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Synthesis and Biological Evaluation of the [D-MeAla11]-Epimer of Coibamide A
Abstract
Coibamide A is a highly potent antiproliferative cyclic depsipeptide, which was originally isolated from a Panamanian marine cyanobacterium. In this study, the synthesis of coibamide A has been investigated using Fmoc-based solid-phase peptide synthesis followed by the cleavage of the resulting linear peptide from the resin and its subsequent macrolactonization. The peptide sequence of the linear coibamide A precursor was constructed on a solid-support following the optimization of the coupling conditions, where numerous coupling agents were evaluated. The macrocyclization of the resulting linear peptide provided the [d-MeAla11]-epimer of coibamide A, which exhibited nanomolar cytotoxic activity towards a number of human cancer cell lines.
... Cytotoxicity A549 IC 50 19.0 nM [35] Cytotoxicity HCT116 IC 50 44 ...
... However, none of the coibamide A analogues were more potent cytotoxins than the natural product, indicating the strong correlation between the observed activity, the core molecular structure and optimization of this structure through natural evolutionary processes. The only analogue that exhibited similar inhibition as natural coibamide A was the [MeAla3-MeAla6]-coibamide (8), which significantly suppressed tumor growth in vivo [31,33,35]. ...
... However, both the 1 H and 13 C NMR data for the synthetic product 2 differed from those of the natural product, which indicated that the absolute configuration of this compound required revision [33,34]. Additionally, Oishi and Fujii synthesized the D-N-Me-Ala epimer of coibamide A (4) due to an epimerization of this residue during the macrocyclization process ( Figure 1) [35]. In 2015, Fang and Su were able to assign the correct configuration of coibamide A (1) with the revision of the L-HVA and L-N-Me-Ala residues to the D-HVA and D-N-Me-Ala after total synthesis of this alternative along with its diastereomeric analogues ( Figure 1) [30]. ...
Leptolyngbya, a well-known genus of cyanobacteria, is found in various ecological habitats including marine, fresh water, swamps, and rice fields. Species of this genus are associated with many ecological phenomena such as nitrogen fixation, primary productivity through photosynthesis and algal blooms. As a result, there have been a number of investigations of the ecology, natural product chemistry, and biological characteristics of members of this genus. In general, the secondary metabolites of cyanobacteria are considered to be rich sources for drug discovery and development. In this review, the secondary metabolites reported in marine Leptolyngbya with their associated biological activities or interesting biosynthetic pathways are reviewed, and new insights and perspectives on their metabolic capacities are gained.
... 11 In 2014, the proposed structure of coibamide A was synthesized by He et al. using a [(4 + 1) +3 + 3]-peptide fragment-coupling strategy in solution phase, but the analytical data and biological activity of the synthetic compound were inconsistent with those reported for natural coibamide A. 15 Then, Nabika et al. reported the synthesis of [D-MeAla11]-epimer of coibamide A by macrolactonization between the hydroxyl group of MeThr5 and C-terminal MeAla11 in low yield. 16 Recently, our group performed the total synthesis of coibamide A by macrolactamization at Ala8-MeIle7 junction, which also revised two stereochemical assignments of the originally proposed structure (Figure 1). 17 Snyder et al. later confirmed that our revision, in which both the macrocycle [MeAla11] and the side chain [HIV2] residues were inverted from L to D, was consistent with the authentic natural product and the computational modeling. ...
... Article than that of natural coibamide A. 16 To further explore the stereochemical influence on the pharmacological activity, we synthesized [L-MeAla11]-epimer (1c), [L-HIV2-D-allo-MeThr5]-diastereomer (1d), and [L-HIV2-D-MeSer(Me)3]diastereomer (1e) of coibamide A. All of them showed low cytotoxicity (GI 50 > 1.9 μM) against the tested cancer cell lines. Compared with coibamide A (1), the stereotopical changes of the residues belonging to the macrocycle (1c and 1d) resulted in a loss of 3 orders of magnitude in cytotoxicity, indicating that the macrocycle plays a crucial role in activity. ...
