Tumor inhibitors. 100. Isolation and structural elucidation of bruceantin and bruceantinol, new potent antileukemic quassinoids from Brucea antidysenterica

Kupchan, S. Morris; Britton, Ronald W.; Lacadie, John A.; Ziegler, Myra F.; Sigel, Carl W.

doi:10.1021/jo00893a023

Cited by 160 publications

(51 citation statements)

References 7 publications

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“…To isolate the alarm cues in opaline, 39 ml of opaline was first partitioned via a modified Kupchans scheme [20]. Because nearly all of the opaline components partitioned into the H 2 O fraction, we combined the hexanes, CHCl 3 , AcOEt, and BuOH partitions for a behavioral bioassay of alarm response, as described in [11] [19].…”

Section: Experimental Partmentioning

confidence: 99%

Isolation and Structural Elucidation of Novel Mycosporine‐Like Amino Acids as Alarm Cues in the Defensive Ink Secretion of the Sea Hare Aplysia californica

Kamio

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Nguyen

et al. 2011

Helvetica Chimica Acta

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Three new mycosporine-like amino acids (MAAs), aplysiapalythines A, B, and C (1, 2, and 3, resp.) were isolated from opaline, a glandular component of the defensive ink secretion of sea hares (Aplysia californica) collected from waters off southern California. Here, we report the structure of these MAAs determined by mass spectrometry and NMR data. These new MAAs are structurally related to two known MAAs that are also present in sea hare opaline, i.e., asterina 330 (4) and palythine (5), and for which we also provide detailed data here for comparison. The fact that three of the five MAAs that we identified from sea hare opaline are novel molecules is interesting given that this represents a relatively large addition to the current list of known MAAs. This is likely because most researchers have identified MAAs through HPLC with UV detection, which is imprecise given similarities in UV spectra for different MAAs. Our findings suggest that there is much greater diversity of MAAs than is currently known. Results published elsewhere show that 1, 2, and 4 are alarm cues for conspecific sea hares at natural concentrations, but 3 and 5 are not.Introduction. -Mycosporine-like amino acids (MAAs) are widely distributed in marine organisms including bacteria, plants, invertebrates, and vertebrates [1]. Animals are generally thought to be incapable of synthesizing MAAs, but rather they are thought to sequester MAAs from their diet or from symbionts; however, this view has been questioned [2]. MAAs, of which ca. 30 are known, are traditionally considered to be screens against solar radiation, but other functions have also been proposed, including anti-oxidants, osmotic regulation, providing a source of amino acids in embryonic development, and induction of spawning [3 -10].A new function for MAAs was recently identified from our work on chemical defenses of sea hares (Aplysia californica) collected from the waters of southern California [11]. We found that MAAs are present in high concentrations in opaline, which is one of the glandular products of the sea hares ink secretion. Of the five major MAAs in opaline of these sea hares, three are novel, and two of these novel MAAs, together with nucleic acids and nucleosides in the ink component of the sea hares ink secretion, function as intraspecific alarm cues [11]. In this article, we describe the isolation and the structure elucidation of these novel MAAs.

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Section: Experimental Partmentioning

confidence: 99%

Isolation and Structural Elucidation of Novel Mycosporine‐Like Amino Acids as Alarm Cues in the Defensive Ink Secretion of the Sea Hare Aplysia californica

Kamio

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Nguyen

et al. 2011

Helvetica Chimica Acta

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“…Isolation and Identification of 13-Hydroxy-15-oxozoapatlin-A methanol extract of Parinari curatellifolia bark was initially fractionated by a modified Kupchan partitioning scheme (30). The extract was dissolved in 500 ml of MeOH/H 2 0 (1:4) and sequentially extracted with hexane (3 ϫ 200 ml), chloroform (3 ϫ 200 ml), and ethyl acetate (3 ϫ 200 ml).…”

Section: Methodsmentioning

confidence: 99%

G2 DNA Damage Checkpoint Inhibition and Antimitotic Activity of 13-Hydroxy-15-oxozoapatlin

