- Total syntheses of tambjamines C, E, F, G, H, i and J, BE-18591, and a related alkaloid from the marine bacterium pseudoalteromonas tunicata
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The acetate salts of tambjamines C, E, and F (2-4, respectively), as well as those of the related alkaloids BE-18591 (5) and 6, have been prepared by treatment of bipyrrole aldehyde 16 with the relevant amine in the presence of acetic acid. The 5′-bromc-a
- Pinkerton, David M.,Banwell, Martin G.,Willis, Anthony C.
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- Metabolomics Reveals Minor Tambjamines in a Marine Invertebrate Food Chain
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Metabolomics analysis detected tambjamine alkaloids in aqueous and EtOAc extracts of the marine invertebrates Virididentula dentata, Tambja stegosauriformis, Tambja brasiliensis, and Roboastra ernsti. Among several tambjamines, the new amino acid derivatives tambjamines M-O (17-19) were identified by Marfey's advanced analysis, UPLC-MS/MS analyses, and total synthesis. The tambjamine diversity increased from the bryozoan V. dentata to its nudibranch predators T. stegosauriformis and T. brasiliensis and attained a higher diversity in R. ernsti, the nudibranch that preys upon T. stegosauriformis and T. brasiliensis. The total tambjamine content also increases among the trophic levels, probably due to biomagnification. Tambjamines A (1), C (3), and D (4) are the major metabolites in the tissues of V. dentata, T. stegosauriformis, T. brasiliensis, and R. ernsti and are likely the main chemical defenses of these marine invertebrates.
- Takaki, Mirelle,Freire, Vítor F.,Nicacio, Karen J.,Bertonha, Ariane F.,Nagashima, Nozomu,Sarpong, Richmond,Padula, Vinicius,Ferreira, Antonio G.,Berlinck, Roberto G. S.
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- DNA binding by 4-methoxypyrrolic natural products. Preference for intercalation at AT sites by tambjamine E and prodigiosin
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The 4-methoxypyrrolic natural products contain a common 4-methoxy-2,2'- bipyrrole chromophore and exhibit promising anticancer, antimicrobial, and immunosuppressive activities. Herein, the ability of two representative members, tambjamine E (1) and prodigiosin (2), to bind calf thymus DNA (CT- DNA), polyd[G-C]2, and polyd[A-T]2 has been characterized using absorption and fluorescence spectroscopy. Scatchard plots showed that 1 occupies a site size (n) of ca. three base pairs and possesses affinity constants (K) ranging from 1 to 0.1 x 105 M-1. Prodigiosin (2) binds DNA by mixed modes, as isobestic points were not evident in titration experiments. The neutral aldehyde precursor 4 was found to possess no measurable DNA binding affinity, indicating that the enamine structure of 1 and the pyrromethene of 2 are essential elements for DNA binding affinity. The enamine of 1 was found to undergo hydrolysis to 4 with a half-life (t( 1/2 )) of 14.5 h at pH 7.4 and 37.5 °C. For the B-ring nitrogen atom of 1, a pK(a) value of 10.06 was also established. From fluorescence spectroscopy it was found that 1, 2, and 4 possess weak emission spectra in water that is increased in nonaqueous solvents. For 1 and 2, DNA binding also increased the emission yield. Energy- transfer measurements suggested an intercalative binding mode, with preference for AT sites. The ability of distamycin to displace 1 and 2 from the helix also suggested that they intercalate from the minor-groove. This specificity differs from other unfused aromatic cations that bind by a minor- groove mode at AT sequences and intercalate at GC sites. Reasons for the specificity displayed by 1 and 2, as well as the implications of our findings to their biological properties are discussed.
- Melvin, Matt S.,Ferguson, David C.,Lindquist, Neils,Manderville, Richard A.