... Flash column chromatography of the crude product (ethyl acetate/hexanes, 40%) afforded compound 2 (3.02 g, 85%) as a pale-yellow oil. 1 H NMR and HRMS data were identical to the data previously reported. 16 (R)-2-(((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-methylbutanoyl)oxy)-3-methylbutanoic Acid (7). ...
... 5,7 The observed biological profile and distinct pattern of selectivity against cell lines of the National Cancer Institute (NCI) 60 human tumor cell line panel has generated considerable interest in CbA, resulting in development of total synthesis methods and revision of the absolute configuration of the natural product. [8][9][10] CbA inhibits expression of the integral membrane receptor, vascular endothelial growth factor receptor 2 (VEGFR-2), and its secreted ligand vascular endothelial growth factor A (VEGF-A). It induces mTOR-independent autophagy in a manner similar to apratoxin A (AprA), a previously characterized inhibitor of protein import into the early secretory pathway, 5 despite yielding different cytotoxic profiles against cell lines of the NCI-60 tumour cell line panel. ...
... All-L-CbA was reported to have moderate micromolar cytotoxicity against three cancer cell lines, 26 while [D-MeAla11]-all-L-CbA displayed high nanomolar activity against four cancer cell lines. 9 Given the adverse effect of the MeAla11 configuration for CbA activity, we anticipated that the Tyr(Me)10 could be involved in target interactions, and could be substituted with the nearly isosteric 4-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenylalanine (Tdf) side-chain. This substitution is further supported by the loss of activity for an AprA analogue in which the MeTyr is epimerized. ...
Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target of CbA remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61α subunit of the Sec61 protein translocon. CbA binding to Sec61 results in broad substrate-nonselective inhibition of ER protein import and potent cytotoxicity against specific cancer cell lines. CbA targets a lumenal cavity of Sec61 that is partially shared with known Sec61 inhibitors, yet profiling against resistance conferring Sec61α mutations identified from human HCT116 cells suggests a distinct binding mode for CbA. Specifically, despite conferring strong resistance to all previously known Sec61 inhibitors, the Sec61α mutant R66I remains sensitive to CbA. A further unbiased screen for Sec61α resistance mutations identified the CbA-resistant mutation S71P, which confirms non-identical binding sites for CbA and apratoxin A and supports the susceptibility of the Sec61 plug region for channel inhibition. Remarkably, CbA, apratoxin A and ipomoeassin F do not display comparable patterns of potency and selectivity in the NCI60 panel of human cancer cell lines. Our work connecting CbA activity with selective prevention of secretory and membrane protein biogenesis by inhibition of Sec61 opens up possibilities for developing new Sec61 inhibitors with improved drug-like properties that are based on the coibamide pharmacophore.
... Total synthesis of coibamide A was accomplished using solid-phase peptide strategy by several synthetic groups. These synthetic efforts led to the revision on the stereochemical assignment on the original reported molecule as well as generation of potent analogues for SAR studies [135][136][137]. Several synthetic analogues, such as 58 and 59 (Figure 11), showed either similar inhibitory activity or increased cytotoxicity as compared to the natural product [136,137]. ...
... These synthetic efforts led to the revision on the stereochemical assignment on the original reported molecule as well as generation of potent analogues for SAR studies [135][136][137]. Several synthetic analogues, such as 58 and 59 (Figure 11), showed either similar inhibitory activity or increased cytotoxicity as compared to the natural product [136,137]. A number of pharmacological studies have also been conducted on coibamide A [138][139][140]. ...
