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The Structure of Clathrodin, a Novel Alkaloid Isolated from the Caribbean Sea Sponge Agelas clathrodes
Abstract
A new alkaloid containing a nonbrominated pyrrole and a guanidine moiety, clathrodin, has been isolated from the MeOH extract of the Caribbean sea sponge Agelas clathrodes. The structure of clathrodin was determined to be 1 on the basis of its spectral data.
... Clarhamnoside (16), containing an unusual L-rhamnose unit in the sugar head, was the first rhamnosylated α-galactosylceramide from A. clathrodes collected along the coast of Grand Bahamas Island (Sweetings Cay) [11]. The Caribbean sponge A. clathrodes could metabolize clathrosides A-C (17)(18)(19) and isoclathrosides A-C (20)(21)(22), which, respectively, belonged to two families of different glycolipids [12]. Compound 23 was also isolated from the Caribbean specimen ( Figure 6) [13]. ...
... In vitro cytotoxic test indicated that [15], while 27 and 28 had a moderate antifungal activity against Aspergillus niger [16]. Interestingly, compound 29 contained a nonbrominated pyrrole and a guanidine moiety [17]. One specimen of A. clathrodes from the South China Sea was shown to produce an ionic compound (30), which had weak cytotoxicity against cancer cell lines A549 and SGC7901 with IC 50 values of 26.5 and 22.7 µg/mL, respectively [18]. ...
... Clarhamnoside (16), containing an unusual Lrhamnose unit in the sugar head, was the first rhamnosylated α-galactosylceramide from A. clathrodes collected along the coast of Grand Bahamas Island (Sweetings Cay) [11]. The Caribbean sponge A. clathrodes could metabolize clathrosides A-C (17)(18)(19) and isoclathrosides A-C (20)(21)(22), which, respectively, belonged to two families of different glycolipids [12]. Compound 23 was also isolated from the Caribbean specimen ( Figure 6) [13]. ...
The marine sponge genus Agelas comprises a rich reservoir of species and natural products with diverse chemical structures and biological properties with potential application in new drug development. This review for the first time summarized secondary metabolites from Agelas sponges discovered in the past 47 years together with their bioactive effects.
... [1] Their intriguing dimeric polycyclic ring systems that were isolated during the last years revealed their elaborate structures and molecular diversity which arise from a variety of modes of dimerization and polycyclization. Structurally, it is assumed that these metabolites arise from the crucial intermediates clathrodin, [2] hymenidin, [3] or oroidin [4] through either an interesting intramolecular or intermolecular reaction occurring at ambident centers. [5] Although the biosynthesis of these intermediates is not clear, it is obvious that dipeptides involving proline and another amino acid residue such as ornithine or arginine constitute an interesting route for early biosynthetic precursors. ...
... ppm and N3' at d = 152.2 ppm indicating similar connection for C7ÀN3' as found in stylissazole B (2). Additional analysis of 1 H-13 C HMBC spectra showed correlations for H6 (d = 5.07 ppm) and H7 (d = 4.39 ppm) with C2' (d = 160.6 ppm). ...
The three title compounds, dimeric pyrrole-2-aminoimidazole alkaloids, were isolated from the marine sponge Stylissa carteri collected in the Solomon Islands. The isolated compounds are exclusively N[BOND]C-bonded “dimers”, which indicates a different mode of dimerization and adds another dimension to the molecular diversity of pyrrole-2-aminoimidazole alkaloids.
This work is part of the Coral Reef Initiative in the South Pacific (grant CZZ 3012.01 T, AFD). We thank the Solomon Islands Government for collection permits, the Fisheries Department and R. Sulu (University of the South Pacific) for their help and assistance, the field team of the IRD-Nouméa for the collection of the sponge, and John Hooper (Queensland Museum, Brisbane) for the identification of the sample.
... [1] Their intriguing dimeric polycyclic ring systems that were isolated during the last years revealed their elaborate structures and molecular diversity which arise from a variety of modes of dimerization and polycyclization. Structurally, it is assumed that these metabolites arise from the crucial intermediates clathrodin, [2] hymenidin, [3] or oroidin [4] through either an interesting intramolecular or intermolecular reaction occurring at ambident centers. [5] Although the biosynthesis of these intermediates is not clear, it is obvious that dipeptides involving proline and another amino acid residue such as ornithine or arginine constitute an interesting route for early biosynthetic precursors. ...
... ppm and N3' at d = 152.2 ppm indicating similar connection for C7ÀN3' as found in stylissazole B (2). Additional analysis of 1 H-13 C HMBC spectra showed correlations for H6 (d = 5.07 ppm) and H7 (d = 4.39 ppm) with C2' (d = 160.6 ppm). ...
