The Experts below are selected from a list of 300 Experts worldwide ranked by ideXlab platform
Hendrik Luesch - One of the best experts on this subject based on the ideXlab platform.
-
caldoramide a modified pentapeptide from the marine cyanobacterium caldora penicillata
Journal of Natural Products, 2016Co-Authors: Sarath P. Gunasekera, Valerie J. Paul, Ranjala Ratnayake, Long H. Dang, Lorelie Imperial, Christiana Garst, Hendrik LueschAbstract:The isolation, structure determination, and biological activities of a new linear pentapeptide, caldoramide (5), from the marine cyanobacterium Caldora penicillata from Florida are described. Caldoramide (5) has structural similarities to belamide A (4), Dolastatin 10 (1), and Dolastatin 15 (2). We profiled caldoramide against parental HCT116 colorectal cancer cells and isogenic cells lacking oncogenic KRAS or hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α). Caldoramide (5) showed differential cytotoxicity for cells containing both oncogenic KRAS and HIF over the corresponding knockout cells. LCMS dereplication indicated the presence of caldoramide (5) in a subset of C. penicillata samples.
-
Caldoramide, a Modified Pentapeptide from the Marine Cyanobacterium Caldora penicillata
2016Co-Authors: Sarath P. Gunasekera, Valerie J. Paul, Ranjala Ratnayake, Long H. Dang, Lorelie Imperial, Christiana Garst, Hendrik LueschAbstract:The isolation, structure determination, and biological activities of a new linear pentapeptide, caldoramide (5), from the marine cyanobacterium Caldora penicillata from Florida are described. Caldoramide (5) has structural similarities to belamide A (4), Dolastatin 10 (1), and Dolastatin 15 (2). We profiled caldoramide against parental HCT116 colorectal cancer cells and isogenic cells lacking oncogenic KRAS or hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α). Caldoramide (5) showed differential cytotoxicity for cells containing both oncogenic KRAS and HIF over the corresponding knockout cells. LCMS dereplication indicated the presence of caldoramide (5) in a subset of C. penicillata samples
-
Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer
2016Co-Authors: Michelle S. Bousquet, Ranjala Ratnayake, Long H. Dang, Jia Jia, Pamela A. Havre, Jin Yao, Nam H. Dang, Valerie J. Paul, Thomas J. Carney, Hendrik LueschAbstract:Colorectal cancer (CRC) is a genetic disease, due to progressive accumulation of mutations in oncogenes and tumor suppressor genes. Large scale genomic sequencing projects revealed >100 mutations in any individual CRC. Many of these mutations are likely passenger mutations, and fewer are driver mutations. Of these, activating mutations in RAS proteins are essential for cancer initiation, progression, and/or resistance to therapy. There has been significant interest in developing drugs targeting mutated cancer gene products or downstream signaling pathways. Due to the number of mutations involved and inherent redundancy in intracellular signaling, drugs targeting one mutation or pathway have been either ineffective or led to rapid resistance. We have devised a strategy whereby multiple cancer pathways may be simultaneously targeted for drug discovery. For proof-of-concept, we targeted the oncogenic KRAS and HIF pathways, since oncogenic KRAS has been shown to be required for cancer initiation and progression, and HIF-1α and HIF-2α are induced by the majority of mutated oncogenes and tumor suppressor genes in CRC. We have generated isogenic cell lines defective in either oncogenic KRAS or both HIF-1α and HIF-2α and subjected them to multiplex genomic, siRNA, and high-throughput small molecule screening. We have identified potential drug targets and compounds for preclinical and clinical development. Screening of our marine natural product library led to the rediscovery of the microtubule agent Dolastatin 10 and the class I histone deacetylase (HDAC) inhibitor largazole to inhibit oncogenic KRAS and HIF pathways. Largazole was further validated as an antiangiogenic agent in a HIF-dependent manner in human cells and in vivo in zebrafish using a genetic model with activated HIF. Our general strategy, coupling functional genomics with drug susceptibility or chemical-genetic interaction screens, enables the identification of potential drug targets and candidates with requisite selectivity. Molecules prioritized in this manner can easily be validated in suitable zebrafish models due to the genetic tractability of the system. Our multidimensional platform with cellular and organismal components can be extended to larger scale multiplex screens that include other mutations and pathways
-
Caldora penicillata gen. nov., comb. nov. (Cyanobacteria), a pantropical marine species with biomedical relevance
Journal of Phycology, 2015Co-Authors: Niclas Engene, Ana Tronholm, Lilibeth A. Salvador-reyes, Hendrik Luesch, Valerie J. PaulAbstract:: Many tropical marine cyanobacteria are prolific producers of bioactive secondary metabolites with ecological relevance and promising pharmaceutical applications. One species of chemically rich, tropical marine cyanobacteria that was previously identified as Symploca hydnoides or Symploca sp. corresponds to the traditional taxonomic definition of Phormidium penicillatum. In this study, we clarified the taxonomy of this biomedically and ecologically important cyanobacterium by comparing recently collected specimens with the original type material and the taxonomic description of P. penicillatum. Molecular phylogenetic analyses of the 16S rRNA gene and the 16S-23S internal transcribed spacer regions showed that P. penicillatum formed an independent clade sister to the genus Symploca, and distantly related to Phormidium and Lyngbya. We propose the new genus Caldora for this clade, with Caldora penicillata comb. nov. as the type species and designate as the epitype the recently collected strain FK13-1. Furthermore, the production of bioactive secondary metabolites among various geographically dispersed collections of C. penicillata showed that this species consistently produced the metabolite Dolastatin 10 and/or the related compound symplostatin 1, which appear to be robust autapomorphic characters and chemotaxonomic markers for this taxon.