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- Stereochemistry and Mechanism of Undecylprodigiosin Oxidative Carbocyclization to Streptorubin B by the Rieske Oxygenase RedG
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The prodiginines are a group of specialized metabolites that share a 4-methoxypyrrolyldipyrromethene core structure. Streptorubin B is a structurally remarkable member of the prodiginine group produced by Streptomyces coelicolor A3(2) and other actinobacteria. It is biosynthesized from undecylprodigiosin by an oxidative carbocyclization catalyzed by the Rieske oxygenase-like enzyme RedG. Undecylprodigiosin derives from the RedH-catalyzed condensation of 2-undecylpyrrole and 4-methoxy-2, 2′-bipyrrole-5-carboxaldehyde (MBC). To probe the mechanism of the RedG-catalyzed reaction, we synthesized 2-(5-pentoxypentyl)-pyrrole, an analogue of 2-undecylpyrrole with an oxygen atom next to the site of C-C bond formation, and fed it, along with synthetic MBC, to Streptomyces albus expressing redH and redG. This resulted in the production of the 6′-oxa analogue of undecylprodigiosin. In addition, a small amount of a derivative of this analogue lacking the n-pentyl group was produced, consistent with a RedG catalytic mechanism involving hydrogen abstraction from the alkyl chain of undecylprodigiosin prior to pyrrole functionalization. To investigate the stereochemistry of the RedG-catalyzed oxidative carbocyclization, [7′-2H](7′R)-2-undecylpyrrole and [7′-2H](7′S)-2-undecylpyrrole were synthesized and fed separately, along with MBC, to S. albus expressing redH and redG. Analysis of the extent of deuterium incorporation into the streptorubin B produced in these experiments showed that the pro-R hydrogen atom is abstracted from C-7′ of undecylprodigiosin and that the reaction proceeds with inversion of configuration at C-7′. This contrasts sharply with oxidative heterocyclization reactions catalyzed by other nonheme iron-dependent oxygenase-like enzymes, such as isopenicillin N synthase and clavaminate synthase, which proceed with retention of configuration at the carbon center undergoing functionalization. (Chemical Equation Presented).
- Withall, David M.,Haynes, Stuart W.,Challis, Gregory L.
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- Defensive Metabolites from Three Nembrothid Nudibranchs
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The nembrothid nudibranchs Tambje abdere, T. eliora, and Roboastra tigris all contain Tambjamines A-D (4-7).The aldehydes 1-3, produced during extraction with methanol, were key compounds in the structural elucidation.The tambjamines were traced to a food source, the bryozoan Sessibugula translucens, and were implicated in the chemical defense mechanism of the Tambje species.
- Carte, Brad,Faulkner, D. John
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- Singlet oxygen reactions of 3-methoxy-2-pyrrole carboxylic acid tert-butyl esters. A route to 5-substituted pyrrole precursors of prodigiosin and analogs
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Reaction of the tert-butyl ester of 3-methoxy-2-pyrrole carboxylic acid with singlet oxygen yields a peroxidic intermediate which undergoes coupling with a range of nucleophiles to yield 5-substituted pyrroles. Among these products are α,α′-bipyrroles whi
- Wasserman, Harry H.,Xia, Mingde,Wang, Jianji,Petersen, Anders K.,Jorgensen, Michael,Power, Patricia,Parr, Jonathan
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- Total Synthesis and Antimalarial Activity of 2-(p-Hydroxybenzyl)-prodigiosins, Isoheptylprodigiosin, and Geometric Isomers of Tambjamine MYP1 Isolated from Marine Bacteria
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Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(p-hydroxybenzyl)-prodigiosins (2-5), isoheptylprodigiosin (6), and geometric isomers of tambjamine MYP1 ((E/Z)-7) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines24-27in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel ofPlasmodium falciparumparasites, with a great therapeutic index. Notably, prodiginines6and24-27provided curative in vivo efficacy against erythrocyticPlasmodium yoeliiat 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines.
- Kancharla, Papireddy,Li, Yuexin,Yeluguri, Monish,Dodean, Rozalia A.,Reynolds, Kevin A.,Kelly, Jane X.