This work is part of the Coral Reef Initiative in the South Pacific (grant CZZ 3012.01 T, AFD). We thank the Solomon Islands Government for collection permits, the Fisheries Department and R. Sulu (University of the South Pacific) for their help and assistance, the field team of the IRD-Nouméa for the collection of the sponge, and John Hooper (Queensland Museum, Brisbane) for the identification of the sample.
... Oroidin ( Figure 21, compound 1) was the first PIA to be isolated, and it was obtained from A. oroides, collected in the Bay of Naples in 1971 [148]. Three closely comparable counterparts have now been found: the monobrominated hymenidin ( Figure 21, compound 3), the N-methylated derivative sventrin ( Figure 21, compound 4) from Bahamas A. sventres [149], and the nonbrominated clathrodin ( Figure 21, compound 2) from Caribbean A. clathrodes collected from Desecheo Island [98]. The most basic PIAs, oroidin (compound 1), clathrodin (compound 2), and hymenidin (compound 3), differ only in their bromine concentration. ...
Bioactive compounds are abundant in animals originating from marine ecosystems. Ion channels, which include sodium, potassium, calcium, and chloride, together with their numerous variants and subtypes, are the primary molecular targets of the latter. Based on their cellular targets, these venom compounds show a range of potencies and selectivity and may have some therapeutic properties. Due to their potential as medications to treat a range of (human) diseases, including pain, autoimmune disorders, and neurological diseases, marine molecules have been the focus of several studies over the last ten years. The aim of this review is on the various facets of marine (or marine-derived) molecules, ranging from structural characterization and discovery to pharmacology, culminating in the development of some "novel" candidate chemotherapeutic drugs that target potassium channels.
... ,167 Ces métabolites secondaires représentent une famille avec des structures variées et originales. Ils se sont montrés avoir des activités biologiques très larges comme antibiotiques, antivirales, antifouling, cytotoxiques, inhibitrices de kinases etc.168 D'un point de vu biosynthétique, la clathrodine 32,169 l'hyménidine 33 170 et l'oroïdine 34 171 constituent les trois monomères principaux de l'ensemble des molécules de cette famille (. ses différents building blocks apportent une diversité moléculaire conséquente à cette famille avec plus de deux cent vingt dérivés isolés.166,172 . ...
Ce manuscrit porte sur la conception, la synthèse et l’évaluation biologique d’analogues de l’oroïdine, monomère de la benzosceptrine C. Ces molécules sont issues de la famille des pyrrole-2-aminoimidazoles, isolées d’éponges marines. La stratégie de simplification et de diversification structurale a conduit à l’identification d’un hit sélectif, inhibiteur de la kinase Aurora B. Celle-ci joue un rôle essentiel dans la division cellulaire et son inhibition conduit à des anomalies mitotiques sévères. De plus, elle est surexprimée dans de nombreux cancers, en faisant une cible thérapeutique de choix en oncologie. L’objectif du projet, à l’interface entre la chimie et la biologie, était de synthétiser un composé chef de file pouvant conduire à un candidat médicament à visée anticancéreuse. Le squelette du hit est constitué de trois parties : une partie 4,5-dibromopyrrole, une partie imidazo[1,2-a]pyrimidine et enfin un linker alcyne. Le travail de chimie médicinal s’est articulé autour de ces trois sites de modulation structurale, qui ont été successivement modifiés et font l’objet des chapitres II à IV, après le chapitre I dédié à l’introduction. Finalement, quatre-vingt deux dérivés ont été synthétisés et évalués in vitro sur Aurora B et un panel de kinases impliquées dans différentes pathologies. Plusieurs analogues se sont avérés très actifs, avec des IC50 allant jusqu’à 34 nM, soit 150 fois plus actifs que le hit initial. Le dernier chapitre porte sur l’étude du mode d’action des inhibiteurs les plus actifs. Des études de cinétiques enzymatiques ont mis en évidence un mode d’inhibition non-ATP compétitif, jusqu’alors jamais décrit pour Aurora B. Par ailleurs, des expériences d’immunomarquage ont permis d’évaluer et de quantifier les effets du meilleur composé sur les cellules traitées, montrant des résultats cohérents avec l’inhibition d’Aurora B. Enfin, des études de modélisation moléculaire avec le meilleur inhibiteur nous ont permis de situer le site de fixation potentiel de nos inhibiteurs afin de poursuivre les pharmacomodulations et l’étude SAR. Le manuscript se termine par une conclusion générale et des perspectives qui proposent des pistes pour optimiser les propriétés physicochimiques et pharmacocinétiques afin d’améliorer les propriétés nécessaires à un candidat médicament.