-
Targeted Natural Products Discovery from Marine Cyanobacteria Using Combined Phylogenetic and Mass Spectrometric Evaluation
2015Co-Authors: Lilibeth A. Salvador-reyes, Niclas Engene, Valerie J. Paul, Hendrik LueschAbstract:Combined phylogenetic and HPLC-MS-based natural products dereplication methods aimed at identifying cyanobacterial collections containing the potent cytotoxins largazole, Dolastatin 10, and symplostatin 1 were developed. The profiling of the phylogeny, chemical space, and antiproliferative activity of cyanobacterial collections served to streamline the prioritization of samples for the discovery of new secondary metabolites. The dereplication methods highlighted the biosynthetic potential and combinatorial pharmacology employed by marine cyanobacteria. We found that largazole was always coproduced with Dolastatin 10 or with symplostatin 1 and consequently tested combinations of these agents against colon cancer cells. Combinatorial regimens of largazole and Dolastatin 10 aimed at curbing the growth of HCT116 cancer cells showed cooperative activity
Valerie J. Paul - One of the best experts on this subject based on the ideXlab platform.
-
caldoramide a modified pentapeptide from the marine cyanobacterium caldora penicillata
Journal of Natural Products, 2016Co-Authors: Sarath P. Gunasekera, Valerie J. Paul, Ranjala Ratnayake, Long H. Dang, Lorelie Imperial, Christiana Garst, Hendrik LueschAbstract:The isolation, structure determination, and biological activities of a new linear pentapeptide, caldoramide (5), from the marine cyanobacterium Caldora penicillata from Florida are described. Caldoramide (5) has structural similarities to belamide A (4), Dolastatin 10 (1), and Dolastatin 15 (2). We profiled caldoramide against parental HCT116 colorectal cancer cells and isogenic cells lacking oncogenic KRAS or hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α). Caldoramide (5) showed differential cytotoxicity for cells containing both oncogenic KRAS and HIF over the corresponding knockout cells. LCMS dereplication indicated the presence of caldoramide (5) in a subset of C. penicillata samples.
-
Caldoramide, a Modified Pentapeptide from the Marine Cyanobacterium Caldora penicillata
2016Co-Authors: Sarath P. Gunasekera, Valerie J. Paul, Ranjala Ratnayake, Long H. Dang, Lorelie Imperial, Christiana Garst, Hendrik LueschAbstract:The isolation, structure determination, and biological activities of a new linear pentapeptide, caldoramide (5), from the marine cyanobacterium Caldora penicillata from Florida are described. Caldoramide (5) has structural similarities to belamide A (4), Dolastatin 10 (1), and Dolastatin 15 (2). We profiled caldoramide against parental HCT116 colorectal cancer cells and isogenic cells lacking oncogenic KRAS or hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α). Caldoramide (5) showed differential cytotoxicity for cells containing both oncogenic KRAS and HIF over the corresponding knockout cells. LCMS dereplication indicated the presence of caldoramide (5) in a subset of C. penicillata samples
-
Caldora penicillata gen. nov., comb. nov. (Cyanobacteria), a pantropical marine species with biomedical relevance
Journal of Phycology, 2015Co-Authors: Niclas Engene, Ana Tronholm, Lilibeth A. Salvador-reyes, Hendrik Luesch, Valerie J. PaulAbstract:: Many tropical marine cyanobacteria are prolific producers of bioactive secondary metabolites with ecological relevance and promising pharmaceutical applications. One species of chemically rich, tropical marine cyanobacteria that was previously identified as Symploca hydnoides or Symploca sp. corresponds to the traditional taxonomic definition of Phormidium penicillatum. In this study, we clarified the taxonomy of this biomedically and ecologically important cyanobacterium by comparing recently collected specimens with the original type material and the taxonomic description of P. penicillatum. Molecular phylogenetic analyses of the 16S rRNA gene and the 16S-23S internal transcribed spacer regions showed that P. penicillatum formed an independent clade sister to the genus Symploca, and distantly related to Phormidium and Lyngbya. We propose the new genus Caldora for this clade, with Caldora penicillata comb. nov. as the type species and designate as the epitype the recently collected strain FK13-1. Furthermore, the production of bioactive secondary metabolites among various geographically dispersed collections of C. penicillata showed that this species consistently produced the metabolite Dolastatin 10 and/or the related compound symplostatin 1, which appear to be robust autapomorphic characters and chemotaxonomic markers for this taxon.