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- Two-step synthesis of the bipyrrole precursor of prodigiosins
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The key intermediate in the synthesis of prodigiosins, 4-methoxy-2, 2′-bipyrrole-5-carboxaldehyde, has been prepared in two steps and 65% overall yield from the commercially available 4-methoxy-3-pyrrolin-2-one.
- Dairi, Kenza,Tripathy, Sasmita,Attardo, Giorgio,Lavallée, Jean-Fran?ois
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- Novel imidazopyridine suppresses STAT3 activation by targeting SHP-1
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The unregulated activation of STAT3 has been demonstrated to occur in many cancers and enhances tumour growth, migration, and invasion. Stimulation by cytokines, growth factors, and hormones triggers this activation by phosphorylating STAT3 at tyrosine 705. Novel imidazopyridine compounds were synthesized to evaluate the inhibition of STAT3 at Y705. Among the tested compounds, 16 reduced the level of phospho-STAT3, inhibited the downstream signalling cascade and subsequently attenuated the survival of hepatocellular carcinoma (HCC) cells. Further assays showed that the reduction effects of compound 16 on tyrosine 705 of STAT3 were attributed to up-regulation of protein tyrosine phosphatase SHP-1.
- Su, Jung-Chen,Wu, Szu-Hsien,Shiau, Chung-Wai,Chang, Chuan-Hsun
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p. 1248 - 1255
(2018/10/31)
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- Antimalarial activity of natural and synthetic prodiginines
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Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds. Herein we describe the in vitro antimalarial activity of four natural (IC50 = 1.7-8.0 nM) and three sets of synthetic prodiginines against Plasmodium falciparum. Set 1 compounds replaced the terminal nonalkylated pyrrole ring of natural prodiginines and had diminished activity (IC 50 > 2920 nM). Set 2 and set 3 prodiginines were monosubstituted or disubstituted at either the 3 or 5 position of the right-hand terminal pyrrole, respectively. Potent in vitro activity (IC50 = 0.9-16.0 nM) was observed using alkyl or aryl substituents. Metacycloprodiginine and more potent synthetic analogues were evaluated in a P. yoelii murine patent infection using oral administration. Each analogue reduced parasitemia by more than 90% after 25 (mg/kg)/day dosing and in some cases provided a cure. The most favorable profile was 92% parasite reduction at 5 (mg/kg)/day, and 100% reduction at 25 (mg/kg)/day without any evident weight loses or clinical overt toxicity.
- Papireddy, Kancharla,Smilkstein, Martin,Kelly, Jane Xu,Shweta,Salem, Shaimaa M.,Alhamadsheh, Mamoun,Haynes, Stuart W.,Challis, Gregory L.,Reynolds, Kevin A.
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experimental part
p. 5296 - 5306
(2011/10/02)
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- Role and substrate specificity of the Streptomyces coelicolor RedH enzyme in undecylprodiginine biosynthesis
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The function of RedH from Streptomyces coelicolor as an enzyme that catalyses the condensation of 4-methoxy-2,2′-bipyrrole-5-carboxaldehyde (MBC) and 2-undecylpyrrole to form the natural product undecylprodiginine has been experimentally proven, and the s
- Haynes, Stuart W.,Sydor, Paulina K.,Stanley, Anna E.,Song, Lijiang,Challis, Gregory L.
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p. 1865 - 1867
(2008/12/22)
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- Chemoenzymatic synthesis of prodigiosin analogues - Exploring the substrate specificity of PigC
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Analogues of prodigiosin, a tripyrrolic pigment produced by Serratia species with potent immunosuppressive and anticancer activities, have been produced by feeding synthetic analogues of the normal precursor MBC to mutants of Serratia sp. ATCC 39006 or to engineered strains of Escherichia coli; in this way it has been shown that the prodigiosin synthesising enzyme, PigC, has a relaxed substrate-specificity. The Royal Society of Chemistry.