... Agelas clathrodes and showed cytotoxicity against CHO-K1 hamster ovary cells (Morales and Rodriguez, 1991). A tetracyclic pyrrole-imidazole alkaloid, namely dibromophakellstatin ( Fig. 3), was isolated from the marine sponge Phakellia mauritiana (Pettit et al., 1997). ...
Alkaloids are important chemical compounds that serve as a rich source for drug discovery. Numerous alkaloids screened from medicinal plants and herbs showed antiproliferative and anticancer effects on wide category of cancers both in vitro and in vivo. Vinblastine, vinorelbine, vincristine, and vindesine have already been successfully developed as anticancer drugs. The available and up-to-date information on the ethnopharmacological uses in traditional medicine, phytochemistry, pharmacology and clinical utility of alkaloids were collected using various resources (PubMed, ScienceDirect, Google Scholar and Springerlink). In this article, we provide a comprehensive and critical overview on naturally-occurring alkaloids with anticancer activities and highlight the molecular mechanisms of action of these secondary metabolites. Furthermore, this review also presents a summary of synthetic derivatives and pharmacological profiles useful to researchers for the therapeutic development of alkaloids. Based on the literature survey compiled in this review, alkaloids represent an important group of anticancer drugs of plant origin with enormous potential for future development of drugs for cancer therapy and management.
... Importantly these natural products also possess H1 anti-histaminic activity, where 1 and 0.1 lM response of histamine was almost completely abolished by 3 and 10 lM solution of III and IV respectively (Aiello et al., 2008;Cafieri et al., 1996;Fattorusso and Taglialatela-Scafati, 2000). V and VI were reported as having antiserotonergic (5-HT3 antagonistic) activity on isolated guinea pig ileum (Morales and Rodriguez, 1991;Cafieri et al., 1995). Similarly VII and VIII exhibited their anti-inflammatory potential by inhibition of P 2 X 7 (Buchanan et al., 2007). ...
Hybrids of bromopyrrole alkaloids with aroyl hydrazone feature were synthesized and evaluated for their anti-inflammatory activity using carrageenan induced rat paw edema method. All the tested hybrids showed good anti-inflammatory activity with 64.78–86.03% inhibition of edema. Most active hybrids 4b and 4f were further investigated for antihistaminic H1 [4b -8.09 μg/mL (18.5 μM); 4f -9.26 μg/mL (24.05 μM)] and anti-serotonergic 5-HT3 [4b -7.01 μg/mL (16.04 μM); 4f -9.64 μg/mL (25.04 μM)] activity. Molecule 4f with anti-inflammatory, anti-histaminic and anti-serotonergic activities emerges as potential anti-inflammatory lead form this study.
... Clathrodin (1) is a 2-aminoimidazole alkaloid containing an unsubstituted pyrrole 2-carboxamide moiety, isolated from the Caribbean sea sponge, Agelas clathrodes, which is structurally related to its 2,3-dibromopyrrole analogue, oroidin, from the sponge, Agelas oroides, and 2-bromopyrrole analogue hymenidin from the sponge, Hymeniacidon sp. [2][3][4]. Clathrodin was shown, in experiments performed in cells isolated from chick embryo sympathetic ganglia using the whole cell configuration of the patch clamp technique, to possess neurotoxic activity. It decreased the average maximum amplitudes of isolated inward sodium currents by 30%. ...
Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (NaV) channels. Since there is an urgent need for small molecule NaV channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin was reinvestigated for its potency and NaV channel subtype selectivity. Clathrodin and its synthetic analogues were subjected to screening on a broad range of NaV channel isoforms, both in voltage clamp and patch clamp conditions. Even though clathrodin was not found to exert any activity, some analogues were capable of modulating the NaV channels, hereby validating the pyrrole-2-aminoimidazole alkaloid structure as a core structure for future small molecule-based NaV channel modulators.
... Alkaloid compounds found in tropical Agelas sponges have been shown to be active on muscle and nerve membrane receptors and channels, including Na V channels, and are excellent pharmacological tools to study the physiology and biophysics of these macromolecules [119]. Morales and Rodriguez [96] reported that Caribbean sponges of the genus Agelas contain alkaloids including monomers of clathrodin (CLA,Figure 7-A) and dibromosceptrin (DBS,Figure 7- B). Both compounds have guanidine moieties linked to pyrrol groups with bromide substitutions ranging from none (CLA) to four (DBS). ...
