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New cytotoxic callipeltins from the Solomon Island marine sponge Asteropus sp
Abstract
Four new callipeltin A derivatives (N–Q) have been isolated from the Solomon Island marine sponge Asteropus sp. Their structures were established by spectroscopic techniques followed by acid hydrolysis and derivatisation of the free amino acids, and subsequent LCMS analysis of the derivatives. The compounds were evaluated for their activity against cancer cell lines A2058 (melanoma), HT-29 (colorectal adenocarcinoma) and MCF-7 (breast adenocarcinoma) and non-malignant MRC-5 fibroblast cells. While the acyclic callipeltins P and Q were inactive the cyclic callipeltins N and O showed significant cytotoxicity against all exposed cell lines with IC50 values as low as 0.16 μM confirming the role of cyclic configuration in biological activity.
... [100][101] The other homoAA found in sponge NPs is hPro that is all in derivatives of papuamides ( Figure 19). [106][107][108][109] Papuamide derivatives share the same or highly relevant structures, but they can be classified into three types, named Type I, II, and III in this manuscript. The structure of papuamide derivatives can be divided into three portions: (1) the cyclic depsipeptide with seven or eight amino acids including a hPro residue (core-1), (2) the 3,4-dimethylglutamine residue attaching to the ring (core-2), and (3) the side chain containing two or three (modified) amino acids with a hydroxylated saturated/unsaturated fatty acid attaching to the N-terminus (core-3) (Figure 19). ...
... The core-3 structure of Type I contains the linear chain of three amino acids followed by 2,3-di-hydroxylated unsaturated branched fatty acid. All amino acids can be modified or replaced with others, but the ester linkage of the core-1 structure is formed between the carboxylic acid of the hPro residue (some are substituted) and the side chain of the Thr residue (some are modified), which can be linearized in a few cases, such as callipeltins P and Q. [107] All papuamide derivatives showed antiviral and/or anticancer activity, except for papuamides E and F that were tested for toxicity to the invertebrate animal brine shrimp. [109h] Other animal NPs: homoAA-containing NPs isolated from non-sponge species have been reported. ...
... The first path is catalyzed by Lys cyclodeaminase which has been proposed to catalyze a four-step reaction similar to Orn Figure 19. Papuamide derivatives are divided into three types (I, II, and III), and papuamide A, [106] callipeltin N, [107] and neamphamide A [108] are shown as an example of each Type, respectively. The core cyclic septadepsipeptide structure in Types I and II is colored in ocher; the core cyclic octadepsipeptide in Type III is colored in dark turquoise; the core side chain structure in Type I is colored in green; the core side chain structure in Types II and III is colored in orange. ...
This review focuses on discussing natural products (NPs) that contain higher homologated amino acids (homoAAs) in the structure as well as the proposed and characterized biosynthesis of these non‐proteinogenic amino acids. Homologation of amino acids includes the insertion of a methylene group into its side chain. It is not a very common modification found in NP biosynthesis as approximately 450 homoAA‐containing NPs have been isolated from four bacterial phyla (Cyanobacteria, Actinomycetota, Myxococcota, and Pseudomonadota), two fungal phyla (Ascomycota and Basidiomycota), and one animal phylum (Porifera), except for a few examples. Amino acids that are found to be homologated and incorporated in the NP structures include the following ten amino acids: alanine, arginine, cysteine, isoleucine, glutamic acid, leucine, phenylalanine, proline, serine, and tyrosine, where isoleucine, leucine, phenylalanine, and tyrosine share the comparable enzymatic pathway. Other amino acids have their individual homologation pathway (arginine, proline, and glutamic acid for bacteria), likely utilize the primary metabolic pathway (alanine and glutamic acid for fungi), or have not been reported (cysteine and serine). Despite its possible high potential in the drug discovery field, the biosynthesis of homologated amino acids has a large room to explore for future combinatorial biosynthesis and metabolic engineering purpose.
... Marine sponges are well known as prolific sources of biologically natural products and are the second largest group of producers of marine-derived depsipeptides (162-212, Figure 8) [71][72][73][74][75][76][77][78][79][80][81][82][83][84]. With respect to the genus and species, however, there are no striking features about these sponges. ...
