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Tomas Hudlicky - One of the best experts on this subject based on the ideXlab platform.
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exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of Pancratistatin in combination with piperlongumine for cancer therapy
The FASEB Journal, 2018Co-Authors: Tyler Gilbert, Sergey Vshyvenko, Christopher Pignanelli, Daniel Tarade, Megan Noel, Fadi Mansour, Manika Gupta, Jesse Ropat, Colin Curran, Tomas HudlickyAbstract:Harsh adverse effects as a result of nonspecific targeting of chemotherapeutics currently pose obstacles in cancer therapy; thus, it would be invaluable to devise novel approaches to specifically target cancer cells. The natural compound Pancratistatin (PST) has been shown to preferentially induce apoptosis in a variety of cancer cell types. Recently, several analogs of PST were shown to be efficacious in inducing apoptosis in a variety of aggressive cancer cell types via cancer cell mitochondrial targeting; it caused dissipation of mitochondrial membrane potential and decreased oxygen consumption, and with isolated mitochondria, it induced the release of apoptogenic factors. The natural compound piperlongumine has been shown to target the stress response to reactive oxygen species in cancer cells. We explored the combinatorial potential of two small molecules (SVTH-6 and piperlongumine) that target these vulnerabilities in cancer cells. Interestingly, when combined with the PST analog, SVTH-6, an increase in mitochondrial dysfunction was observed, leading to an enhanced cytotoxic effect against several human cancer cell types. Additionally, this combination treatment was effective in reducing cancer cell growth in physiologically more relevant 3-dimensional spheroid cell cultures. This enhanced effect was found to be dependent on reactive oxygen species generation because an antioxidant could rescue cancer cells from this combination treatment. Importantly, noncancerous cells were markedly less sensitive to this combination treatment. Thus, targeting mitochondrial and oxidative stress vulnerabilities of cancer cells could be an effective strategy for cancer therapy.-Ma, D., Gilbert, T., Pignanelli, C., Tarade, D., Noel, M., Mansour, F., Gupta, M., Ma, S., Ropat, J., Curran, C., Vshyvenko, S., Hudlicky, T., Pandey. S. Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of Pancratistatin in combination with piperlongumine for cancer therapy.
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Chemoenzymatic Formal Total Synthesis of Pancratistatin from Narciclasine-Type Compounds via Myers Transposition: Model Study for a Short Conversion of Narciclasine to Pancratistatin
Synlett, 2017Co-Authors: Ringaile Lapinskaite, Mukund Ghavre, Chelsea L. Rintelmann, Korey Bedard, Helen E. Dela Paz, Tomas HudlickyAbstract:A formal total synthesis of Pancratistatin was accomplished by conversion of advanced intermediates, used in the synthesis of narciclasine, to Pancratistatin precursors via Myers’ reductive transposition as the key strategic step. The synthesis began with the whole cell fermentation of m -dibromobenzene with JM109(pDTG601a), a recombinant strain that over-expresses toluene dioxygenase, which provided the corresponding cis -dihydrodiol 16 as a single isomer with complete optical purity. The key reductive transposition of the allylic alcohol 8a to olefin 9a allowed for further installation of the C-1/C-2 trans -diol, required for the Pancratistatin scaffold, through the introduction of a cyclic sulfate and its subsequent opening. The formal synthesis of Pancratistatin was accomplished in 14 steps (12 operations) from commercially available m -dibromobenzene. Experimental and spectral data are provided for all new compounds.
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cancer cell mitochondria targeting by Pancratistatin analogs is dependent on functional complex ii and iii
Scientific Reports, 2017Co-Authors: Christopher Pignanelli, Sergey Vshyvenko, Tyler Gilbert, Daniel Tarade, Megan Noel, Fadi Mansour, Scott Adams, Alexander Dowhayko, Kyle Stokes, Tomas HudlickyAbstract:Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound Pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with the inhibition of mitochondrial complex II and III, suggesting mitochondrial or metabolic vulnerabilities may be exploited by this analog. This work provides a scaffold for characterizing distinct mitochondrial and metabolic features of cancer cells and reveals several lead compounds with high therapeutic potential.