Eukaryotic, voltage-gated sodium (NaV) channels are large membrane proteins which underlie generation and propagation of rapid electrical signals in nerve, muscle and heart. Nine different NaV receptor sites, for natural ligands and/or drugs, have been identified, based on functional analyses and site-directed mutagenesis. In the marine ecosystem, numerous toxins have evolved to disrupt NaV channel function, either by inhibition of current flow through the channels, or by modifying the activation and inactivation gating processes by which the channels open and close. These toxins function in their native environment as offensive or defensive weapons in prey capture or deterrence of predators. In composition, they range from organic molecules of varying size and complexity to peptides consisting of ~10-70 amino acids. We review the variety of known NaV-targeted marine toxins, outlining, where known, their sites of interaction with the channel protein and their functional effects. In a number of cases, these natural ligands have the potential applications as drugs in clinical settings, or as models for drug development.
... (Rinehart, 1989), Astrosclera willeyana (Williams and Faulkner, 1996b), Agelas sp. (Nakamura et al., 1984b), Agelas sceptrum (Walker et al., 1981), Agelas mauritiana (Fathi-Afshar and Allen, 1988), Agelas conifera (Keifer et al., 1991), Agelas nemoechinata (Kobayashi et al., 1991b), Agelas clathrodes (Morales and Rodriguez, 1991), Agelas schmidti (Braekman et al., 1992), Agelas dendromorpha (D'Ambrosio et al., 1993), Agelas oroides (Garcia et al., 1973) Agelas longissima (Cafieri et al., 1995), Agelas novaecaledoniae (Vassas et al., 1996), Agelas dispar (Cafieri et al., 1996), Agelas wiedenmayeri (Assmann et al., 1999), Agelas nakamurai (Iwagawa et al., 1998) and Agelas sventres (Assmann et al., 2001b). ...
Biochemical compounds are a suggested alternative for morphological characters in sponge systematics. The monophyly of the crucial demosponge order Halichondrida is still largely unresolved. Here, we performed a search for synapomorphies, which might aid to define the order and its five families Axinellidae, Bubaridae, Dictyonellidae, Desmoxyidae and Halichondriidae. We also investigated possible links of the order Halichondrida with other demosponge taxa such as suberitids (Hadromerida). Our survey of published compounds revealed hydroxy-nor-sterols as a potential synapomorphy for axinellid taxa, 2,3,6 sulfated sterol nuclei as possible connection between Agelasida and Halichondrida, besides the known pyrrol-2-carboxylic acids and galactosylceramides, furthermore carbonimidic dichlorides, pupukeananes, diterpene isocyanides for the order Halichondrida and linear and cyclic diterpenes for the family Desmoxyidae. The suitability of biochemical characters in systematics is discussed.
... Cyclooroidin (28) isolated from Mediterranean sponge Agelas oroides, was tested on isolated guinea pig ileum for anticholinergic, antiserotonergic, antihistaminic activity but showed no activity [35]. Cytotoxic alkaloid 29 was isolated from Agelas clathrodes collected near Desecheo Island, Puerto Rico, March 1989 [36]. ...
This review provides a detailed account on the biological activities of structurally diverse secondary metabolites from marine sponges having 2-aminoimidazole, glycociamidine and/or 2-thiohydantoin ring functions. This review will complement two previous short reviews which did however not address the potential of these natural products for drug discovery. We will discuss the naturally occurring alkaloids and give an account on their structure activity relationships.
... The NÀH pyrrole subclass was the first group of analogues studied. The dihydro derivatives of the natural products cla- throdin, [34] hymenidin, [35] and oroidin represent the various successive degrees of NÀH pyrrole bromination and were synthesized and screened for their ability to inhibit the formation of P. aeruginosa biofilms (Table 1). As previously reported, scaffold 16 was relatively inactive against both strains (20 % inhibition against PAO1, 15 % against PA14). ...
A 50-compound library based on the marine natural product oroidin was synthesized and assayed for anti-biofilm activity against PAO1 and PA14, two strains of the medically relevant gamma-proteobacterium Pseudomonas aeruginosa. Through structure-activity relationship (SAR) analysis of analogues based on the oroidin template, several conclusions can be drawn as to what structural properties of the synthetic derivatives are necessary to elicit a biological response. Notably, the most active analogues identified were those that contained a 2-aminoimidazole (2-AI) motif and a dibrominated pyrrolecarboxamide subunit. Here we disclose the synthesis and subsequently determined biological activity of this unique class of compounds as inhibitors of biofilm formation that have no direct antibiotic effect.