The prokaryotic filamentous marine cyanobacteria are photosynthetic microbes that are found in diverse marine habitats, ranging from epiphytic to endolithic communities. Their successful colonization in nature is largely attributed to genetic diversity as well as the production of ecologically important natural products. These cyanobacterial natural products are also a source of potential drug leads for the development of therapeutic agents used in the treatment of diseases, such as cancer, parasitic infections and inflammation. Major sources of these biomedically important natural compounds are found predominately from marine cyanobacterial orders Oscillatoriales, Nostocales, Chroococcales and Synechococcales. Moreover, technological advances in genomic and metabolomics approaches, such as mass spectrometry and NMR spectroscopy, revealed that marine cyanobacteria are a treasure trove of structurally unique natural products. The high potency of a number of natural products are due to their specific interference with validated drug targets, such as proteasomes, proteases, histone deacetylases, microtubules, actin filaments and membrane receptors/channels. In this review, the chemistry and biology of selected potent cyanobacterial compounds as well as their synthetic analogues are presented based on their molecular targets. These molecules are discussed to reflect current research trends in drug discovery from marine cyanobacterial natural products.
... Nevertheless, due to their powerful antiproliferative effects, mechanism of action, and novel chemical structure, several analogs have recently been synthesized to develop more effective and selective antineoplastic drugs that reduce the exhibited toxicity. However, coibamide A has a well-defined conformational structure and is very sensitive to backbone modifications, resulting in analogs with significantly decreased activities [66,67]. Among these derivatives, a simplified analog, [MeAla3-MeAla6]-coibamide (3) (Figure 10), showed an inhibition of growth similar to coibamide A against MDA-MB-231, A549, and PANC-1 cancer cells, with GI 50 values of 5.1, 7.3, and 7 nM, respectively. ...
The marine environment is highly diverse, each living creature fighting to establish and
proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules’ origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic,
and antiproliferative activity with potential pharmacological uses. Some are currently under
clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.
... Although early studies indicated that triple-negative MDA-MB-231 cells undergo apoptosis in response to coibamide A [49,50], the relatively limited supply of the field-collected natural product had prevented further biological evaluation. With refinement of routes for total synthesis and a revision of the stereochemistry [59][60][61], we were able to evaluate the cytotoxic potential of synthetic coibamide A against an expanded panel of triple-negative breast cancer cells with varying basal EGFR expression. Coibamide A was synthesized in the laboratory of Professor Shinya Oishi (Kyoto Pharmaceutical University) and verified as identical to the natural product based on high resolution mass data, specific optical rotation, overlay of 1 H and 13 C NMR data with the natural product data, and Marfey's analysis of key residues [52]. ...
Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A, Biochemical Pharmacology (2020), doi: https://doi. Abstract Coibamide A is a potent cancer cell toxin and one of a select group of natural products that inhibit protein entry into the secretory pathway via a direct inhibition of the Sec61 protein translocon. Many Sec61 client proteins are clinically relevant drug targets once trafficked to their final destination in or outside the cell, however the use of Sec61 inhibitors to block early biosynthesis of specific proteins is at a pre-clinical stage. In the present study we evaluated the action of coibamide A against human epidermal growth factor receptor (HER, ErbB) proteins in representative breast and lung cancer cell types. HERs were selected for this study as they represent a family of Sec61 clients that is frequently dysregulated in human cancers, including coibamide-sensitive cell types. Although coibamide A inhibits biogenesis of a broad range of Sec61 substrate proteins in a presumed substrate-nonselective manner, endogenous HER3 (ErbB-3) and EGFR (ErbB-1) proteins were more sensitive to coibamide A, and the related Sec61 inhibitor apratoxin A, than HER2 (ErbB-2). Despite this rank order of sensitivity (HER3 > EGFR > HER2), Sec61-dependent inhibition by coibamide A was sufficient to decrease cell surface expression of HER2. We report that coibamide A-or apratoxin A-mediated block of HER3 entry into the secretory pathway is unlikely to be mediated by the HER3 signal peptide alone. HER3 (G11L/S15L), that is fully resistant to the highly substrate-selective cotransin analogue CT8, was more resistant than wild-type HER3 but only at low coibamide A (3 nM) concentrations; HER3 (G11L/S15L) expression was inhibited by higher concentrations of either natural product. Time-and concentration-dependent decreases in HER protein expression induced a commensurate reduction in AKT/MAPK signaling in breast and lung cancer cell types and loss in cell viability. Coibamide A potentiated the cytotoxic efficacy of small molecule kinase inhibitors lapatinib and erlotinib in breast and lung cancer cell types, respectively. These data indicate that natural product modulators of Sec61 function have value as chemical probes to interrogate HER/ErbB signaling in treatment-resistant human cancers.