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unnatural c 1 homologues of Pancratistatin synthesis and promising biological activities
Canadian Journal of Chemistry, 2012Co-Authors: Sergey Vshyvenko, Tomas Hudlicky, Alexander Kornienko, Jon Scattolon, Anntherese E Romero, Ian Tuffley, Siyaram PandeyAbstract:Several C-1 homologues of Pancratistatin and 7-deoxyPancratistatin were synthesized by a phenanthrene-phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of Pancratistatin and 7-deoxyPancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control.
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synthesis of c 1 homologues of Pancratistatin and their preliminary biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Sergey Vshyvenko, Tomas Hudlicky, Jon Scattolon, Anntherese E Romero, Alexander KornienkoAbstract:The synthesis of two C-1 analogues of Pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.
James Mcnulty - One of the best experts on this subject based on the ideXlab platform.
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Pancratistatin induces apoptosis and autophagy in metastatic prostate cancer cells
International Journal of Oncology, 2011Co-Authors: Carly Griffin, James Mcnulty, Siyaram PandeyAbstract:The Amaryllidaceae alkaloid Pancratistatin has been proven to selectively induce apoptotic cell death in a variety of human cancer cells with an insignificant effect on non-cancerous cells. In this study we report, for the first time, the effects of Pancratistatin (PST) on models of metastatic prostate cancer. The effects of Pancratistatin on prostate cancer DU145 and LNCaP cell lines was assessed by microscopy, enzymatic activity assays and Western blotting. Apoptosis was determined by nuclear condensation and caspase activation, and autophagy was observed by MDC staining and LC3 expression levels. Human prostate xenografts were used to test the potential therapeutic efficacy of intra-tumor administration of Pancratistatin in vivo. Pancratistatin treatment reduced cell viability and induced apoptosis in androgen-responsive (LNCaP) and androgen-refractory (DU145) prostate cancer cell lines in a dose- and time-dependent manner, but with an insignificant effect on normal human fibroblast (NHF) cells at the effective dose. Increased reactive oxygen species production and collapse of mitochondrial membrane potential resulted from treatment with Pancratistatin in both cancer cell lines. This study presents the novel finding that Pancratistatin treatment caused decreased migration capacity and increased autophagy levels in metastatic prostate cancer cells. Importantly, in this proof-of-concept study, Pancratistatin reduced the volume of xenograft tumors compared to control-treated animals, and was well-tolerated. Our results highlight the potential of Pancratistatin for clinical development as a selective therapeutic for treatment of metastatic prostate cancer.
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sensitization of human melanoma cells by tamoxifen to apoptosis induction by Pancratistatin a nongenotoxic natural compound
Melanoma Research, 2011Co-Authors: Sudipa June Chatterjee, James Mcnulty, Siyaram PandeyAbstract:The objective of this study was to determine the efficacy of the natural compound Pancratistatin (PST), isolated from the Hymenocallis littoralis, in human melanoma cells. Melanoma is an aggressive form of skin cancer that is commonly fatal if not diagnosed in its early stage of development. Melanoma is resistant to many treatments, thus drastically limiting chemotherapy options for this cancer. We have shown that exposure to PST induces apoptosis in human melanoma within 72 h using Hoechst staining. Interestingly tamoxifen (TAM), an estrogen receptor antagonist, sensitizes these cells to apoptosis induction by PST as observed with Hoechst and annexin-V staining. This cotreatment did not affect the viability of normal noncancerous human fibroblasts. Both of these compounds have been shown to target the mitochondria synergistically, as indicated by higher levels of reactive oxygen species generation from isolated mitochondria. PST alone and in combination with TAM shows depolarization of the mitochondrial membrane potential as shown by JC-1 staining. Melanoma drug resistance was not observed after posttreatment recuperation, as cells displayed apoptotic morphology up to 96 h after drug-free media replacement. Our results indicate that TAM alone does not induce apoptosis in this cell line, but sensitizes the mitochondria, thereby enhancing the effect of PST exposure. In conclusion, combination of two nongenotoxic compounds offers a novel treatment regime for this notoriously resilient form of skin cancer.
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Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts
Molecular Cancer Therapeutics, 2011Co-Authors: Carly Griffin, James Mcnulty, Aditya Karnik, Siyaram PandeyAbstract:The naturally occurring Amaryllidaceae alkaloid Pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of Pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that Pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53 -mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, Pancratistatin was found to be ineffective against mtDNA-depleted (ρ) cancer cells. Moreover, Pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of Pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of Pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice ( n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that Pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth. Mol Cancer Ther; 10(1); 57–68. ©2011 AACR .