Neurodegenerative diseases occur when a progressive degeneration of neurons leads to the loss of neuron structure or function and even death. Common neurodegenerative disorders include Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and other dementias. Alzheimer’s is the leading neurodegenerative disease, responsible for more than 60% of dementia cases worldwide. The available treatments for such diseases are inadequate and only help to improve certain symptoms. Hence, developing new treatments and drugs for such diseases is critical. Natural marine products are rich sources of novel compounds that can alter mammalian neurological activity. Though some novel compounds of medicinal importance have been reported from marine sources, this environment remains largely unexplored. Thus far, more than 75 compounds have been isolated from sponges and identified as having neuromodulatory and neuroprotective activities. While most of these compounds are still in the preclinical and clinical study phases, a few have hit the market. Marine sponges are one of the most sustainable and efficient sources to explore when bio-prospecting for neuroprotective compounds can play a role in medicine. Awareness of sponge-derived compounds’ classifications and modes of action is critical to understanding their role in treating neurological disorders.
As one of the most common marine sponges in tropical and subtropical oceans, the sponges of the genus Agelas, have emerged as unique and yet under-investigated pools for discovery of natural products with fabulous molecular diversity and myriad interesting biological activities. The present review highlights the chemical structure and biological activity of 355 compounds that have been isolated and characterized from the members of Agelas sponges, over the period of about five decades (from 1971 to November 2021). For a better understanding, these numerous compounds are firstly classified and presented according to their carbon skeleton as well as their biosynthetic origins. Relevant summaries focusing on the source organism and the associated bioactivity of these compounds belonging to different chemical classes are also provided. This review highlights sponges of the genus Agelas as exciting source for discovery of intriguing natural compounds.
Hymenialdisine an alkaloid of oroidin class has drawn the attention of researchers owing to its unique structural features and interesting biological properties. Hymenialdisine exhibited promising inhibitory activity against a number of therapeutically important kinases viz., CDKs, GSK-3β etc., and showed anti-cancer, anti-inflammatory, anti-HIV, neuroprotective, anti-fouling, anti-plasmodium properties. Hymenialdisine and other structurally related oroidin alkaloids such as dibromo-hymenialdisine, Stevensine, Hymenin, axinohydantoin, Spongicidine A-C, Latonduines and Callyspongisines contain pyrrolo[2,3-c] azepin-8-one core in common. Keeping in view of the interesting structural and therapeutic features of HMD, several structural modifications were carried around the fused-azepinone core which resulted in a number of diverse structural motifs like indolo-azepinones, Paullones, aza-paullones, Darpones and 5,7-dihydro-6H-benzo[b]pyrimido[4,5-d] azepin-6-one. In this review, an attempt is made to collate and review the structures of diverse Hymenialdisine and related fused-azepinones of synthetic/natural origin and their biological properties.
Three new non-brominated pyrrole alkaloids, nakamurines A–C (1–3) were isolated from the South China Sea sponge Agelas nakamurai. Their structures were elucidated on the basis of spectroscopic data. Compound 2 showed weak antimicrobial activity against Candida albicans with MIC of 60 μg/mL.
Covering: up to 2016Dictazoles and sceptrins are singular metabolites of marine origin. The present dichotomic case study provides a comprehensive perspective on these cyclobutane-centered alkaloids and their respective families. Indeed, their upstream and downstream chemistry are both treated herein. Relevant isolation reports and bio-inspired total syntheses are used to decipher the currently admitted biosynthetic hypotheses as well as the emergence of diversity in the two series. This review proposes a transversal vision of the topic, where most aspects of natural product chemistry have a critical importance.
Activation of apoptosis in cancer cells could stop the development of several cancers. Through testing in different human cancer cell lines (blood, liver, pancreas) and cancer stem cell lines (pancreas and testis), a cytomic approach was performed to investigate kinetic differences in the mechanism of proapoptotic activity induced by four synthetic analogues of clathrodin – an alkaloid isolated from Caribbean sea sponge. Active on the tested cancer stem cell lines, analogue 5 interestingly shows a differential response in apo-ptosis induction in the presence of pan caspase inhibitor Z-VAD-fmk in monocytic THP-1 cells. Thus in monocytic cells, contrary to cancer stem cells, this caspase independent mechanism could reflect either a scramblase modulation, a disturbed bidirectional trafficking of the membrane between the surface and cy-toplasm or a necroptosis induction.
