Three new ent-trachylobane diterpenoids (1-3) were isolated and structures elucidated from Mitrephora glabra Scheff. (Annonaceae). Mitrephorone A (1) possesses a hexacyclic ring system with adjacent ketone moieties and an oxetane ring, both of which are unprecedented among trachylobanes. All compounds were evaluated for cytotoxicity against a panel of cancer cells, where 1 displayed the most potent and broadest activity, and against a battery of antimicrobial assays, where all compounds were approximately equipotent.As part of our collaborative program to search for new compounds from the plant kingdom with promising anticancer activity, 1 Mitrephora glabra Scheff. (Annonaceae) was selected for investigation. The genus Mitrephora, representing approximately 40 species distributed widely throughout tropical Asia, 2 has been under-explored for biologically active secondary metabolites, and to the best our knowledge, only four species have been studied previously: M. celebica ,3,4 M. maingayi ,5,6 M. tomentosa ,7 and M. zippeliana. 8 The organic extract of M. glabra showed promising anticancer activity in cell cytotoxicity assays, and bioactivitydirected fractionation led to the isolation of a series of three new ent-trachylobane diterpenoids (1-3) and the related, known compound ent-trachyloban-18-oic-acid (4). 9,10The molecular formula of compound 1 was determined by HRMS to be C 21 H 26 O 5 , establishing an index of unsaturation of nine. Examination of the 1 H, 13 C, and DEPT-135 NMR data showed the presence of four singlet methyl groups (including a methoxy unit), six methylene groups, two methine groups, and nine quaternary carbons, including two oxygenated carbons in the aliphatic region and three carbonyl groups. These data accounted for all of the protons, indicating the absence of a free hydroxyl group. Importantly, the lack of any olefinic moieties required the presence of six rings to satisfy the degrees of unsaturation.Analysis of the COSY data revealed two major spin systems. One of these comprised H 2 -1/ H 2 -2/H 2 -3, which was extended to form the western part of the structure through HMBC studies (Fig. 1A). For example, H 2 -1 displayed HMBC correlations with C-2, C-3, and C-10, while the methyl protons of H 3 -20 showed correlations with C-1, C-5, and C-10; the combination of these data construed the connections of both C-1 and C-20 to C-10 and then C-10 to C-5. A methoxycarbonyl group was inferred based on the chemical shifts of C-19 and C-21 along with a relevant HMBC correlation (H 3 -21 to C-19). Also, the methyl protons of H 3 -18 displayed HMBC correlations with C-3, C-4, C-5, and C-19, and, in conjunction with an HMBC correlation from H 2 -3 to C-19, these data permitted the connectivities of both the C-18 methyl group and the C-19 methoxycarbonyl moiety to the quaternary C-4. The other spin-system deduced from the COSY spectrum corresponded to the H 2 -11/H-12/H-13/H 2 -14 unit, and these were confirmed in turn via HMBC correlations (Fig. 1B). Positions C-8, C-9, C-16, and C-17 ...

Bioactivity-guided fractionation of the stem bark of Mitrephora glabra yielded nine compounds, comprising three ent-kaurenoids (1-3), five polyacetylenic acids/esters (4-8), and one aporphine alkaloid, liriodenine (9). The structures of the six new compounds (1-3, 5, 7, and 8) were determined by spectroscopic data interpretation. All compounds were evaluated for their inhibitory activities against a panel of cancer cell lines and a battery of microorganisms.Over the last two decades, plants of the Annonaceae have been investigated rather extensively, largely for the presence of cytotoxic and/or insecticidal acetogenins. 1 Of these natural productbased investigations, however, the genus Mitrephora is relatively under-explored, probably because Annonaceous acetogenins have not been discovered therein, at least to date. There are nearly 50 described species of Mitrephora, and although a few species are relatively widespread in its native range, which extends from mainland China in the north to India in the west to Australia in the southeast, most of these shrubs and small to large trees have very narrow to localized distributions. [2][3][4] Representatives of such ecological niches may yield secondary metabolites of unique structures; yet, to the best of our knowledge, only five species of Mitrephora have been investigated for bioactive secondary metabolites, specifically, M. celebica ,5,6 M. maingayi ,7-9 M. thorelii, 10,11 M. tomentosa ,12 and M. zippeliana In an ongoing study of potential anticancer agents from the plant kingdom, 14,15 an investigation of the constituents of the stem bark of Mitrephora glabra Scheff. (Annonaceae), collected in Indonesia, has been conducted. In an earlier communication, we reported from this plant three new ent-trachylobane diterpenoids, mitrephorenones AC, of which one was shown to possess an unusual oxetane ring, making it the first hexacyclic representative of this compound class. 16 A more comprehensive investigation of this species, with the aim of isolating more potent cytotoxic constituents led to the isolation and elucidation of six additional new compounds (1-3, 5, 7, and 8) and three known substances (4, 6, 9). These can be subdivided into three entkaurane diterpenoids (1-3) and five polyacetylenic acids/esters (4-8). The known alkaloid, liriodenine (9), for which the structural data were in good agreement with those in the literature, 17,18 was isolated as well. This alkaloid was reported recently from M. maingayi 9 and may be common to species in the Mitrephora genus; it has been found in at least two other genera of the Annonaceae as well. 17 Along with testing in cytotoxicity assays, all compounds were evaluated for antimicrobial activity, largely due to the literature precedence for antimicrobial constituents from this genus. 5,6 Results and DiscussionCompound 1 exhibited a molecular formula of C 20 H 30 O 2 , as deduced from HREIMS and 1D NMR data, suggesting an index of hydrogen deficiency of six. An examination of the literature quickly led to the known ...

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Bioactivity-directed fractionation of an extract of the leaves of Alvaradoa haitiensis, using the KB (human oral epidermoid carcinoma) cell line, led to the isolation and identification of 10 new anthracenone C-glycosides, alvaradoins E-N (1-10), along with the known compound chrysophanol (11). The cytotoxicity of all compounds was evaluated, and preliminary structure-activity relationships are suggested. The most potent compounds in the in vitro assays (1 and 2) were evaluated in vivo versus the P388 (murine lymphocytic leukemia) model, and alvaradoin E (1) showed antileukemic activity (125% T/C) at a dose of 0.2 mg kg-1 per injection when administered intraperitoneally.