... Callipeltin A (162), obtained from a shallow water sponge of the genus Callipelta, exhibited a protective effect on cells infected with human immunodeficiency (HIV) virus [74]. Callipeltins N (164) and O (165) showed significant cytotoxicity against A2058, HT-29, MCF-7 and MRC-5 cell lines, with an IC50 value of 0.16 µ M [75]. Cyclolithistide A (166) was discovered as a novel antifungal cyclodepsipeptide containing the unique amino acids 4-amino-3,5-dihydroxyhexanoic acid, formyl-leucine and chloroisoleucine [76]. ...
... Compound 261 had significant cytotoxicity in the NCI-60 cell line panel (median GI50 = 9.1μM), with highly enhanced selectivity against the CNS cancer cell line SF-268 (GI50 = 6.5 nM) and the renal cancer cell line RXF 393 (GI50≤5.0nM) [75]. ...
Depsipeptides, an important group of polypeptides containing residues of hydroxy acids and amino acids linked together by amide and ester bonds, have potential applications in agriculture and medicine. A growing body of evidence demonstrates that marine organisms are prolific sources of depsipeptides, such as marine cyanobacteria, sponges, mollusks, microorganisms and algae. However, these substances have not yet been comprehensively summarized. In order to enrich our knowledge about marine depsipeptides, their biological sources and structural features, as well as bioactivities, are highlighted in this review after an extensive literature search and data analysis .
... Recently, callipeltins O (1) and Q (2) were isolated from the Solomon Islands marine sponge Asteropus sp. by Tabudravu's group ( Fig. 1) (Stierhof et al. 2016). The chemical structures of both peptides were established by 1D-and 2D-NMR experiments, as well as MS/MS fragmentation analysis. ...
... (3), (R)-allo-Thr (4), 4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE), and 3-hydroxy-2,4,6-trimethylheptanoic acid (HTH). The stereochemistry of these amino acids, with exception of 3-MeGln (3), was determined by Marfey's method after acid hydrolysis of callipeltins O (1) and Q (2) (Stierhof et al. 2016). Although the configurations of 3-MeGln (3) have not been unambiguously determined, it is expected to be (2S,3S). ...
... Cyclic depsipeptide, callipeltin O (1) possesses potent cytotoxicity toward normal cell line MRC-5 and cancer cell lines A2058, HT-29 and MCF-7 (IC 50 = 0.16-2.08 μM) (Stierhof et al. 2016). On the other hand, linear peptide, callipeltin Q (2) exhibits no biological activities against these cell lines ( Fig. 1) (Stierhof et al. 2016). ...
Practical new routes for preparation of (2S,3S)-3-Me-glutamine and (R)-allo-threonine derivatives, the key structural components of cytotoxic marine peptides callipeltin O and Q, suitable for the Fmoc-SPPS, were developed. (2S,3S)-Fmoc-3-Me-Gln(Xan)-OH was synthesized via Michael addition reactions of Ni (II) complex of chiral Gly-Schiff base; while Fmoc-(R)-allo-Thr-OH was prepared using chiral Ni (II) complex-assisted α-epimerization methodology, starting form (S)-Thr(tBu)-OH.
... These derivatives are classified as conformationally constrained tailor-made AAs and are found in several unique peptidyl natural products [85][86][87]. In particular, 3-Me-glutamine residue is a structural part of callipeltins O and Q isolated from a marine sponge [88]. Michael additions of (S)-Gly-Schiff base Ni(II) complexes of type 18 provide a reliable access to -substituted glutamic acid derivatives [46,47,52]. ...
... Michael additions of (S)-Gly-Schiff base Ni(II) complexes of type 18 provide a reliable access to -substituted glutamic acid derivatives [46,47,52]. In the recent work, this approach was used for preparation of derivatives 89 and 90 needed for the total synthesis of some analogs of natural callipletins [88]. Complex (S)-(2S,3S)-87 was prepared via Michael addition of (S)-Gly-Schiff base 18 and ethyl crotonate (61% yield and 80% de). ...