-
Targeted Natural Products Discovery from Marine Cyanobacteria Using Combined Phylogenetic and Mass Spectrometric Evaluation
2015Co-Authors: Lilibeth A. Salvador-reyes, Niclas Engene, Valerie J. Paul, Hendrik LueschAbstract:Combined phylogenetic and HPLC-MS-based natural products dereplication methods aimed at identifying cyanobacterial collections containing the potent cytotoxins largazole, Dolastatin 10, and symplostatin 1 were developed. The profiling of the phylogeny, chemical space, and antiproliferative activity of cyanobacterial collections served to streamline the prioritization of samples for the discovery of new secondary metabolites. The dereplication methods highlighted the biosynthetic potential and combinatorial pharmacology employed by marine cyanobacteria. We found that largazole was always coproduced with Dolastatin 10 or with symplostatin 1 and consequently tested combinations of these agents against colon cancer cells. Combinatorial regimens of largazole and Dolastatin 10 aimed at curbing the growth of HCT116 cancer cells showed cooperative activity
-
combinatorial strategies by marine cyanobacteria symplostatin 4 an antimitotic natural Dolastatin 10 15 hybrid that synergizes with the coproduced hdac inhibitor largazole
ChemBioChem, 2009Co-Authors: Kanchan Taori, Valerie J. Paul, Yanxia Liu, Hendrik LueschAbstract:Combinatorial biosynthesis meets combinatorial pharmacology, cyanobacterial style: A new antimitotic natural product with features of both Dolastatins 10 and 15 was isolated from the same Floridian Symploca sp. sample that produced the histone deacetylase inhibitor largazole. Both agents in combination are more effective in inhibiting cancer cell proliferation than either agent alone.
Thomas H Corbett - One of the best experts on this subject based on the ideXlab platform.
-
symplostatin 3 a new Dolastatin 10 analogue from the marine cyanobacterium symploca sp vp452
Journal of Natural Products, 2002Co-Authors: Hendrik Luesch, Susan L Mooberry, Wesley Y. Yoshida, Richard E. Moore, Valerie J. Paul, Thomas H CorbettAbstract:Symplostatin 3 (1), a new analogue of Dolastatin 10 (2), has been isolated from a tumor selective extract of a Hawaiian variety of the marine cyanobacterium Symploca sp. VP452. Compound 1 differs from 2 only in the C-terminal unit; the dolaphenine unit is substituted by a 3-phenyllactic acid residue. Symplostatin 3 (1) possesses IC50 values for in vitro cytotoxicity toward human tumor cell lines ranging from 3.9 to 10.3 nM. It disrupts microtubules, but at a higher concentration than 2, correlating with the weaker in vitro cytotoxicity.
-
isolation of Dolastatin 10 from the marine cyanobacterium symploca species vp642 and total stereochemistry and biological evaluation of its analogue symplostatin 1
Journal of Natural Products, 2001Co-Authors: Hendrik Luesch, Susan L Mooberry, Richard E. Moore, Valerie J. Paul, Thomas H CorbettAbstract:The potent antitumor agent Dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be l. Symplostatin 1 (2), like Dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.
-
symplostatin 1 a Dolastatin 10 analogue from the marine cyanobacterium symploca hydnoides
Journal of Natural Products, 1998Co-Authors: Hendrik Luesch, Susan L Mooberry, Thomas H Corbett, Wesley Y. Yoshida, Richard E. Moore, Valerie J. Paul, Fred ValerioteAbstract:A new solid tumor selective cytotoxic analogue of Dolastatin 10 (1) has been isolated from the marine cyanobacterium Symploca hydnoides, collected near Guam. This metabolite has been assigned the trivial name symplostatin 1 (2). This discovery supports the proposal that many compounds isolated from the seahare Dolabella auricularia, the original source of the Dolastatins, are of dietary origin.
Wesley Y. Yoshida - One of the best experts on this subject based on the ideXlab platform.