Rundle

Andersen

et al. 2001

Journal of Biological Chemistry

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Checkpoints activated in response to DNA damage cause arrest in the G 1 and G 2 phases of the cell cycle. Inhibitors of the G 2 checkpoint may be used as tools to study this response and also to increase the effectiveness of DNA-damaging therapies against cancers lacking p53 function. Using a cell-based assay for G 2 checkpoint inhibitors, we have screened extracts from the NCI National Institutes of Health Natural Products Repository and have identified 13-hydroxy-15-oxozoapatlin (OZ) from the African tree Parinari curatellifolia. Flow cytometry with a mitosis-specific antibody showed that checkpoint inhibition by OZ was maximal at 10 M, which released 20% of irradiated MCF-7 cells expressing defective p53 and 30% of irradiated HCT116p53 ؊/؊ cells from G 2 arrest. OZ additively increased the response to the checkpoint inhibitors isogranulatimide and debromohymenialdisine, but it did not augment the effects of UCN-01 or caffeine. Unlike other checkpoint inhibitors, OZ did not inhibit ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), Chk1, Chk2, Plk1, or Ser/ Thr protein phosphatases in vitro. Treatment with OZ also caused G 2 -arrested and cycling cells to arrest in mitosis in a state resembling prometaphase. In these cells, the chromosomes were condensed and scattered over disordered mitotic spindles. The results demonstrate that OZ is both a G 2 checkpoint inhibitor and an antimitotic agent.In response to DNA damage, cell cycle progression pauses to allow time for DNA repair. This checkpoint response helps to maintain the integrity of the genome, and loss of checkpoints may enable the accumulation of mutations during carcinogenesis (1, 2). Cell cycle arrest is achieved by inhibiting the activities of cyclin-dependent kinases that govern entry into S phase or mitosis. In G 1 phase, DNA damage leads to the stabilization and nuclear localization of the p53 transcription factor, resulting in up-regulation of p21Waf1/Cip1 , an inhibitor of G 1 cyclindependent kinase activities (3-6). The G 2 checkpoint operates through a different mechanism, and the details of this pathway are beginning to emerge (7). In the current model, regulation is exerted through a phosphorylation cascade and by control of the subcellular localization of enzymes and their substrates. ATM 1 and ATR kinases play a role in the early signaling of DNA damage and cause phosphorylation of Chk1 and Chk2 kinases (8 -12). Phosphorylation of the phosphatase Cdc25C by Chk1 and Chk2 creates a 14 -3-3 binding site and inhibits its phosphatase activity in vitro, preventing its activation of Cdc2 kinase, the master regulator of mitosis (13-15). Cdc2 activity is also regulated by inhibitory phosphorylation by Wee1 and Myt1 kinases (16,17).Inhibitors of the G 2 checkpoint, such as caffeine, 2-aminopurine, pentoxifylline, staurosporine, and UCN-01, have been studied extensively in tissue culture model systems (18 -22). More recently, we have identified isogranulatimide (IGR) and debromohymenialdisine (DBH) as checkpoint inhibitors from marine inv...

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“…10-12 Bruceantin ( 17 ), which has a terminal isopropyl rather than methyl group in the C-15 ester side chain compared with 16 (Figure 7), was previously isolated from B. antidysenterica by Kupchan et al by bioactivity-guided fractionation 13. Our laboratories first reported two synthetic methods for the conversion of 10 into 17 , which was in anticancer clinical trials 14.…”

Section: Antitumor Agentsmentioning

confidence: 99%

Discovery and Development of Natural Product-Derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach

2010

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Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogs, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analog synthesis, as well as structure-activity relationship and mechanism of action studies. Current clinical trials agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in Phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called “maturation inhibitors”. In addition, an etoposide analog, GL-331, progressed to anticancer Phase II clinical trials, and the curcumin analog JC-9 is in Phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trials candidates will also be discussed.

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Tumor inhibitors. 100. Isolation and structural elucidation of bruceantin and bruceantinol, new potent antileukemic quassinoids from Brucea antidysenterica

Cited by 160 publications

References 7 publications

Isolation and Structural Elucidation of Novel Mycosporine‐Like Amino Acids as Alarm Cues in the Defensive Ink Secretion of the Sea Hare Aplysia californica

Isolation and Structural Elucidation of Novel Mycosporine‐Like Amino Acids as Alarm Cues in the Defensive Ink Secretion of the Sea Hare Aplysia californica

G2 DNA Damage Checkpoint Inhibition and Antimitotic Activity of 13-Hydroxy-15-oxozoapatlin

Discovery and Development of Natural Product-Derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach

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