Beta-Apopicropodophyllin

beta-Apopicropodophyllin functions as a radiosensitizer targeting ER stress in non-small cell lung cancer.[Pubmed:30870718]

Biomed Pharmacother. 2019 May;113:108769.

AIMS: In this study, we examined whether Beta-Apopicropodophyllin (APP) could act as a radiosensitizer in non-small cell lung cancer (NSCLC) cells. MAIN METHODS: The in vitro radiosensitizing activity of APP was demonstrated with clonogenic assay, immunoblotting, Annexin V-Propidium iodide (PI) assay, BrdU incorporation, detection of mitochondrial ROS/intracellular of H2O2, mitochondrial membrane potential detection, and performing of isolation of mitochondrial and cytosolic fractions. The in vivo radiosensitizing activity of APP was determined in xenografted mice with co-treatment of APP and IR based on measurement of tumor volumes and apoptotic cell death. KEY FINDINGS: The results of a clonogenic assay indicated that a combination of APP and gamma-ionizing radiation (IR) inhibits cell growth and increases cell death in NSCLC cells. Several signal transduction pathways were examined for their potential involvement in the apparent radiosensitization effect of APP, as assessed by immunoblotting analyses and mitochondrial potential determination in vitro. Treatment of NCI-H460 cells with 15 nM APP and NCI-H1299 cells with 10 nM APP yielded dose-enhancement ratios of 1.44 and 1.24, respectively. Enhanced ER stress, disrupted mitochondrial membrane potential, and increased reactive oxygen species (ROS) were observed in cells co-treated with APP and IR, and this was followed by the cytosolic release of cytochrome c and consequent activation of caspase-3 and -9. Notably, inhibition of JNK, which prevents caspase activation, blocked the APP/IR-induced activations of ER stress and apoptotic cell death. In NCI-H460 or NCI-H1299 cell-xenografted mice, APP/IR treatment delayed the time it took tumors to reach a threshold size by 22.38 and 16.83 days, respectively, compared with controls, to yield enhancement factors of 1.53 and 1.38, respectively. SIGNIFICANCE: APP has a radiosensitizing function derived from its ability to induce apoptotic cell death via activation of ER stress, disruption of mitochondrial membrane potential, and induction of the caspase pathway.

A novel anti-cancer role of beta-apopicropodophyllin against non-small cell lung cancer cells.[Pubmed:30170025]

Toxicol Appl Pharmacol. 2018 Oct 15;357:39-49.

We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of Beta-Apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16.9, 13.1 and 17.1nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2alpha, CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.

Synthesis of Cyclic beta-Silylalkenyl Triflates via an Alkenyl Cation Intermediate.[Pubmed:30118234]

Org Lett. 2018 Sep 7;20(17):5474-5477.

Trimethylsilylalkyne derivatives are transformed into cyclic beta-silylalkenyl triflates through cationic cyclization and subsequent trapping of the alkenyl cation by a triflate anion. beta-Silylcyclohexenyl triflates and 3-trimethylsilyl-1,4-dihydronaphth-2-yl triflates are generated efficiently using this methodology. These products provide ready access to substituted cyclohexynes, exemplified by a concise total synthesis of Beta-Apopicropodophyllin.

Total Synthesis of the Claimed Structure of (+/-)-Hyptinin and Structural Revision of Natural Hyptinin.[Pubmed:28421764]

J Nat Prod. 2017 May 26;80(5):1446-1449.

A total synthesis of (+/-)-hyptinin was achieved via a convergent route using the key phosphonate, cyclic ketone, and aryl Grignard components. The (1)H and (13)C NMR spectra of natural hyptinin did not agree with those of the synthesized compound. In particular, there were considerable differences between the signals assigned to the protons and carbons surrounding the lactone carbonyl group for the natural and synthesized compounds. The NMR data strongly suggested that the naturally occurring compound, hyptinin, was a structural isomer of the synthesized compound. The structure of the natural compound was eventually established as (+)-Beta-Apopicropodophyllin, based on the synthesis results.

Antiproliferative Compounds from Cleistanthus boivinianus from the Madagascar Dry Forest.[Pubmed:26091020]

J Nat Prod. 2015 Jul 24;78(7):1543-7.