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Pancratistatin induces apoptosis in clinical leukemia samples with minimal effect on non cancerous peripheral blood mononuclear cells
Cancer Cell International, 2010Co-Authors: Carly Griffin, James Mcnulty, Caroline Hamm, Siyaram PandeyAbstract:Pancratistatin, a natural compound extracted from Hymenocallis littoralis, can selectively induce apoptosis in several cancer cell lines. In this ex vivo study, we evaluated the effect of Pancratistatin on peripheral blood mononuclear cells obtained from 15 leukemia patients prior to clinical intervention of newly diagnosed patients, as well as others of different ages in relapse and at various disease progression states. Mononuclear cells from healthy volunteers and leukemia patients were exposed to 1 μM Pancratistatin for up to 48 h. Irrespective of leukemia type, Pancratistatin induced apoptosis in the leukemic samples, with minimal effects on non-cancerous peripheral blood mononuclear control cells. Our results show that Pancratistatin is an effective and selective anti-cancer agent with potential for advancement to clinical trials.
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Potent and selective inhibition of human cytochrome P450 3A4 by seco-Pancratistatin structural analogs.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: James Mcnulty, Jerald J. Nair, Denis J. Crankshaw, Mohini Singh, Alison C. HollowayAbstract:Abstract seco-Derivatives of the anticancer agent Pancratistatin bearing the 2S,3S,4S,5S configuration were accessed via a novel, highly diastereoselective anti-aldol reaction. Structure–activity relationships reveal important insights into the seco-Pancratistatin pharmacophore as a potent and selective inhibitor of human cytochrome P450 3A4 (CYP3A4), and highlight features of concern in advancing a potent, selective anticancer agent in the Pancratistatin series.
Siyaram Pandey - One of the best experts on this subject based on the ideXlab platform.
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unnatural c 1 homologues of Pancratistatin synthesis and promising biological activities
Canadian Journal of Chemistry, 2012Co-Authors: Sergey Vshyvenko, Tomas Hudlicky, Alexander Kornienko, Jon Scattolon, Anntherese E Romero, Ian Tuffley, Siyaram PandeyAbstract:Several C-1 homologues of Pancratistatin and 7-deoxyPancratistatin were synthesized by a phenanthrene-phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of Pancratistatin and 7-deoxyPancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control.
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Pancratistatin induces apoptosis and autophagy in metastatic prostate cancer cells
International Journal of Oncology, 2011Co-Authors: Carly Griffin, James Mcnulty, Siyaram PandeyAbstract:The Amaryllidaceae alkaloid Pancratistatin has been proven to selectively induce apoptotic cell death in a variety of human cancer cells with an insignificant effect on non-cancerous cells. In this study we report, for the first time, the effects of Pancratistatin (PST) on models of metastatic prostate cancer. The effects of Pancratistatin on prostate cancer DU145 and LNCaP cell lines was assessed by microscopy, enzymatic activity assays and Western blotting. Apoptosis was determined by nuclear condensation and caspase activation, and autophagy was observed by MDC staining and LC3 expression levels. Human prostate xenografts were used to test the potential therapeutic efficacy of intra-tumor administration of Pancratistatin in vivo. Pancratistatin treatment reduced cell viability and induced apoptosis in androgen-responsive (LNCaP) and androgen-refractory (DU145) prostate cancer cell lines in a dose- and time-dependent manner, but with an insignificant effect on normal human fibroblast (NHF) cells at the effective dose. Increased reactive oxygen species production and collapse of mitochondrial membrane potential resulted from treatment with Pancratistatin in both cancer cell lines. This study presents the novel finding that Pancratistatin treatment caused decreased migration capacity and increased autophagy levels in metastatic prostate cancer cells. Importantly, in this proof-of-concept study, Pancratistatin reduced the volume of xenograft tumors compared to control-treated animals, and was well-tolerated. Our results highlight the potential of Pancratistatin for clinical development as a selective therapeutic for treatment of metastatic prostate cancer.