Tailor-made amino acids are indispensable structural components of modern medicinal chemistry and drug design. Consequently, stereo-controlled preparation of amino acids is the area of high research activity. Over last decade, application of Ni(II) complexes of Schiff bases derived from glycine and chiral tridentate ligands has emerged as a leading methodology for the synthesis of various structural types of amino acids. This review article summarizes examples of asymmetric synthesis of tailor-made α-amino acids via the corresponding Ni(II) complexes, reported in the literature over the last four years. A general overview of this methodology is provided, with the emphasis given to practicality, scalability, cost-structure and recyclability of the chiral tridentate ligands.
... Therefore, the bioactivity studies of this compound are desperately needed. Vitilevuamide (57), another ascidian derivative with a bicyclic structure, was found in two species of ascidians, Didemnum cuculiferum and Polysyncranton lithostrotum. It displayed potent cytotoxicity against HCT116 cells, with an IC 50 value of 6.24 nM. ...
Cyclopeptides or cyclic peptides are polypeptides formed by ring closing of terminal amino acids. A large number of natural cyclopeptides have been reported to be highly effective against different cancer cells, some of which are renowned for their clinical uses. Compared to linear peptides, cyclopeptides have absolute advantages of structural rigidity, biochemical stability, binding affinity as well as membrane permeability, which contribute greatly to their anticancer potency. Therefore, the discovery and development of natural cyclopeptides as anticancer agents remains attractive to academic researchers and pharmaceutical companies. Herein, we provide an overview of anticancer cyclopeptides that were discovered in the past 20 years. The present review mainly focuses on the anticancer efficacies, mechanisms of action and chemical structures of cyclopeptides with natural origins. Additionally, studies of the structure–activity relationship, total synthetic strategies as well as bioactivities of natural cyclopeptides are also included in this article. In conclusion, due to their characteristic structural features, natural cyclopeptides have great potential to be developed as anticancer agents. Indeed, they can also serve as excellent scaffolds for the synthesis of novel derivatives for combating cancerous pathologies.
... ?: Unassigned stereochemistry.3.1.5. CallipeltinsCallipeltins are a small family of marine peptides comprising 17 members (callipeltins A-Q), 13 of which (callipeltins A-M) originate from an unidentified Latrunculia sp., collected in Vanuatu, Oceania(Figure 8)[42][43][44]101]. Structurally, callipeltins are characterized by the presence of several non-proteinogenic units. ...
Marine sponges are exceptionally prolific sources of natural products for the discovery and development of new drugs. Until now, sponges have contributed around 30% of all natural metabolites isolated from the marine environment. Family Latrunculiidae Topsent, 1922 (class Demospongiae Sollas, 1885, order Poecilosclerida Topsent, 1928) is a small sponge family comprising seven genera. Latrunculid sponges are recognized as the major reservoirs of diverse types of pyrroloiminoquinone-type alkaloids, with a myriad of biological activities, in particular, cytotoxicity, fuelling their exploration for anticancer drug discovery. Almost 100 pyrroloiminoquinone alkaloids and their structurally related compounds have been reported from the family Latrunculiidae. The systematics of latrunculid sponges has had a complex history, however it is now well understood. The pyrroloiminoquinone alkaloids have provided important chemotaxonomic characters for this sponge family. Latrunculid sponges have been reported to contain other types of metabolites, such as peptides (callipeltins), norditerpenes and norsesterpenes (trunculins) and macrolides (latrunculins), however, the sponges containing latrunculins and trunculins have been transferred to other sponge families. This review highlights a comprehensive literature survey spanning from the first chemical investigation of a New Zealand Latrunculia sp. in 1986 until August 2020, focusing on the chemical diversity and biological activities of secondary metabolites reported from the family Latrunculiidae. The biosynthetic (microbial) origin and the taxonomic significance of pyrroloiminoquinone related alkaloids are also discussed.
... Callipeltins N-Q are callipeltin derivatives isolated from the Asteropus sp., where callipeltins P and Q are acyclic callipeltins, while callipeltins N and O are cyclic callipeltins. Callipeltins N and O exhibited significant cytotoxicity against various cell-lines at an IC 50 value of 0.16 μM, explaining the significance of macrocyclisation as well as amino-acid composition in biological activity [56] (Figs. [11][12]. ...
