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1.
Yakugaku Zasshi ; 142(2): 91-100, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-35110456

RESUMO

Among my recent work on the syntheses of complex natural products based on the development of a novel synthetic method for the heteroaromatic skeleton, this article primarily deals with the total syntheses of (+)-CC-1065, isobatzeline A/B, and batzeline A. These syntheses were accomplished via a novel indole synthesis utilizing a ring expansion reaction of benzocyclobutenone oxime sulfonate as the key step. The 1,2-dihydro-3H-pyrrolo[3,2-e]indole segments of (+)-CC-1065 were rapidly constructed via a two-directional double-ring expansion strategy. Highly substituted pyrrolidine-fused common 5-chloro-2-methylthioindoles of isobatzeline A/B and batzeline A were constructed using a ring expansion reaction of benzocyclobutenone oxime sulfonate with NaSMe and a benzyne-mediated cyclization/functionalization reaction.


Assuntos
Produtos Biológicos/síntese química , Química Orgânica/métodos , Duocarmicinas/síntese química , Indóis/síntese química , Pirroliminoquinonas/síntese química , Quinolonas/síntese química , Ciclização , Oximas/química
2.
Bioorg Med Chem Lett ; 40: 127910, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711443

RESUMO

Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them were synthesized using an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.


Assuntos
Alcaloides/síntese química , Inibidores Enzimáticos/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pirroliminoquinonas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Triptofano Oxigenase/antagonistas & inibidores , Alcaloides/metabolismo , Organismos Aquáticos/química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Alcaloides Indólicos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Pirróis/química , Pirroliminoquinonas/metabolismo , Quinolinas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade
3.
Mar Drugs ; 19(2)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525412

RESUMO

Sponges of the Latrunculiidae family produce bioactive pyrroloiminoquinone alkaloids including makaluvamines, discorhabdins, and tsitsikammamines. The aim of this study was to use LC-ESI-MS/MS-driven molecular networking to characterize the pyrroloiminoquinone secondary metabolites produced by six latrunculid species. These are Tsitsikamma favus, Tsitsikamma pedunculata, Cyclacanthia bellae, and Latrunculia apicalis as well as the recently discovered species, Tsitsikamma nguni and Tsitsikamma michaeli. Organic extracts of 43 sponges were analyzed, revealing distinct species-specific chemical profiles. More than 200 known and unknown putative pyrroloiminoquinones and related compounds were detected, including unprecedented makaluvamine-discorhabdin adducts and hydroxylated discorhabdin I derivatives. The chemical profiles of the new species T. nguni closely resembled those of the known T. favus (chemotype I), but with a higher abundance of tsitsikammamines vs. discorhabdins. T. michaeli sponges displayed two distinct chemical profiles, either producing mostly the same discorhabdins as T. favus (chemotype I) or non- or monobrominated, hydroxylated discorhabdins. C. bellae and L. apicalis produced similar pyrroloiminoquinone chemistry to one another, characterized by sulfur-containing discorhabdins and related adducts and oligomers. This study highlights the variability of pyrroloiminoquinone production by latrunculid species, identifies novel isolation targets, and offers fundamental insights into the collision-induced dissociation of pyrroloiminoquinones.


Assuntos
Biodiversidade , Redes Reguladoras de Genes/fisiologia , Poríferos/genética , Pirroliminoquinonas/isolamento & purificação , Animais
4.
Mar Drugs ; 17(8)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31357586

RESUMO

Non-melanoma skin cancer is one of the major ailments in the United States. Effective drugs that can cure skin cancers are limited. Moreover, the available drugs have toxic side effects. Therefore, skin cancer drugs with less toxic side effects are urgently needed. To achieve this goal, we focused our work on identifying potent lead compounds from marine natural products. Five lead compounds identified from a class of pyrroloiminoquinone natural products were evaluated for their ability to selectively kill squamous cell carcinoma (SCC13) skin cancer cells using an MTT assay. The toxicity of these compounds was also evaluated against the normal human keratinocyte HaCaT cell line. The most potent compound identified from these studies, C278 was further evaluated for its ability to inhibit cancer cell migration and invasion using a wound-healing assay and a trans-well migration assay, respectively. To investigate the molecular mechanism of cell death, the expression of apoptotic and autophagy proteins was studied in C278 treated cells compared to untreated cells using western blot. Our results showed that all five compounds effectively killed the SCC13 cells, with compound C278 being the most effective. Compound C278 was more effective in killing the SCC13 cells compared to HaCaT cells with a two-fold selectivity. The migration and the invasion of the SCC13 cells were also inhibited upon treatment with compound C278. The expression of pro-apoptotic and autophagy proteins with concomitant downregulation in the expression of survival proteins were observed in C278 treated cells. In summary, the marine natural product analog compound C278 showed promising anticancer activity against human skin cancer cells and holds potential to be developed as an effective anticancer agent to combat skin cancer.