Epimerisation is basically a chemical conversion that includes the transformation of an epimer into another epimer or its chiral partner. Epimerisation of amino acid is a side reaction that sometimes happens during peptide synthesis. It became the most avoided reaction because the process affects the overall conformation of the molecule, eventually even altering the bioactivity of the peptide. Epimerised products have a high similarity of physical characteristics, thus making it difficult for them to be purified. In regards to amino acids, epimerisation is very important in keeping the chirality of the assembled amino acids unchanged during the peptide synthesis and obtaining the desirable product without any problematic purification. In this review, we report several factors that induce epimerisation during peptide synthesis, including how to characterise and affect the bioactivities. To avoid undesirable epimerisation, we also describe several methods of suppressing the process.
Covering: July 2010 to August 2021This article summarizes more than 200 cases of misassigned marine natural products reported between July 2010 and August 2021, sorting out errors according to the structural elements. Based on a comparative analysis of the original and the revised structures, major pitfalls still plaguing the structural elucidation of small molecules were identified, emphasizing the role of total synthesis, crystallography, as well as chemical- and biosynthetic logic to complement spectroscopic data. Distinct "trends" in natural product misassignment are evident between compounds of marine and plant origin, with an overall much lower incidence of "impossible" structures within misassigned marine natural products.
Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure–activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N-methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.
Covering: up to the end of 2019
Diverse natural product small molecules have allowed critical insights into processes that govern eukaryotic cells' ability to secrete cytosolically synthesized secretory proteins into their surroundings or to insert newly synthesized integral membrane proteins into the lipid bilayer of the endoplasmic reticulum. In addition, many components of the endoplasmic reticulum, required for protein homeostasis or other processes such as lipid metabolism or maintenance of calcium homeostasis, are being investigated for their potential in modulating human disease conditions such as cancer, neurodegenerative conditions and diabetes. In this review, we cover recent findings up to the end of 2019 on natural products that influence protein secretion or impact ER protein homeostasis, and serve as powerful chemical tools to understand protein flux through the mammalian secretory pathway and as leads for the discovery of new therapeutics.
Covering: up to 2018
With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
Gymnopeptides A and B are unprecedented highly N-methylated cyclic β-hairpin octadecapeptides with striking antiproliferative activities isolated from the mushroom Gymnopus fusipes. Using Fmoc-based solid-phase peptide synthesis, followed by macrolactamization of the resulting linear peptides, the first total synthesis of gymnopeptides A and B was successfully achieved in this study. The coupling methods used for the solid-phase synthesis and the cyclization were optimized, and the configuration of the Ser1/Thr1 residue in gymnopeptide A/B was determined to be l.
Effects of replacement and addition of an amino acid in a cyclic decapeptide 1 (cyclic-CYNPTTYQMC) for inhibitory activity to dimerization of human epidermal growth factor receptor (EGFR) were examined. By alanine scanning of 1 corresponding to the arm structure (residues 246-254) of a β-hairpin loop sequence (residues 242-259) of EGFR, it was confirmed that replacement of any amino acid in the loop structure lowered the dimerization inhibitory activity of 1. Among the residues examined, Tyr at position 246 and Thr at 250 were found to be crucial for dimer formation. Addition of an amino acid to the N-terminus of 1 also affected the dimerization inhibitory activity. Addition of an amino acid containing a moderately hydrophilic side-chain increased the inhibitory activity. In contrast, an intramolecular hydrogen bond of 1 is not thought to be crucial for holding the dimer structure on the basis of the dimerization inhibitory activities of N-methylated analogues of 1. These results will be useful for the design and evaluation of a potent dimerization inhibitor as an anti-proliferation agent. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Odoamide is a novel cyclic depsipeptide with highly potent cytotoxic activity isolated from the Okinawan marine cyanobacterium Okeania sp. It contains a 26-membered macrocycle composed of a fatty acid moiety, a peptide segment and isoleucic acid. Four possible stereoisomers of the odoamide polyketide substructure were synthesised using a chiral pool approach. The first total synthesis of odoamide was also successfully achieved. The structure of synthetic odoamide was verified by comparing its NMR spectra with those of the natural product.