Marine sponges continue to attract wide attention from marine natural product chemists and pharmacologists alike due to their remarkable diversity of bioactive compounds. Since the early days of marine natural products research in the 1960s, sponges have notoriously yielded the largest number of new metabolites reported per year compared to any other plant or animal phylum known from the marine environment. This not only reflects the remarkable productivity of sponges with regard to biosynthesis and accumulation of structurally diverse compounds but also highlights the continued interest of marine natural product researchers in this fascinating group of marine invertebrates.
Among the numerous classes of natural products reported from marine sponges over the years, alkaloids, peptides, and terpenoids have attracted particularly wide attention due to their unprecedented structural features as well as their pronounced pharmacological activities which make several of these metabolites interesting candidates for drug discovery. This chapter consequently highlights several important groups of sponge-derived alkaloids, peptides, and terpenoids and describes their biological and/or pharmacological properties.
A series of N-(methoxycarbonylalkyl)bromopyrrole-2-carboamides were synthesized by acylation of amino acid methyl esters with bromo-2- trichloroacetylpyrroles at room temperature in 64.8%-92.2% yields. The structures of products were determined on the basis of 1H NMR, IR, MS spectra and elemental analyses. One of these products was analyzed by single crystal X-ray diffraction. Preliminary antibiotic tests showed that some target compounds inhibit the five bacteria such as Staphylococcus aureus and Streptococcus faecalis.
A series of N-(pyrrole-1-carbonyl)-amino acid methyl esters were synthesized by acylation of amino acid methyl esters with 2-(trichloroacetyl) pyrroles, without using pyrrole-2-carbonyl chloride as an acylating agent, at room temperature in 80.3%-95.6% yields. And the structures of products were determined on the basis of 1H NMR, IR, MS and elemental analyses.
A series of 2-aminobenzothiazole and benzimidazole analogs based on the clathrodin scaffold was synthesized and investigated for their antimicrobial and antiproliferative activities as well as for their effects in hepatitis C virus (HCV) replicon model. Compound 7, derived from 2-aminobenzothiazole, exhibited moderate antimicrobial activity only against the Gram-positive bacterium, Enterococcus faecalis. In the antiviral assay, compounds 4d and 7 were found to suppress the HCV replicon by >70%, but also to exhibit cytotoxicity against the host cells (35 and 44%, respectively). Compounds 4a and 7 demonstrated good activity in the antiproliferative assays on the human melanoma cell line A-375. To assess the selectivity of the effects between cancerous and noncancerous cells, a mouse fibroblast cell line was used. The IC50 values for compound 7 against the melanoma cell line A-375 and the fibroblast cell line BALB/c 3T3 were 16 and 71 µM, respectively, yielding fourfold selectivity toward the cancer cell line. These results suggest that compound 7 should be studied further in order to fully explore its potential for drug development.
This chapter focuses on the biological origin and synthesis of makaluvamines and discorhabdins, and imidazole, pyrrole-imidazole alkaloids.
Game, SET und Match: Pyrrolaminoimidazol‐Alkaloide (PAIs) werden durch Metabiosynthese ausgehend von chlorierten Oroidin‐Analoga in zellfreien Präparationen PAI produzierender Schwämme erhalten. Die Ergebnisse liefern Hinweise, dass die Biosynthese von PAIs über Einelektronentransfers (SETs) verläuft, die C‐C‐Bindungsknüpfungen der Vorstufenmoleküle vermitteln.
A convenient strategy for the scalable synthesis of the 2-aminoimidazole alkaloids, clathrodin, oroidin, and hymenidin derived from marine Agelas species and their analogs possessing a saturated or unsaturated linker moiety is described. The key intermediates, 4-(3-aminopropyl)-1H-imidazol-2-amine and (E)-4-(3-aminoprop-1-en-1-yl)-1H-imidazol-2-amine were obtained through two different synthetic pathways starting from L-omithine and benzyl 1,2-dihydropyridine-1-carboxylate respectively, using (i) an innovative combination of Weinreb amide strategy with di-Boc protection, and (ii) a modified pyridine-1(2H)-carboxylate based strategy. Convenient access to these 2-aminoimidazole amines is crucial for the synthesis of libraries of clathrodin, oroidin, and hymenidin analogs.
A new bisuracil analogue, 3,3-bis(uracil-1-yl)-propan-1-aminium (1), together with four known N-containing metabolites (2-5), were isolated from the South China Sea sponge Agelas clathrodes. Their chemical structures were established on the basis of spectroscopic and spectrometric analysis and comparison with known compounds. Compound 1 is an unusual naturally occurring bisuracil analogue, and compound 2 was isolated from a natural source for the first time. Compounds 2 and 4 exhibit moderate cytotoxicity against cancer cell line SGC7901.