Malignant melanoma is the most dangerous type of skin cancer. It is becoming more common globally and is increasingly resistant to treatment options. Despite extensive research into its pathophysiology, there are still no proven cures for metastatic melanoma. Unfortunately, current treatments are frequently ineffective and costly, and have several adverse effects. Natural substances have been extensively researched for their anti-MM capabilities. Chemoprevention and adjuvant therapy with natural products is an emerging strategy to prevent, cure or treat melanoma. Numerous prospective drugs are found in aquatic species, providing a plentiful supply of lead cytotoxic chemicals for cancer treatment. Anticancer peptides are less harmful to healthy cells and cure cancer through several different methods, such as altered cell viability, apoptosis, angiogenesis/metastasis suppression, microtubule balance disturbances and targeting lipid composition of the cancer cell membrane. This review addresses marine peptides as effective and safe treatments for MM and details their molecular mechanisms of action.
To combat the ineffectiveness of currently available pharmaceutical medications, caused by the emergence of increasingly resistant bacterial and fungal strains, novel antibacterial and anti-fungal medications are urgently needed. Novel natural compounds with antimicrobial activities can be obtained by exploring underexplored habitats such as the world's oceans. The oceans represent the largest ecosystem on earth, with a high diversity of organisms. Oceans have received some attention in the past few years, and promising compounds with antimicrobial activities were isolated from marine organisms such as bacteria, fungi, algae, sea cucumbers, sea sponges, etc. This review covers 56 antifungal and 40 antibacterial compounds from marine organisms. These compounds are categorized according to their chemical structure groups, including polyketides, alkaloids, riboso-mal peptides, and terpenes, and their organismal origin. The review provides the minimum inhibi-tory concentration MIC values and the bacterial/fungal strains against which these chemical compounds show activity. This study shows strong potential for witnessing the development of new novel antimicrobial drugs from these natural compounds isolated and evaluated for their antimi-crobial activities. Key Contribution: This review was conducted to summarize and categorize compounds isolated from marine organisms and showed significant antifungal and antimicrobial activities.
Most of the drugs used in medicine have been obtained from natural products or their synthetic derivatives. Bioactive peptides are an important group of natural product sources isolated from marine organisms, plants, animals, and microorganisms. Bioactive peptides have been investigated to promote health because of their high tissue affinity, specificity, and efficiency. Therefore, they possess a key role in cancer, including early diagnosis, prognostic predictors, and treatment. Anticancer effects of peptides have been widely investigated and shown to have many advantages as peptide-based drugs. Many naturally occurring peptides such as plitidepsin, dolastatin 10, didemnin B, and kahalalide F are used in clinical trials for the treatment of various cancers. The structure-activity relationship of these peptides can contribute to the design and development of peptide-based drugs. The aim of this chapter is to review the recent developments in bioactive peptides and their role in cancer therapy.
Matteson homologations of chiral boronic esters proved to be an excellent tool for the synthesis of highly functionalized amino and hydroxy acid residues. This method provides straightforward stereoselective access to the side chain of callipeltin A, a natural marine product with interesting biological activities. Furthermore, this protocol should allow for variations in the substitution pattern in future SAR studies, simply by choosing suitable nucleophiles during the homologation steps.
Macrolactonisation of a suitable heptapeptide precursor provides the cyclic depsipeptide core of callipeltin A in excellent yield.
In order to accelerate the isolation and characterization of structurally new or novel secondary metabolites, it is crucial to develop efficient strategies that prioritize samples with greatest promise early in the workflow so that resources can be utilized in a more efficient and cost-effective manner. We have developed a metrics-based prioritization approach using exact LC-HRMS, which uses data for 24 618 marine natural products held in the PharmaSea database. Each sample was evaluated and allocated a metric score by a software algorithm based on the ratio of new masses over the total (sample novelty), ratio of known masses over the total (chemical novelty), number of peaks above a defined peak area threshold (sample complexity), and peak area (sample diversity). Samples were then ranked and prioritized based on these metric scores. To validate the approach, eight marine sponges and six tunicate samples collected from the Fiji Islands were analyzed, metric scores calculated, and samples targeted for isolation and characterization of new compounds. Structures of new compounds were elucidated by spectroscopic techniques, including 1D and 2D NMR, MS, and MS/MS. Structures were confirmed by computer-assisted structure elucidation methods (CASE) using the ACD/Structure Elucidator Suite.