Assuntos
Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Pirroliminoquinonas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Pele/diagnóstico por imagem
5.
Mar Drugs ; 17(1)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654589

RESUMO

The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.


Assuntos
Poríferos/metabolismo , Pirroliminoquinonas/química , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/isolamento & purificação , Antimetabólitos Antineoplásicos/farmacologia , Vias Biossintéticas , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , DNA/química , DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Ensaios Enzimáticos , Células HEK293 , Células HeLa , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/isolamento & purificação , Substâncias Intercalantes/farmacologia , Estrutura Molecular , Pirroliminoquinonas/isolamento & purificação , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/farmacologia , Espectrometria de Massas em Tandem/métodos , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia
6.
J Nat Prod ; 81(7): 1666-1672, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-29979591

RESUMO

Six new macrophilone-type pyrroloiminoquines were isolated and identified from an extract of the marine hydroid Macrorhynchia philippina. The proton-deficient and heteroatom-rich structures of macrophilones B-G (2-7) were elucidated by spectroscopic analysis and comparison of their data with those of the previously reported metabolite macrophilone A (1). Compounds 1-7 are the first pyrroloiminoquines to be reported from a hydroid. The macrophilones were shown to inhibit the enzymatic conjugation of SUMO to peptide substrates, and macrophilones A (1) and C (3) exhibit potent and selective cytotoxic properties in the NCI-60 anticancer screen. Bioinformatic analysis revealed a close association of the cytotoxicity profiles of 1 and 3 with two known B-Raf kinase inhibitory drugs. While compounds 1 and 3 showed no kinase inhibitory activity, they resulted in a dramatic decrease in cellular protein levels of selected components of the ERK signal cascade. As such, the chemical scaffold of the macrophilones could provide small-molecule therapeutic leads that target the ERK signal transduction pathway.


Assuntos
Hidrozoários/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pirroliminoquinonas/isolamento & purificação , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirroliminoquinonas/farmacologia , Sumoilação/efeitos dos fármacos
7.
Mar Drugs ; 16(4)2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29597332

RESUMO

Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We found that pyrroloiminoquinone alkaloid Makaluvamine G (MG) inhibits several subtypes of nicotinic receptors and ionotropic γ-aminobutiric acid receptors, showing a higher affinity and moderate selectivity toward muscle nAChR. The action of MG on the latter was studied by a combination of electrophysiology, radioligand assay, fluorescent microscopy, and computer modeling. MG reveals a combination of competitive and un-competitive inhibition and caused an increase in the apparent desensitization rate of the murine muscle nAChR. Modeling ion channel kinetics provided evidence for MG binding in both orthosteric and allosteric sites. We also demonstrated that theα1 (G153S) mutant of the receptor, associated with the myasthenic syndrome, is more prone to inhibition by MG. Thus, MG appears to be a perspective hit molecule for the design of allosteric drugs targeting muscle nAChR, especially for treating slow-channel congenital myasthenic syndromes.


Assuntos
Alcaloides/farmacologia , Músculo Esquelético/metabolismo , Pirróis/farmacologia , Pirroliminoquinonas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Alcaloides/química , Sítio Alostérico , Animais , Modelos Moleculares , Estrutura Molecular , Poríferos , Ligação Proteica , Conformação Proteica , Subunidades Proteicas , Pirróis/química , Pirroliminoquinonas/química , Torpedo/fisiologia
8.
Mar Drugs ; 15(4)2017 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-28353633

RESUMO

This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS² runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC50 data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC-1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC50 values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC50 = 120 nM vs. that of 15 having IC50 = 8.6 nM.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Pirroliminoquinonas/química , Pirroliminoquinonas/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética/métodos , Poríferos/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Relação Estrutura-Atividade
9.
Mar Drugs ; 14(11)2016 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-27801775

RESUMO

Makaluvamines are pyrroloiminoquinones isolated from Zyzzya sponges. Until now, they have been described as topoisomerase II inhibitors with cytotoxic effects in diverse tumor cell lines. In the present work, seven makaluvamines were tested in several antioxidant assays in primary cortical neurons and neuroblastoma cells. Among the alkaloids studied, makaluvamine J was the most active in all the assays. This compound was able to reduce the mitochondrial damage elicited by the well-known stressor H2O2. The antioxidant properties of makaluvamine J are related to an improvement of the endogenous antioxidant defenses of glutathione and catalase. SHSY5Y assays proved that this compound acts as a Nrf2 activator leading to an improvement of antioxidant defenses. A low concentration of 10 nM is able to reduce the reactive oxygen species release and maintain a correct mitochondrial function. Based on these results, non-substituted nitrogen in the pyrrole plus the presence of a p-hydroxystyryl without a double bond seems to be the most active structure with a complete antioxidant effect in neuronal cells.