-
malevamide d isolation and structure determination of an isoDolastatin h analogue from the marine cyanobacterium symploca hydnoides
Journal of Natural Products, 2002Co-Authors: David F Horgen, Emily B Kazmierski, Hans E Westenburg, Wesley Y. Yoshida, Peter J ScheuerAbstract:Malevamide D (1), a highly cytotoxic peptide ester, and the known compound curacin D (5) were isolated from a Hawaiian sample of Symploca hydnoides. The structure of 1 was elucidated by spectroscopic analysis including NMR and high-resolution MS/MS. Partial stereochemical assignments of 1 were made by chiral HPLC analysis of acid and base hydrolysates. Malevamide D (1) demonstrated toxicity against P-388, A-549, HT-29, and MEL-28 cell lines in the subnanomolar range, while curacin D (5) was weakly cytotoxic. Malevamide D (1) is closely related to isoDolastatin H (2), which was previously isolated in low yield from the sea hare Dolabella auricularia. A second Hawaiian sample of S. hydnoides yielded curacin D (5) along with the known Dolastatin-10 analogue symplostatin-1 (3).
-
symplostatin 3 a new Dolastatin 10 analogue from the marine cyanobacterium symploca sp vp452
Journal of Natural Products, 2002Co-Authors: Hendrik Luesch, Susan L Mooberry, Wesley Y. Yoshida, Richard E. Moore, Valerie J. Paul, Thomas H CorbettAbstract:Symplostatin 3 (1), a new analogue of Dolastatin 10 (2), has been isolated from a tumor selective extract of a Hawaiian variety of the marine cyanobacterium Symploca sp. VP452. Compound 1 differs from 2 only in the C-terminal unit; the dolaphenine unit is substituted by a 3-phenyllactic acid residue. Symplostatin 3 (1) possesses IC50 values for in vitro cytotoxicity toward human tumor cell lines ranging from 3.9 to 10.3 nM. It disrupts microtubules, but at a higher concentration than 2, correlating with the weaker in vitro cytotoxicity.
-
symplostatin 1 a Dolastatin 10 analogue from the marine cyanobacterium symploca hydnoides
Journal of Natural Products, 1998Co-Authors: Hendrik Luesch, Susan L Mooberry, Thomas H Corbett, Wesley Y. Yoshida, Richard E. Moore, Valerie J. Paul, Fred ValerioteAbstract:A new solid tumor selective cytotoxic analogue of Dolastatin 10 (1) has been isolated from the marine cyanobacterium Symploca hydnoides, collected near Guam. This metabolite has been assigned the trivial name symplostatin 1 (2). This discovery supports the proposal that many compounds isolated from the seahare Dolabella auricularia, the original source of the Dolastatins, are of dietary origin.
Richard E. Moore - One of the best experts on this subject based on the ideXlab platform.
-
symplostatin 3 a new Dolastatin 10 analogue from the marine cyanobacterium symploca sp vp452
Journal of Natural Products, 2002Co-Authors: Hendrik Luesch, Susan L Mooberry, Wesley Y. Yoshida, Richard E. Moore, Valerie J. Paul, Thomas H CorbettAbstract:Symplostatin 3 (1), a new analogue of Dolastatin 10 (2), has been isolated from a tumor selective extract of a Hawaiian variety of the marine cyanobacterium Symploca sp. VP452. Compound 1 differs from 2 only in the C-terminal unit; the dolaphenine unit is substituted by a 3-phenyllactic acid residue. Symplostatin 3 (1) possesses IC50 values for in vitro cytotoxicity toward human tumor cell lines ranging from 3.9 to 10.3 nM. It disrupts microtubules, but at a higher concentration than 2, correlating with the weaker in vitro cytotoxicity.
-
isolation of Dolastatin 10 from the marine cyanobacterium symploca species vp642 and total stereochemistry and biological evaluation of its analogue symplostatin 1
Journal of Natural Products, 2001Co-Authors: Hendrik Luesch, Susan L Mooberry, Richard E. Moore, Valerie J. Paul, Thomas H CorbettAbstract:The potent antitumor agent Dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be l. Symplostatin 1 (2), like Dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.
-
symplostatin 1 a Dolastatin 10 analogue from the marine cyanobacterium symploca hydnoides
Journal of Natural Products, 1998Co-Authors: Hendrik Luesch, Susan L Mooberry, Thomas H Corbett, Wesley Y. Yoshida, Richard E. Moore, Valerie J. Paul, Fred ValerioteAbstract:A new solid tumor selective cytotoxic analogue of Dolastatin 10 (1) has been isolated from the marine cyanobacterium Symploca hydnoides, collected near Guam. This metabolite has been assigned the trivial name symplostatin 1 (2). This discovery supports the proposal that many compounds isolated from the seahare Dolabella auricularia, the original source of the Dolastatins, are of dietary origin.