Stellatolide H (1) was isolated from a deep-sea sponge Discodermia sp. as the cytotoxic constituent. The planar structure of 1 was elucidated on the basis of the NMR spectroscopic and mass spectrometric data. The absolute configurations of the constituent amino acid residues were determined by the Marfey's method. Stellatolide H (1) is a peptide lactone of the callipeltin class with its N-terminus blocked by 3-hydroxy-6,8-dimethyldeca-(4Z,6E)-dienoic acid (Hdda).
Covering: 2016. Previous review: Nat. Prod. Rep., 2017, 34, 235–294
This review covers the literature published in 2016 for marine natural products (MNPs), with 757 citations (643 for the period January to December 2016) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1277 in 432 papers for 2016), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included.
The novel cyclic depsipeptides papuamides A (1), B (2), C (3), and D (4) have been isolated from Papua New Guinea collections of the sponges Theonella mirabilis and Theonella swinhoei. Their structures were determined by a combination of spectroscopic analysis and chemical degradation and derivatization studies. In addition to glycine, alanine, and threonine, these peptides contain a number of unusual amino acids including 3,4-dimethylglutamine, β-methoxytyrosine, 3-methoxyalanine, and 2,3-diaminobutanoic acid or 2-amino-2-butenoic acid residues. Papuamides A−D (1−4) are also the first marine-derived peptides reported to contain 3-hydroxyleucine and homoproline residues. These peptides also contain a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid moiety N-linked to a terminal glycine residue. Papuamides A (1) and B (2) inhibited the infection of human T-lymphoblastoid cells by HIV-1RF in vitro with an EC50 of approximately 4 ng/mL. Compound 1 was also cytotoxic against a panel of human cancer cell lines with a mean IC50 of 75 ng/mL.
Ascidians (tunicates) are rich sources of structurally elegant, pharmaceutically potent secondary metabolites and, more recently, potential biofuels. It has been demonstrated that some of these compounds are made by symbiotic bacteria and not by the animals themselves, and for a few other compounds evidence exists supporting a symbiotic origin. In didemnid ascidians, compounds are highly variable even in apparently identical animals. Recently, we have explained this variation at the genomic and metagenomic levels and have applied the basic scientific findings to drug discovery and development. This review discusses what is currently known about the origin and variation of symbiotically derived metabolites in ascidians, focusing on the family Didemnidae, where most research has occurred. Applications of our basic studies are also described.
Two new cyclic depsipeptides, pipecolidepsins A and B (1 and 2), have been isolated from the sponge Homophymia lamellosa collected off the coast of Madagascar. Their structures were determined by a combination of NMR experiments and by LC-MS analysis of the amino acid fragments obtained by hydrolysis and derivatization using Marfey's reagent. In addition to several common amino acids, these peptides contain unusual residues, including 2-amino-3-hydroxy-4,5-dimethylhexanoic acid, 3-ethoxyasparagine, 3,4-dimethylglutamine, 4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, and 3-hydroxyaspartic acid as well as a terminal 3-hydroxy-2,4,6-trimethylheptanoic acid residue. Pipecolidepsins A and B displayed cytotoxic activity against a panel of different human tumor cell lines.
Continued investigation of the polar extracts of the marine sponge Latrunculia sp. has resulted in the discovery of callipeltins J–M. The new structures were determined by interpretation of their NMR and MS data. The stereochemistry of the unusual 3-methylglutamine residue in callipeltins J and K was secured by stereoselective synthesis and Marfey's LC–MS analysis.
A triterpene monosaccharide, stelliferin riboside (1), was isolated from the Fijian marine sponge Geodia globostellifera. In addition, stellettins A and B (2, 3) were also isolated. This is the first report of a stelliferin from this species and the first example of a saccharide derivative of a stelliferin.
