullatacin against A549, MCF-7, HeLa, HepG2, SMMC-7721, and MKN-45 cell lines. 11 Anticancer studies on ACGs were not only limited to in vitro but also in vivo investigation.…”

“…2 According to their relative stereostructures across the THF rings, ACGs are classified into mono-THF, adjacent bis-THF, nonadjacent bis-THF, non-THF ring, tri-THF, and nonclassical acetogenins. 3,4 The bis-adjacent-THF acetogenins are the most potent among this family. Moreover, a series of acetogenin mimetics has also been successfully developed by using both random and systematic syntheses, and some of the non-THF analogs showed remarkable cytotoxicity against tumor cell lines and good selectivity between human tumor cells and normal cells.…”

Annonaceous acetogenins nanosuspensions stabilized by PCL–PEG block polymer: significantly improved antitumor efficacy

“…[4][5][6] For example, bullatacin, the major component from ACGs, displayed 10 4 -10 5 times the antitumor activity of doxorubin against both the A549 (human lung carcinoma cells) and the MCF-7 (human breast cancer cells) 7 cell lines and 300 times the activity of taxol in L1210 (murine leukemia cells)-bearing mice. 8 The three bis-tetrahydrofuran compounds from Annona squamosa seeds showed 50% inhibitory concentration (IC 50 ) values that were one to two orders of magnitude less than fluorouracil against SMMC 7721 (human hepatocellular carcinoma), HeLa (human cervix carcinoma), MKN-45 (human gastric cancer), and HepG2 (human hepatocellular carcinoma) cell lines.…”

“…12 In vivo tests in mice showed the antitumor effects and even some possible adverse effects of ACGs. 5 It was reported that bullatacin led to liver and kidney…”