- Chawrai, Suresh R.,Williamson, Neil R.,Salmond, George P. C.,Leeper, Finian J.
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p. 1862 - 1864
(2008/12/22)
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- Pyrrole-singlet oxygen reactions leading to α,α'-bipyrroles. Synthesis of prodigiosin and analogs
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Reaction of the tert-butyl ester of 3-methoxy-2-pyrrolecarboxylic acid with singlet oxygen yields a hydroperoxide intermediate which undergoes coupling with pyrroles to yield precursors of prodigiosin and ring A analogs, readily convertible to the corresponding tripyrromethenes.
- Wasserman, Harry H.,Petersen, Anders K.,Xia, Mingde,Wang, Jianji
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p. 7587 - 7589
(2007/10/03)
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- THE CHEMISTRY OF VICINAL TRICARBONYLS A TOTAL SYNTHESIS OF PRODIGIOSIN
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The addition of primary amines to alkenyl vicinal tricarbonyls leads to 5-substituted-3-hydroxypyrroles.This reaction has been employed in a synthesis of the 2-formyl-3-methoxy-α,α'-bipyrrole precursor of the prodigiosin family of natural products.
- Wasserman, Harry H.,Lombardo, Louis J.
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p. 1725 - 1728
(2007/10/02)
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- Total Synthesis of Prodigiosin, Prodigiosene, and Desmethoxyprodigiosin: Diels-Adler Reactions of Heterocyclic Azadienes and Development of an Effective Palladium(II)-Promoted 2,2'-Bipyrrole Coupling Procedure
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The total synthesis of prodigiosin (1), a red pigment first isolated from Serratia marcescens, possessing the characteristic pyrrolylpyrromethene skeleton of a class of naturally occurring polypyrroles exhibiting antimicrobial and cytotoxic properties, is detailed.The approach is based application of an inverse electron demand Diels-Adler reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate in a 1,2,4,5-tetrazine--->1,2-diazine--->pyrrole strategy for preparation of prodigiosin pyrrole ring B and the subsequent implementation of an effective intramolecular palladium(II)-promoted 2,2'-diaryl coupling for construction of the prodigiosin 2,2'-bipyrrole AB ring system.In situ generated activated ester derivatives of pyrrole-1-carboxylic acid or the use of pyrrole-1-carboxylic acid anhydride proved suitable for the generation of mixed 1,1'-carbonyldipyrrole compounds for use in the palladium(II)-promoted mixed, 2,2'-bipyrrole coupling.Extensions of this approach to the preparation of the naturally occurring parent pyrrolylpyrromethene, prodigiosene (2a), and 2-methyl-3-pentylprodigiosene (2e, desmethoxyprodigiosin) are detailed.A comparison of the in vitro cytotoxic properties of prodigiosin (1), prodigiosene (2a), and 2-methyl-3-pentylprodigiosene (2e) are reported and reveal exceptional cytotoxic potency (3.7*10-4 μg/mL = 3.7*10-10 g/mL) for prodigiosin against 9PS (P388) mouse leukemia which may be attributed to the presence of the prodigiosin C-6 methoxy substituent.
- Boger, Dale L.,Patel, Mona
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p. 1405 - 1415
(2007/10/02)
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- TOTAL SYNTHESIS OF PRODIGIOSIN
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The total synthesis of prodigiosin (1), possessing the characteristic pyrrolylpyrromethene skeleton of a class of naturally-occuring polypyrroles, is detailed.The approach is based on the application of an inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate in a 1,2,4,5-tetrazine -> 1,2-diazine -> pyrrole strategy for preparation of prodigiosin pyrrole ring B and the subsequent implementation of an intramolecular palladium(II)-promoted 2,2'-diaryl (2,2'-bipyrrole) coupling for construction of the prodigiosin 2,2'-bipyrrole AB ring system.
- Boger, Dale L.,Patel, Mona
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p. 2499 - 2502
(2007/10/02)
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