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sensitization of human melanoma cells by tamoxifen to apoptosis induction by Pancratistatin a nongenotoxic natural compound
Melanoma Research, 2011Co-Authors: Sudipa June Chatterjee, James Mcnulty, Siyaram PandeyAbstract:The objective of this study was to determine the efficacy of the natural compound Pancratistatin (PST), isolated from the Hymenocallis littoralis, in human melanoma cells. Melanoma is an aggressive form of skin cancer that is commonly fatal if not diagnosed in its early stage of development. Melanoma is resistant to many treatments, thus drastically limiting chemotherapy options for this cancer. We have shown that exposure to PST induces apoptosis in human melanoma within 72 h using Hoechst staining. Interestingly tamoxifen (TAM), an estrogen receptor antagonist, sensitizes these cells to apoptosis induction by PST as observed with Hoechst and annexin-V staining. This cotreatment did not affect the viability of normal noncancerous human fibroblasts. Both of these compounds have been shown to target the mitochondria synergistically, as indicated by higher levels of reactive oxygen species generation from isolated mitochondria. PST alone and in combination with TAM shows depolarization of the mitochondrial membrane potential as shown by JC-1 staining. Melanoma drug resistance was not observed after posttreatment recuperation, as cells displayed apoptotic morphology up to 96 h after drug-free media replacement. Our results indicate that TAM alone does not induce apoptosis in this cell line, but sensitizes the mitochondria, thereby enhancing the effect of PST exposure. In conclusion, combination of two nongenotoxic compounds offers a novel treatment regime for this notoriously resilient form of skin cancer.
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Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts
Molecular Cancer Therapeutics, 2011Co-Authors: Carly Griffin, James Mcnulty, Aditya Karnik, Siyaram PandeyAbstract:The naturally occurring Amaryllidaceae alkaloid Pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of Pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that Pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53 -mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, Pancratistatin was found to be ineffective against mtDNA-depleted (ρ) cancer cells. Moreover, Pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of Pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of Pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice ( n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that Pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth. Mol Cancer Ther; 10(1); 57–68. ©2011 AACR .
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Pancratistatin induces apoptosis in clinical leukemia samples with minimal effect on non cancerous peripheral blood mononuclear cells
Cancer Cell International, 2010Co-Authors: Carly Griffin, James Mcnulty, Caroline Hamm, Siyaram PandeyAbstract:Pancratistatin, a natural compound extracted from Hymenocallis littoralis, can selectively induce apoptosis in several cancer cell lines. In this ex vivo study, we evaluated the effect of Pancratistatin on peripheral blood mononuclear cells obtained from 15 leukemia patients prior to clinical intervention of newly diagnosed patients, as well as others of different ages in relapse and at various disease progression states. Mononuclear cells from healthy volunteers and leukemia patients were exposed to 1 μM Pancratistatin for up to 48 h. Irrespective of leukemia type, Pancratistatin induced apoptosis in the leukemic samples, with minimal effects on non-cancerous peripheral blood mononuclear control cells. Our results show that Pancratistatin is an effective and selective anti-cancer agent with potential for advancement to clinical trials.
David Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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chemoenzymatic synthesis of triazololactams structurally related to Pancratistatin
European Journal of Organic Chemistry, 2017Co-Authors: V De La Sovera, Ana Bellomo, Leopoldo Suescun, David GonzalezAbstract:Fil: de la Sovera, Victoria. Universidad de la Republica. Facultad de Quimica. Departamento de Quimica Organica; Uruguay
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click chemistry approach to structurally simplified Pancratistatin analogs
Proceedings of the 14th Brazilian Meeting on Organic Synthesis Proceedings, 2013Co-Authors: V De La Sovera, Ana Bellomo, David GonzalezAbstract:The alkaloid Pancratistatin isolated from the Polynesian plant Pancratium litoralle exhibits strong antitumor, antiviral, and antiparasitic activity. 1 The mechanism of action has not been fully elucidated but it is known that the compound acts as a selective apoptosis inducer in tumor cells without affecting the normal tissue. There are several syntheses of Pancratistatin but none of the available methods has been adapted to produce large quantities of material which cannot be obtained efficiently from the natural source either. In that sense, research has focused in the synthesis of simplified Pancratistatin analogs. 2
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click chemistry and biocatalysis for the preparation of Pancratistatin analogs
Tetrahedron Letters, 2011Co-Authors: V De La Sovera, Ana Bellomo, David GonzalezAbstract:Tricyclic compounds that are advanced precursors for the synthesis of analogs of the antitumoral alkaloid Pancratistatin were prepared by a short sequence that involved enzymatic dihydroxylation, epoxidation, and intramolecular Huisgen cycloaddition.