A simple and direct synthesis of 2-aminoimidazoles from vinyl azides and cyanamide was developed. An attractive feature of this protocol is that the desired products are generated in a highly efficient and eco-friendly manner without the use of a catalyst. A plausible mechanism has been proposed.
The full details for our enantioselective total syntheses of (-)-agelastatins A-F (1-6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (-)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (-)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure activity relationship within the natural series. Significantly, (-)-agelastatin A (1) is highly potent against six blood cancer cell lines (20-190 nM) without affecting normal red blood cells (>333 micromolar). (-)-Agelastatin A (1) and (-)-agelastatin D (4), the two most potent members of this family, induce dose dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy we have determined that neither alkaloid affects tubulin dynamics within cells.
Aminoimidazole skeleton represents a unique building block which is often used in the design of modulators of different targets and small molecule drugs. Alkaloids isolated from marine sponges are known to be one of the most common sources of the 2-aminoimidazole compounds and from a medicinal chemistry perspective, the marine alkaloids' fascinating structures as well as their broad spectrum of pharmacological activity make them promising lead compounds for various druggable targets. This review will focus on the presentation of biologically evaluated 2-aminoimidazole compounds showing a variety of pharmacological properties and their structure-activity relationship. The importance of 2-aminoimidazoles as bioisosteres of guanidine, acylguanidine, benzamidine and triazole groups will be highlighted.
The total syntheses of oroidin, hymenidin and clathrodin are reported via the intermediacy of an imidazo[1,2-a]pyrimidine derivative. The chemistry described herein obviates the need for expensive guanidine reagents, multiply protected prefunctionalized 2-aminoimidazole synthons, or the need for laborious olefinations thereby achieving synthetic efficiency amenable to scale-up. The approach outlined in this manuscript provides an opportunity for further functionalizations through the imidazo[1,2-a]pyrimidine core and through functional groups placed strategically on the side chain.
The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.
Convenient synthesis of 2-amino-1,5-disubstituted and 2-amino-1,4,5-trisubstituted imidazoles has been reported using readily available starting materials and simple reagents under mild conditions. Guanylation of 1-amidino-3-trityl-thioureas 1 and 7 using mercury(II) chloride (Caution) as a thiophile resulted in corresponding guanidines 2 and 8 which on reaction with α-bromo ketones yielded 2-tritylaminoimidazoles. Deprotection of 2-tritylaminoimidazoles using trifluoroacetic acid at room temperature furnished desired 2-aminoimidazoles 4 and 10 in good to moderate yields.
Aminoacetonitrile (1) reacted with acetamidinium chloride to give 4-aminoimidazole (4), which reacted with DMFDMA to yield imidazole derivative 7 and with benzylidinemalononitrile and ethoxymethylene malononitrile to give imidazo[1,5-a]pyrimidine derivatives 12 and 15. Compound 1 reacted with β-crotononitrile to yield pyridine derivative 20. Imidazo[1,2-a]pyridine derivative 23 could be obtained via the reaction of 20 with DMFDMA. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:503–508, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10178
The isolation and characterization of the known pyrrole alkaloid agelongine (6) and of the new natural product daminin (7), the bromine-free analogue of 6, from a specimen of the marine sponge Axinella damicornis is described. Compound 7 showed significant neuroprotective properties. Moreover, for the supply of sufficient material for future medicinal investigations, a short total synthesis of 7 was developed.
Game-SET-match: Pyrrole aminoimidazole alkaloids (PAIs) are metabiosynthesized from chlorinated analogues of oroidin by cell-free enzyme preparations from PAI-producing sponges. Evidence and implications for the biosynthesis of PAIs include putative single-electron transfers (SETs) that promote C-C bond-forming reactions of precursors.
Natural Guanidines from marine invertebrates represent a group of bioactive secondary metabolites that revealed prominent pharmacological activities such as antimicrobial, antiproliferative, analgesic, and anti-coagulant properties. Acyclovir (Zovirax(®)), the first guanidine-derived pharmaceutical for the treatment of herpes infections since late 1970s, was synthesized based on a marine arabinosyl nucleoside, spongosine. Recently, ziconotide (Prialt(®)), a synthetic form of the marine-derived peptide (ω-conotoxin MVIIA) comprising a guanidine moiety, has been approved for the treatment of chronic pain. This review surveys over 130 compounds of guanidine-containing secondary metabolites from marine invertebrates with emphasis on their pharmacological significance and structure-activity relationships.
The pyrrole-imidazole family of marine alkaloids, derived from linear clathrodin-like precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that possess a tetracyclic molecular framework incorporating C4-C8 and C7-N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of all known agelastatin alkaloids including the first total syntheses of agelastatins C, D, E, and F. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones.