The “advanced Marfey's method” proposed in our preceding paper has been developed to nonempirically determine the absolute configuration of constituent amino acids in a peptide using liquid chromatography/mass spectrometry (LC/MS). For the establishment of this method, we had to resolve the following three problems: (1) elucidation of the limitation of Marfey's method, which is chosen as the chromatography technique, and its separation mechanism, because this proposed method relies on the elution order of an amino acid derivatized with 1-fluoro-2,4-dinitrophenyl-5-l-alaninamide (l-FDAA) to determine its absolute configuration; (2) how to effectively combine Marfey's method with mass spectrometry in order to detect and identify a desired amino acid without a standard sample; and (3) how to obtain the corresponding enantiomer from either the l- or d-amino acid in a peptide sample. In a preceding paper, we investigated problem 1 and finally described the rational application guideline for Marfey's method to elucidate the elution order of a desired amino acid according to the proposed separation mechanism. In this paper, we further investigated the two remaining problems. Because the sensitivity of the amino acids derivatized with the original derivatizing reagent, l-FDAA, was poor for LC/MS analysis using any interfaces due to their possible thermal instability and low hydrophobicity, we chose electrospray ionization and frit-fast atom bombardment (Frit-FAB) as the interface and developed 1-fluoro-2,4-dinitrophenyl-5-l-leucinamide (l-FDLA) instead of l-FDAA as a new derivatizing reagent in order to combine Marfey's method with mass spectrometry. Furthermore, we introduced a racemization procedure using 1-fluoro-2,4-dinitrophenyl-5-dl-leucinamide (dl-FDLA), the “dl-FDLA derivatization”, instead of the conventional chemical racemization for obtaining the corresponding enantiomer from either the l- or d-amino acid. Thus, we have established a nonempirical method using LC/MS, the “advanced Marfey's method”. The method was successfully applied to the characterization of constituent amino acids in microcystin LR produced by cyanobacteria.
Four new antifungal peptides, callipeltins F-1, were isolated from the marine sponge Latrunculia sp., collected off Vanuatu islands. Their structures were elucidated by NMR and MS analysis. The new callipeltins exhibited anti Candida activity in the 10(-4) M range. (c) 2005 Elsevier Ltd. All rights reserved.
Following the characterization of callipeltin A (1), two new cytotoxic peptides, callipeltin B (2) and C (3), were isolated from the New Caledonian sponge Callipelta sp.. Callipeltin B (2) possess the same cyclic depsipeptidal structure as in callipeltin A (1) and differs from 1 by having the N-terminal 2,3-dimethylpyroglutamic acid unit instead of the tripeptide chain with the N-terminus blocked by an hydroxyacid. Callipeltin C (3) is simply the acyclic callipeltin A. The structures 2–3 have been determined by NMR experiments, FAB mass spectrometry, evaluation of the aminoacids obtained by acid hydrolysis and by comparison of the data with those of callipeltin A (1).Following the characterization of callipeltin A (1), two new peptides, callipeltin B (2) and C (3), were isolated form Callipelta sp.. Callipeltin B (2) possess the same cyclic depsipeptidal structure as in callipeltin A (1) and differs from 1 by having the N-terminal 2,3-dimethylpyroglutamic acid unit instead of the tripeptide chain with the N-terminus blocked by an hydroxyacid. Callipeltin C (3) is the acyclic callipeltin A. Callipeltins have been found to be cytotoxic against various human carcinoma cells.
Two known papuamides C (1) and D (2) together with two new depsipeptides, papuamides E (3) and F (4), were isolated from an undescribed sponge of the genus Melophlus collected in the Solomon Islands. The planar structures of the compounds were elucidated on the basis of spectroscopic studies. Papuamides C-F (1-4) showed cytotoxicity against brine shrimp with LD(50) values between 92 and 106 μg/mL.
The structure of a new cyclic octapeptide, axinellin C, (cyclo[Thr(1)-Val(2)-Pro(3)-Trp(4)-Pro(5)-Phe(6)-Pro(7)-Leu(8)]), with all-trans peptide bond geometry, was elucidated by a combination of 2D NMR methods and tandem mass spectrometry. The solution state conformation was determined by ROE restrained molecular dynamics calculations. The structural features were found to be similar to those of the crystal structure of the cyclic decapeptide, phakellistatin 8, despite differing peptide sequences.
