Two new minor silvestrol analogues [2‴-epi-silvestrol (1) and 2‴,5‴-diepi-silvestrol (2)], together with a new 21-norbaccharane-type triterpene (3), two new 3,4-seco-dammarane triterpenes (4 and 5), and a new eudesmane sesquiterpene (6), as well as nine known compounds, were isolated from a large-scale recollection of the CHCl3-soluble extract of the stem bark of Aglaia foveolata obtained in Kalimantan, Indonesia. The structures of the new compounds were established by interpretation of their spectroscopic data. All of the isolates were tested for cytotoxicity against HT-29 cells. The new silvestrol analogues, 1 and 2, were considerably less active as cytotoxic agents than silvestrol (7) and episilvestrol (5‴-epi-silvestrol) (8), against this cell line, showing the importance of the configuration at C-2‴ in mediating such activity within this compound class. Several of the compounds isolated were also evaluated in a NF-κB (p65) inhibition assay.
Recent progress is described in an ongoing collaborative multidisciplinary research project directed towards the purification, structural characterization, chemical modification, and biological evaluation of new potential natural product anticancer agents obtained from a diverse group of organisms, comprising tropical plants, aquatic and terrestrial cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which initial extracts, chromatographic fractions, and purified isolated compounds of these acquisitions are tested. Several promising biologically active lead compounds from each major organism major class investigated are described, and these may be seen to be representative of very wide chemical diversity.
As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 63935; related to Phoma sp.). The initial extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) and SF268 (human astrocytoma) cell lines and was selected for further study. Bioactivity-directed fractionation yielded resorcylic acid lactones (RALs) 1 (a new natural product) and 3 (a new compound) and the known RALs zeaenol (2), 5E-7-oxozeaenol (4), 5Z-7-oxozeaenol (5) and LL-Z1640-1 (6). Reduction of 5E-7-oxozeaenol (4) with sodium borohydride produced 3, which allowed assignment of the absolute configuration of 3. Other known resorcylic acid lactones (7–12) were purchased and assayed in parallel for cytotoxicity with isolated 1–6 to investigate structure-activity relationships in the series. Moreover, the isolated compounds (1–6) were examined for activity in a suite of biological assays, including antibacterial, mitochondria transmembrane potential, and NF-κB. In the latter assay, compounds 1 and 5 displayed sub-micromolar activities that were on par with the positive control, and as such, these compounds may serve as a lead scaffold for future medicinal chemistry studies.
A collaborative multidisciplinary research project is described in which new natural product anticancer drug leads are obtained from a diverse group of organisms, constituted by tropical plants, aquatic cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which crude extracts of these acquisitions are tested. Progress made in the isolation of lead bioactive secondary metabolites from three tropical plants is discussed.
As part of an ongoing investigation of filamentous fungi for anticancer leads, an active culture was identified from the Mycosynthetix library (MSX 70741, of the order Hypocreales, Ascomycota). The fungal extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) cell line, and bioactivity-directed fractionation yielded peptaibols 1–12 and harzianums A (13) and B (14). Structure elucidation of 1–12 was facilitated by high-resolution MS/MS obtained on a Thermo LTQ Orbitrap XL using Higher-Energy Collisional Dissociation (HCD) and by high field NMR (950 MHz). The absolute configuration was determined by Marfey’s analysis of the individual amino acids; the time required for such analysis was decreased via the development of a 10 min UPLC method. The isolated peptaibols (1–12), along with three other peptaibols isolated and elucidated from a different fungus (MSX 57715) of the same Order (15–17), were examined for activity in a suite of biological assays, including those for cytotoxic, antibacterial, and anthelmintic activities.
A new caged xanthone (1), a new prenylxanthone (2), seven known xanthones, and a known sterol glucoside were isolated from the stems of Cratoxylum cochinchinense, collected in Vietnam. Compounds 1 and 2 were determined structurally by analysis of their spectroscopic data. In addition, five new (10 and 16–19) and eight known prenylated xanthone derivatives were synthesized from the known compounds, α-mangostin (3) and cochinchinone A (6). Several of these substances were found to be cytotoxic towards HT-29 human colon cancer cells, with the most potent being 3,6-di-O-acetyl-α-mangostin (8, ED50, 1.0 μM), which was tested further in an in vivo hollow fiber assay, but found to be inactive at the highest dose used (20 mg/kg; ip). Of the substances evaluated in a NF-κB p65 inhibition assay, 1,3,7-trihydroxy-2,4-diisoprenylxanthone (5) exhibited the most potent activity (IC50, 2.9 μM). In a mitochondrial transmembrane potential (MTP) assay, two new compounds, 1 (IC50, 3.3 μM) and 10 (IC50, 1.4 μM), and two known compounds, 3 (α-mangostin, IC50, 0.2 μM) and 11 (3,6-di-O-methyl-α-mangostin, IC50, 0.9 μM), were active. A preliminary analogue development study showed that 3,6-di-acetylation and 6-benzoylation both slightly increased the cytotoxicity of α-mangostin (3), whereas methylation reduced such activity. In contrast, neither acetylation, benzoylation, nor methylation enhanced the cytotoxicity of cochinchinone A (6).
Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogues, Sch 52900 (2), verticillin A (3), gliocladicillin C (4), Sch 52901 (5), 11′-deoxyverticillin A (6), and gliocladicillin A (7). The structures of compounds 1–7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds (1–7) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC50 values ranging from 1.2 µM to 10 nM. Compounds 1–5 were examined for activity in the NF-κB assay, where compounds 2 and 3 revealed activity in the sub-micromolar range. Additionally, compounds 1, 3, and 4 were tested for EGFR inhibition using an enzymatic assay, while compound 3 was examined against an overexpressing EGFR+ve cancer cell line.
Six new 5,6-dihydro-α-pyrone derivatives (1-6), namely, brevipolides A-F, together with seven known compounds, including a 5,6-dihydro-α-pyrone derivative (7), three flavonoids, a steroid glycoside, and two triterpenoids, were isolated from the entire plant of Hyptis brevipes. Compounds 1-7 were assigned with the absolute configuration, 5R, 6S, 7S, and 9S, as elucidated by analysis of data obtained from their CD spectra and by Mosher ester reactions. Compounds 2, 6, and 7 exhibited ED 50 values of 6.1, 6.7 and 3.6 μM against MCF-7 cells, and compounds 1, 2, 6, and 8 (the known 5,6,3′-trihydroxy-3,7,4′-trimethoxyflavone) gave ED 50 values of 5.8, 6.1 7.5, and 3.6 μM against HT-29 cells, respectively. However, no significant cytotoxicity was found against Lu1 cells for any of the compounds isolated. When these compounds were subjected to evaluation in a panel of mechanism-based in vitro assays, compound 7 were found to be active in an enzyme-based ELISA NF-κB assay, with an ED 50 value of 15.3 μM. In a mitochondrial transmembrane potential assay, compounds 3, 7, and 8 showed ED 50 values of 8.5, 75, and 310 nM, respectively. However, no potent activity was found in a proteasome inhibition assay for any of the isolated compounds.The genus Hyptis (Lamiaceae) is composed of approximately 350-400 species in the form of small herbs to large bushes, which are distributed in the tropics and warmer temperate regions all over the world. Previous studies on the constituents of species of the genus Hyptis have revealed diterpenoids, 1,2 flavonoids, 3,4 lignans, 4,5 and α-pyrone derivatives. 6,7 Hyptis brevipes Piot. originated from tropical America but is now widely distributed in other tropical regions of the world as an alien invasive species. Biological studies on crude extracts of this plant have shown inhibitory activities against bacterial and fungal growth, as well as DNA intercalation activity. 8,9 There has been no previous report on the phytochemical evaluation of this plant to date.* To whom correspondence should be addressed. Tel: .edu. † Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University. ‡ University of Illinois at Chicago. § Division of Pharmacy Practice and Administration, The Ohio State University. ⊥ Research Center for Indonesian Medicinal Plants, Tawangmangu, Indonesia. || Indonesian Institute of Science, Tangerang, Indonesia. ∇ Present address: College of Pharmacy, University of Hawaii-Hilo, Hilo, Hawaii 96720. Supporting Information Available: 1 H and 13 C NMR spectra of compounds 1 -6, DEPT and 2D NMR spectra including 1 H-1 H COSY, HSQC, HMBC, and NOESY of compound 1, as well as 1 H NMR spectra of R-and S-TPMA esters of compound 3. This material is available free-of-charge via the Internet at http://pubs.acs.org. As part of a collaborative, multi-disciplinary approach to the discovery of new naturally occurring anticancer drugs, 10,11 the entire plant of H. brevipes was selected for further investigation, following initial cytotoxicity screening using the MCF-7 human b...
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