George R. Pettit - One of the best experts on this subject based on the ideXlab platform.
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Marine animal and terrestrial plant anticancer constituentsa
2015Co-Authors: George R. PettitAbstract:Abstract- Substantial advances in improving human cancer treatment continue to require discovery and development of new and curative anticancer drugs. Our recent (1989-93) progress in discovery and development of new anticancer drugs derived from marine animal and terrestrial plant biosynthetic products has been reviewed. Special emphasis was placed upon the bryostatin (1,2), dolastatin (4-6), halichondrin (15), halistatin (16,17), spongistatin (18-20), cephalostatin (7-14) and Pancratistatin (34) series of potentially useful anticancer drugs. Real advances in improving human cancer treatment require discovery and development of new and curative anticancer drugs, and we are sharply focused on those objectives. To follow is a 1989-93 review of research progress aimed at discovery of structurally unique and promising anticancer drugs. The summary begins with a historical overview and then places major emphasis on our discoveries of the very important bryostatin (1, ref. l), dolastatin (4,6, ref. 2), halichondrin (15, ref. 3), halistatin (16,17, ref
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Antineoplastic Agents. 587. Isolation and Structure of 3-EpiPancratistatin from Narcissus cv. Ice Follies
2012Co-Authors: George R. Pettit, Noeleen Melody, Rui Tan, Guan-hu Bao, Dennis L. Doubek, Song Gao, Jean-charles Chapuis, Lee WilliamsAbstract:Bioassay-guided (cancer cell line) separation of an extract prepared from Narcissus cv. Ice Follies (from The Netherlands) led to the isolation of a new Amaryllidaceae isocarbostiryl, 3-epiPancratistatin (1b), as well as narciclasine (2). This Narcissus cultivar was found to be a good source of narciclasine. The structure of 1b was established by high-resolution mass and high-field 2D NMR spectroscopic analyses. Against a panel of murine and human cancer cell lines, 3-epiPancratistatin (1b) led to cell growth inhibition (GI50 2.2–0.69 μg/mL) some 100× less than that found for Pancratistatin (1a) and narciclasine (2), thereby revealing an important configurational requirement in 1a for strong cancer cell growth inhibition
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cyclotrimerization approach to unnatural structural modifications of Pancratistatin and other amaryllidaceae constituents synthesis and biological evaluation
Canadian Journal of Chemistry, 2006Co-Authors: Tomas Hudlicky, Jean-charles Chapuis, Michael Moser, Scott C Banfield, Uwe Rinner, George R. PettitAbstract:The phenanthridone core of Pancratistatin lacking all aromatic oxygenation was prepared by cyclotrimerization of acetylene-containing scaffolds 30 and 41, reflecting the natural and the C-1 epi con...
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synthesis and biological activity of some structural modifications of Pancratistatin
ChemInform, 2004Co-Authors: Uwe Rinner, Tomas Hudlicky, Heather Hillebrenner, David R Adams, George R. PettitAbstract:Structurally modified derivatives of 7-deoxyPancratistatin have been synthesized and evaluated in cancer cell line inhibition studies.
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antineoplastic agents 511 direct phosphorylation of phenpanstatin and Pancratistatin
Journal of Natural Products, 2004Co-Authors: George R. Pettit, Noeleen Melody, Delbert L. HeraldAbstract:Selective phosphorylation of phenpanstatin (3a) with tetrabutylammonium dihydrogen phosphate and dicyclohexylcarbodiimide in pyridine followed by cation-exchange chromatographic procedures was found to provide an efficient route to a new series (3b-3d) of promising 3,4-O-cyclic phosphate prodrugs designated phenpanstatin phosphates. Application of analogous reaction conditions to Pancratistatin (1a) led to a mixture of monophosphate derivatives where sodium Pancratistatin 4-O-phosphate (4a) was isolated and the structure confirmed by X-ray crystallography. Modification of the reaction conditions allowed direct phosphorylation of Pancratistatin followed by cation-exchange chromatography to afford sodium Pancratistatin 3,4-O-cyclic phosphate (5a), which was selected for preclinical development.