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The study of the n-butanol extract of the New Caledonian sponge Agelas dendromorpha led to the isolation and identification of three new pyrrole-2-aminoimidazole (P-2-AI) alkaloids, named agelastatins E (3) and F (4) and benzosceptrin C (5), together with 10 known metabolites, agelastatin A (1), agelastatin D (2), sceptrin (6), manzacidin A, tauroacidin A, taurodispacamide A, nortopsentin D, thymine, longamide, and 4,5-dibromopyrrole-2-carboxamide. Their structures were assigned by spectroscopic data interpretation. All the compounds were tested for cytotoxic activity.
Four new dimeric pyrrole-2-aminoimidazole alkaloids have been isolated from the Pacific marine sponges Agelas cf. mauritiana and Phakellia sp. They include the unusual C2 symmetrical benzosceptrins A (4) and B (5), which each possess a unique benzocyclobutane skeleton and nagelamides S (6) and T (7). Their structures and relative configuration were elucidated from spectroscopic data. Plausible biogenetic paths for these compounds are also proposed in this paper.
(Chemical Equation Presented) Two novel spiroaminals, marineosins A and B (1, 2), containing two pyrrole functionalities, were isolated from cultures of a marine sediment-derived actinomycete related to the genus Streptomyces. The marineosins, which appear to be derived from unknown modifications of prodigiosin-like pigment pathways, showed significant inhibition of human colon carcinoma (HCT-116) in an in vitro assay (IC 50 = 0.5 μΜ for marineosin A) and selective activities in diverse cancer cell types.
Pyrrole was discovered in the coal tar by Friedlieb Ferdinand Runge (1794–1867) in May 1834. Only 24 years later — in 1858 — it was obtained in a pure state by Thomas Anderson (1819–1874) by distillation of bone oil. The actual structure of pyrrole, which was suggested by Adolf von Baeyer (1835–1917) in 1870 on the basis of his work on the elucidation of the structure of indigo (1), was proved later (1877) by synthesis by Chichester A. Bell (2). The later development of synthetic methods for the preparation of pyrrole derivatives by Ludwig Knorr in 1884 and Carl Ludwig Paal in 1885 paved the way for Hans Fischer’s overwhelming work on the synthesis of naturally occurring pyrrolic pigments, which culminated in 1929 with the total synthesis of haemin. The relationship of the latter with pyrrole had been already established, at the beginning of the 20th century, by the Russian physician Marceli Nencki (1847–1901) and by William Küster (1863—1929). On the other hand, Leon Pavel Teodor Marchlewski (1869–1946), in collaboration with Nencki, proved in 1901 that haemin and chlorophyll are structurally related. The enormous biological significance of the tetrapyrrolic pigments — the so-called pigments of life (3) — delayed manifestly the search for more simple derivatives of pyrrole in nature. Of great significance, therefore, was the observation made by Sachs in 1931 that the urine of patients affected by acute porphyria gives a positive Ehrlich reaction, which is characteristic for pyrrole and its derivatives (4).
[reaction: see text] A short synthesis of the C(11)N(5) oroidin derivatives is reported. The key step of the strategy is a one-pot oxidative bromine-mediated addition of protected guanidines to the N-acyl-1,2-dihydropyridines 9a-c. The new N-acyl-1,2-dihydropyridines were prepared directly from pyridine and pyrrole-2-carbonyl chloride by reduction with borohydride reagent in one step.
Two new bromopyrrole alkaloids, dispyrin (6) and dibromoagelaspongin methyl ether (12), were isolated from the Caribbean sponge Agelas dispar, collected near the Venezuelan island La Blanquilla, and their structures were elucidated from spectroscopic data analysis. Dispyrin (6) contains a novel bromopyrrole tyramine motif that has no precedent in marine natural products chemistry and represents a notable variation from the oroidin class compounds consistently produced by species of Agelas in general. Compounds isolated from Caribbean Agelas species were found to possess a unique biogeographical bromination trend.
A microwave-assisted protocol was developed for the construction of di- and monosubstituted 2-aminoimidazoles. The two-step reaction involves the synthesis of N-(1H-imidazol-2-yl)acetamides from readily available alpha-haloketones and N-acetylguanidine, followed by deacetylation. Significant rate enhancement was observed for both steps of the protocol, and the overall reaction time was shortened to 20 min compared to 48 h of the conventional procedures. A representative set of di- and monosubstituted 2-aminoimidazoles was prepared using commercially available parallel reactors.
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