Assuntos
Antioxidantes/farmacologia , Poríferos/química , Pirróis/química , Pirróis/farmacologia , Pirroliminoquinonas/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Glutationa/metabolismo , Peróxido de Hidrogênio/toxicidade , Camundongos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
10.
J Nat Prod ; 79(5): 1267-75, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27140429

RESUMO

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 µM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 µM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 µM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 µM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.


Assuntos
Alcaloides/farmacologia , Proteína p300 Associada a E1A/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Poríferos/química , Pirroliminoquinonas/farmacologia , Alcaloides/química , Animais , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Masculino , Biologia Marinha , Estrutura Molecular , Neovascularização Patológica , Neoplasias da Próstata/tratamento farmacológico , Pirroliminoquinonas/química , Quinonas , Compostos de Espiro , Tiazepinas , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
J Phys Chem A ; 119(21): 5368-76, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25584854

RESUMO

The first-order hyperpolarizability, ß, has been calculated for a group of marine natural products, the makaluvamines. These compounds possess a common cationic pyrroloiminoquinone structure that is substituted to varying degrees. Calculations at the MP2 level indicate that makaluvamines possessing phenolic side chains conjugated with the pyrroloiminoquinone moiety display large ß values, while breaking this conjugation leads to a dramatic decrease in the calculated hyperpolarizability. This is consistent with a charge-transfer donor-π-acceptor (D-π-A) structure type, characteristic of nonlinear optical chromophores. Dynamic hyperpolarizabilities calculated using resonance-convergent time-dependent density functional theory coupled to polarizable continuum model (PCM) solvation suggest that significant resonance enhancement effects can be expected for incident radiation with wavelengths around 800 nm. The results of the current work suggest that the pyrroloiminoquinone moiety represents a potentially useful new chromophore subunit, in particular for the development of molecular probes for biological imaging. The introduction of solvent-solute interactions in the theory is conventionally made in a density matrix formalism, and the present work will provide detailed account of the approximations that need to be introduced in wave function theory and our program implementation. The program implementation as such is achieved by a mere combination of existing modules from previous developments, and it is here only briefly reviewed.


Assuntos
Produtos Biológicos/química , Modelos Químicos , Poríferos/química , Pirróis/química , Pirroliminoquinonas/química , Animais , Simulação por Computador , Estrutura Molecular , Dinâmica não Linear , Oceanos e Mares , Processos Fotoquímicos , Solventes/química
12.
Org Lett ; 15(7): 1516-9, 2013 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-23472820

RESUMO

A new pyrroloiminoquinone alkaloid, named atkamine, with an unusual scaffold was discovered from a cold, deep water Alaskan sponge Latrunculia sp. collected from the Aleutian Islands. Olefin metathesis was utilized to determine the location of the double bond in the hydrocarbon chain. The absolute configuration was determined by using computational approaches combing with the ECD (electronic circular dichroism) spectroscopy.


Assuntos
Alcaloides/isolamento & purificação , Poríferos/química , Pirroliminoquinonas/isolamento & purificação , Alaska , Alcaloides/química , Animais , Dicroísmo Circular , Estrutura Molecular , Pirroliminoquinonas/química , Estereoisomerismo , Água
13.
J Med Chem ; 55(12): 5851-8, 2012 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-22686608

RESUMO

A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 µM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).


Assuntos
Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Poríferos/química , Pirroliminoquinonas/isolamento & purificação , Pirroliminoquinonas/farmacologia , Animais , Antimaláricos/metabolismo , Antimaláricos/toxicidade , Linhagem Celular , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/toxicidade
14.
Mar Biotechnol (NY) ; 14(6): 681-91, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22310802

RESUMO

Tsitsikamma favus is a latrunculid sponge endemic to the coast of South Africa that produces unique pyrroloiminoquinones known as tsitsikammamines. Wakayin and makaluvamine A are structurally similar to the tsitsikammamines and are the only pyrroloiminoquinones isolated from a source other than Porifera (namely a Fijian ascidian Clavelina sp. and a laboratory culture of the myxomycete Didymium bahiense, respectively). The source of the tsitsikammamines is hypothesised to be microbial, which could provide a means of overcoming the current supply problem. This study focuses on characterising the microbial diversity associated with T. favus. We have used denaturing gradient gel electrophoresis together with clonal and deep sequencing of microbial 16S rRNA gene amplicons to show that specimens of this sponge species contain a distinct and conserved microbial population, which is stable over time and is dominated by a unique Betaproteobacterium species.