Callipeltin A (1) is a cyclic depsidecapeptide from a shallow water sponge of the genus Callipelta (order Lithistida), collected in the waters off New Caledonia. The structure of callipeltin A (1), which possesses the N-terminus blocked with a beta-hydroxy acid, and the C-terminus lactonized with a threonine residue, was determined by interpretation of spectral data, chemical degradation, and evaluation of the amino acids obtained by acid hydrolysis. Along with four common L-, one D-, and two N-methyl amino acids, it contains three new amino acid residues: beta-methoxytyrosine (beta OMeTyr), (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE), and (3S,4R)- 3,4-dimethyl-L-glutamine. Callipeltin A (1) has been found to protect cells infected by human immunodeficiency (HIV) virus.
Six new depsipeptides belonging to two different structural classes, termed celebesides A-C and theopapuamides B-D, have been isolated from the marine sponge Siliquariaspongia mirabilis. Their structures were determined using extensive 2D NMR and ESI-MS/MS techniques. Celebesides are unusual cyclic depsipeptides that comprise a polyketide moiety and five amino acid residues, including an uncommon 3-carbamoyl threonine, and a phosphoserine residue in celebesides A and B. Theopapuamides B-D are undecapeptides with an N-terminal fatty acid moiety containing two previously unreported amino acids, 3-acetamido-2-aminopropanoic acid and 4-amino-2,3-dihydroxy-5-methylhexanoic acid. The relative configuration of the polyketide moiety in celebesides was resolved by J-based analysis and quantum mechanical calculations, the results of which were self-consistent. Celebeside A neutralized HIV-1 in a single-round infectivity assay with an IC(50) value of 1.9 +/- 0.4 microg/mL while the nonphosphorylated analog celebeside C was inactive at concentrations as high as 50 microg/mL. Theopapuamides A-C showed cytotoxicity against human colon carcinoma (HCT-116) cells with IC(50) values between 2.1 and 4.0 microg/mL and exhibited strong antifungal activity against wildtype and amphotericin B-resistant strains of Candida albicans at loads of 1-5 microg/disk.
A new HIV-inhibitory cyclic depsipeptide, neamphamide A (2), was isolated from a Papua New Guinea collection of the marine sponge Neamphius huxleyi. Its structure was established through interpretation of spectroscopic data and by acid hydrolysis, derivatization of the free amino acids, and LC-MS analysis of the derivatives. Neamphamide A (2) contains 11 amino acid residues and an amide-linked 3-hydroxy-2,4,6-trimethylheptanoic acid moiety. The amino acid constituents were identified as L-Leu, L-NMeGln, D-Arg, D- and L-Asn, two residues of D-allo-Thr, L-homoproline, (3S,4R)-3,4-dimethyl-L-glutamine, beta-methoxytyrosine, and 4-amino-7-guanidino-2,3-dihydroxyheptanoic acid. In a cell-based XTT assay, 2 exhibited potent cytoprotective activity against HIV-1 infection with an EC50 of approximately 28 nM.
Theopapuamide (1), a new cytotoxic peptide, has been isolated from the lithistid sponge Theonella swinhoei from Papua New Guinea. The structure was established by analysis of NMR, mass spectrometry, and chemical methods. The undecapeptide (1) contains several unusual amino acid residues, of which the occurrence of beta-methoxyasparagine and 4-amino-5-methyl-2,3,5-trihydroxyhexanoic acid (Amtha) is unprecedented in natural peptides. Compound 1 also contains an amide-linked fatty acid moiety, 3-hydroxy-2,4,6-trimethyloctanoic acid (Htoa). Theopapuamide (1) was cytotoxic against CEM-TART and HCT-116 cell lines, with EC50 values of 0.5 and 0.9 microM, respectively.
A new anti-HIV cyclodepsipeptide, homophymine A, was isolated from a New Caledonian collection of the marine sponge Homophymia sp. The structure of homophymine A was determined by interpretation of spectroscopic data, acid hydrolysis, and LC-MS analysis. Homophymine A contains 11 amino acid residues and an amide-linked 3-hydroxy-2,4,6-trimethyloctanoic acid moiety. Along with four D-, two L-, and one N-methyl amino acids, it also contains four unusual amino acid residues: (2S,3S,4R)-3,4-diMe-Gln, (2R,3R,4S)-4-amino-2,3-dihydroxy-1,7-heptandioic acid, L-ThrOMe, and (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid. In a cell-based XTT assay, homophymine A exhibited cytoprotective activity against HIV-1 infection with a IC50 of 75 nM.