The two new lignans 3alpha-O-(beta-D-glucopyranosyl)desoxypodophyllotoxin (1) and 4-O-(beta-D-glucopyranosyl)dehydropodophyllotoxin (2) were isolated from Cleistanthus boivinianus, together with the known lignans deoxypicropodophyllotoxin (3), (+/-)-Beta-Apopicropodophyllin (4), (-)-desoxypodophyllotoxin (5), (-)-yatein (6), and beta-peltatin-5-O-beta-D-glucopyranoside (7). The structures of all compounds were characterized by spectroscopic techniques. Compounds 1, 4, and 5 showed potent antiproliferative activities against the A2780 ovarian cancer cell line, with IC50 values of 33.0 +/- 3.6, 63.1 +/- 6.7, and 230 +/- 1 nM, respectively. Compounds 2 and 7 showed only modest A2780 activities, with IC50 values of 2.1 +/- 0.3 and 4.9 +/- 0.1 muM, respectively, while compounds 3 and 6 had IC50 values of >10 muM. Compound 1 also had potent antiproliferative activity against the HCT-116 human colon carcinoma cell line, with an IC50 value of 20.5 nM, and compound 4 exhibited modest antiproliferative activity against the A2058 human caucasian metastatic melanoma and MES-SA human uterine sarcoma cell lines, with IC50 values of 4.6 and 4.0 muM, respectively.

Podophyllotoxin derivatives show activity against Brontispa longissima larvae.[Pubmed:20839628]

Nat Prod Commun. 2010 Aug;5(8):1247-50.

In an attempt to find biorational insecticides, eleven podophyllotoxin analogues were tested for their insecticidal activity against the fifth-instar larvae of Brontispa longissima in vivo for the first time. Among all of the tested compounds, deoxypodophyllotoxin (3) and Beta-Apopicropodophyllin (4) showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia toosendan, and important SAR information has been revealed. Together, these preliminary results may be useful in guiding further modification of podophyllotoxins in the development of potential new insecticides.

Structure-activity relationship of chemical defenses from the freshwater plant Micranthemum umbrosum.[Pubmed:16793072]

Phytochemistry. 2006 Jun;67(12):1224-31.

Vascular plants produce a variety of molecules of phenylpropanoid biosynthetic origin, including lignoids. Recent investigations indicated that in freshwater plants, some of these natural products function as chemical defenses against generalist consumers such as crayfish. Certain structural features are shared among several of these anti-herbivore compounds, including phenolic, methoxy, methylenedioxy, and lactone functional groups. To test the relative importance of various functional groups in contributing to the feeding deterrence of phenylpropanoid-based natural products, we compared the feeding behavior of crayfish offered artificial diets containing analogs of elemicin (1) and Beta-Apopicropodophyllin (2), chemical defenses of the freshwater macrophyte Micranthemum umbrosum. Both allyl and methoxy moieties of 1 contributed to feeding deterrence. Disruption of the lactone moiety of 2 reduced its deterrence. Finally, feeding assays testing effects of 1 and 2 at multiple concentrations established that these two natural products interact additively in deterring crayfish feeding.

Chemical defenses promote persistence of the aquatic plant Micranthemum umbrosum.[Pubmed:16586032]

J Chem Ecol. 2006 Apr;32(4):815-33.

Five of the most common macrophytes from an aquaculture facility with high densities of the herbivorous Asian grass carp (Ctenopharyngodon idella) were commonly unpalatable to three generalist consumers-grass carp and the native North American crayfishes Procambarus spiculifer and P. acutus. The rooted vascular plant Micranthemum umbrosum comprised 89% of the total aboveground plant biomass and was unpalatable to all three consumers as fresh tissues, as homogenized pellets, and as crude extracts. Bioassay-guided fractionation of the crude extract from M. umbrosum led to four previously known compounds that each deterred feeding by at least one consumer: 3,4,5-trimethoxyallylbenzene (1) and three lignoids: Beta-Apopicropodophyllin (2); (-)-(3S,4R,6S)-3-(3',4'-methylenedioxy-alpha-hydroxybenzyl)-4-(3'',4''-dimethoxyb enzyl)butyrolactone (3); and (-)-hibalactone (4). None of the remaining four macrophytes produced a chemically deterrent extract. A 16-mo manipulative experiment showed that the aboveground biomass of M. umbrosum was unchanged when consumers were absent, but the biomass of Ludwigia repens, a plant that grass carp preferentially consumed over M. umbrosum, increased over 300-fold. Thus, selective feeding by grass carp effectively eliminates most palatable plants from this community and promotes the persistence of the chemically defended M. umbrosum, suggesting that plant defenses play critical yet understudied roles in the structure of freshwater plant communities.