Assuntos
Betaproteobacteria/isolamento & purificação , Betaproteobacteria/metabolismo , Biodiversidade , Poríferos/microbiologia , Pirróis/metabolismo , Pirroliminoquinonas/metabolismo , Quinolinas/metabolismo , Animais , Betaproteobacteria/classificação , Oceano Índico , Consórcios Microbianos/fisiologia , Especificidade da Espécie
17.
Mar Drugs ; 8(4): 1394-416, 2010 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-20479983

RESUMO

Many natural products with biologically interesting structures have been isolated from marine animals and plants such as sponges, corals, worms, etc. Some of them are discorhabdin alkaloids. The discorhabdin alkaloids (discorhabdin A-X), isolated from marine sponges, have a unique structure with azacarbocyclic spirocyclohexanone and pyrroloiminoquinone units. Due to their prominent potent antitumor activity, discorhabdins have attracted considerable attention. Many studies have been reported toward the synthesis of discorhabdins. We have accomplished the first total synthesis of discorhabdin A (1), having the strongest activity in vitro among discorhabdins in 2003. In 2009, we have also accomplished the first total synthesis of prianosin B (2), having the 16,17-dehydropyrroloiminoquinone moiety, by a novel dehydrogenation reaction with a catalytic amount of NaN(3). These synthetic studies, as well as syntheses of the discorhabdins by various chemists to-date, are reviewed here.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Pirroliminoquinonas/síntese química , Alcaloides/isolamento & purificação , Animais , Antineoplásicos/síntese química , Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Humanos , Poríferos/química , Pirroliminoquinonas/isolamento & purificação
18.
Org Lett ; 12(3): 436-9, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-20039698

RESUMO

An approach to the synthesis of the tetrahydropyrroloiminoquinone alkaloids has been developed and applied to the preparation of N-1-beta-D-ribofuranosyltetrahydropyrroloiminoquinones. The strategy utilizes oxidative cyclization of aryl-methoxyamides by hypervalent iodine to construct the quinoline framework shared by members of this alkaloid family. The hypervalent iodine oxidant is generated in situ by anodic oxidation of iodobenzene.


Assuntos
Alcaloides/química , Alcaloides/síntese química , Monossacarídeos/síntese química , Pirróis/síntese química , Pirroliminoquinonas/síntese química , Alcaloides/farmacologia , Animais , Catálise , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Iodobenzenos/química , Células KB , Biologia Marinha , Camundongos , Estrutura Molecular , Monossacarídeos/química , Monossacarídeos/farmacologia , Oxirredução , Pirróis/química , Pirróis/farmacologia , Pirroliminoquinonas/química , Pirroliminoquinonas/farmacologia , Estereoisomerismo , Inibidores da Topoisomerase II
19.
Magn Reson Chem ; 48(1): 9-12, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19824003

RESUMO

The structural assignment of bispyrroloquinone and bispyrroloiminoquinone regioisomers was achieved using (13)C NMR spectral data. In the case of bispyrroloiminoquinones, the carbonyl group in the regioisomer possessing a nitrogen atom in both alpha-positions was systematically less deshielded than the carbonyl group in the other regioisomer. In the case of bispyrroloquinones, the most deshielded carbonyl group in the regioisomer with a nitrogen atom in both alpha-positions was more deshielded than the same carbonyl group in the other regioisomer.


Assuntos
Pirroliminoquinonas/química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirroliminoquinonas/síntese química , Estereoisomerismo
20.
Anticancer Drugs ; 20(2): 149-55, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19209032

RESUMO

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The prognosis of the disease is very negative, because the cancer will be usually metastasized by the time a patient manifests symptoms. Although combination therapy shows some promise, new drugs to treat the disease are needed. Given our interest in finding new therapies for pancreatic cancer, we sought to determine whether the known cytotoxic activity of the batzellines extended to pancreatic cancer cell lines. The batzellines are pyrroloiminoquinones alkaloids obtained from the deep-water Caribbean sponge Batzella sp (family Esperiopsidae, order Poecilosclerida). We show here that batzellines exhibit selective cytotoxicity towards the pancreatic cancer cell lines AsPC-1, Panc-1, BxPC-3, and MIA PaCa2 compared with the normal African green monkey kidney epithelial cell line Vero. The batzellines cause cytotoxicity by inducing cell cycle arrest that is mediated by their ability to intercalate into DNA and/or inhibit topoisomerase II activity. The cytotoxic abilities of isobatzellines A and C against pancreatic cancer cell lines, their low toxicity against normal cells, and their reported ability to be synthesized makes them interesting compounds with potential chemotherapeutic effects that may merit further research.


Assuntos
Alcaloides/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Poríferos/química , Pirroliminoquinonas/farmacologia , Alcaloides/toxicidade , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/farmacologia , DNA/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Substâncias Intercalantes/farmacologia , Pirróis/farmacologia , Pirroliminoquinonas/toxicidade , Quinolinas/farmacologia , Especificidade por Substrato , Inibidores da Topoisomerase II
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