Rhenium-catalyzed aromatic propargylation.[Pubmed:15070328]

Org Lett. 2004 Apr 15;6(8):1325-7.

A mild aromatic propargylation reaction, employing an air- and moisture-tolerant rhenium-oxo complex ((dppm)ReOCl(3)) as a catalyst and a propargyl alcohol as the electrophile, is described. The reaction tolerates a broad range of functional groups and regioselectively affords propargylic arenas without formation of the isomeric allenyl adducts. The potential of this rhenium(V)-catalyzed reaction is exemplified by application of the propargylation to the synthesis of O-methyldetrol, mimosifoliol, and Beta-Apopicropodophyllin. [reaction: see text]

Immunosuppressive cyclolignans.[Pubmed:8709118]

J Med Chem. 1996 Jul 5;39(14):2865-8.

The immunosuppressive activity of several lactonic, nonlactonic, and heterocycle-fused cyclolignans has been demonstrated for the first time by use of a T-cell-mediated immune response. Of the compounds tested, 4'-demethyldeoxypodophyllotoxin (8), Beta-Apopicropodophyllin (6), and the isoxazoline-fused cyclolignan 15 are the most potent with respect to their suppression of activated splenocytes.

Cytotoxic constituents from Hyptis verticillata.[Pubmed:8277312]

J Nat Prod. 1993 Oct;56(10):1728-36.

A new cytotoxic (P-388 ED50 4 microgm/ml) arylnaphthalene lignan has been isolated from the Mexican medicinal plant Hyptis verticillata (Lamiaceae) and characterized as 5-methoxydehydropodophyllotoxin [1]. Eight additional lignans were also obtained by bioactivity-directed fractionation using the brine shrimp lethality test. Of these, the dehydro-beta-peltatin methyl ether 2 (P-388 ED50 1.8 microgm/ml) is reported for the first time as a natural product isolate. The other bioactive compounds were identified as dehydropodophyllotoxin [3], deoxydehydropodophyllotoxin [4]. (--)-yatein [5], 4'-demethyldeoxypodophyllotixin [6], isodeoxypodophyllotoxin [7], deoxypicropodophyllin [8], and Beta-Apopicropodophyllin [9]. Each of these compounds was evaluated against a panel of cell lines comprising a number of human cancer cell types [breast, colon, fibrosarcoma, lung, prostate, KB, and KB-VI (a multi-drug resistant cell line derived from KB)] and murine lymphocytic leukemia (P-388). Lignans 1-4 showed marginal cytotoxic activity against the human cell lines tested. In contrast, compounds 5-9 demonstrated a general nonspecific activity comparable to that of podophyllotoxin [12] (ED50 < 10-2 microgm/ml). In addition, the antimitotic potential of these compounds was determined in the astrocytoma (ASK) assay. Finally, the plant was also shown to contain the flavonoid sideritoflavone (KB ED50 1.6 microgm/ml) and the known pentacyclic triterpenoids ursolic, maslinic, 2 alpha-hydroxyursolic and oleanolic acids.

Thermal chemistry of podophyllotoxin in ethanol and a comparison of the cytostatic activity of the thermolysis products.[Pubmed:3820102]

J Pharm Sci. 1986 Nov;75(11):1076-80.

Podophyllotoxin (1) in buffered ethanolic solution is degraded by two pathways. One leads to (a) picropodophyllin (2), which undergoes dehydration to give alpha-apopicropodophyllin (5), which rearranges to give Beta-Apopicropodophyllin (6), (b) the ethyl ether of picropodophyllotoxin, 8, and (c) the ethyl ether of epipicropodophyllotoxin, 7. The other pathway leads directly to epipodophyllotoxin (10) and the corresponding ethyl ether, 9, and possibly, via a transient 3,4-dehydropodophyllotoxin (5'), to Beta-Apopicropodophyllin (6). The 1H NMR spectra of these compounds are described, their in vitro cytostatic activity compared, and their syntheses, including that of podophyllotoxin ethyl ether, reported.

Selective IGF1R inhibitor,Linsitinib (OSI-906) is a selective inhibitor of IGF-1R with IC50 of 35 nM in cell-free assays; modestly potent to InsR with IC50 of 75 nM, and no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc. Phase 3.

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