The effectiveness of computational tools in determining relative configurations of complex molecules is investigated, using natural products mandelalides A-D and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical NMR chemical shift predictions, and DP4 analyses led to confirmation of the revised structures of mandelalides A-D and coibamide A. All chiral centers in the northern hemisphere of mandelalides A-D are inverted with respect to the originally proposed structures, in agreement with recent total syntheses of mandelalide A by Ye, Fürstner & Carter. In the case of coibamide A, it was found that Fang & Su's revision, in which both the macrocycle [MeAla(11)] and the side chain [HIV(2)] residues are inverted from l to d, was consistent with the authentic natural product and computations.
Solid-phase total syntheses of highly methylated cyclic azacoibamide A and its O-desmethyl analogue were achieved. Two ester linkages of natural coibamide A were replaced by amide bonds to improve its pharmacokinetic properties. The synthetic strategy consists of the key on-resin macrocyclization, N,N-dimethylation, and final solution phase O-methylation reactions. Compared to the naturally occurring coibamide A, azacoibamide A and its O-desmethyl analogue displayed low micromolar activities against tested cancer cell lines.
Coibamide A is a highly potent antiproliferative cyclodepsipeptide originally isolated from a Panamanian marine cyanobacterium. Herein we report an efficient solid-phase strategy for assembly of highly N-methylated cyclodepsipeptides, which is invaluable in generating coibamide A derivatives for structure-activity relationship studies. As a consequence of our synthetic studies, two stereochemical assignments of coibamide A were revised and the total synthesis of this natural compound was achieved for the first time.
The solid-phase total synthesis of the proposed structure of cyclic depsipeptide coibamide A and its derivative O-desmethyl coibamide A is reported. In this study, we demonstrate the solid-phase synthetic strategy and final solution-phase O-methylation for highly N-methylated cyclic depsipeptides. On-resin macrocyclization, N,N-dimethylation and solution-phase O-methylation were the key steps of these syntheses. The mass of synthetic coibamide A is consistent with that of the natural product according to liquid chromatography-mass spectroscopy (LCMS) analysis but significant differences are observed upon 1H and 13C NMR analysis. The 2D NMR analysis and modeling studies of the synthetic compound compared with the isolated natural compound revealed that either they are conformationally different or the stereochemistry of the natural product was incorrectly assigned.
Coibamide A is an N-methyl-stabilized depsipeptide that was isolated from a marine cyanobacterium as part of an International Cooperative Biodiversity Groups (ICBG) program based in Panama. Previous testing of coibamide A in the NCI in vitro 60 cancer cell line panel revealed a potent anti-proliferative response and "COMPARE-negative" profile indicative of a unique mechanism of action. We report that coibamide A is a more potent and efficacious cytotoxin than was previously appreciated, inducing concentration- and time-dependent cytotoxicity (EC50
A new two-step synthesis of Fmoc-protected N-alkyl amino acids has been developed. The first step involves acid-catalyzed condensation of an Fmoc-protected amino acid with an aldehyde to form an oxazolidinone. This intermediate is then reduced with triethylsilane and trifluoroacetic acid to the N-alkylated derivative. The procedure is applicable to a variety of amino acids and aldehydes and results in less than 0.1% racemization as measured by a sensitive NMR assay which uses 13C satellite signals as internal reference peaks.
Hydroxysäuren (I) lassen sich in verdünnter Lösung in Gegenwart von DCC und von Dimethylaminopyridin (DMAP)-Hydrochlorid (II) in die Lactone (III) überführen.
Total synthesis of the originally proposed structure of coibamide A, a highly N- and O-methylated cytotoxic marine cyclodepsipeptide, has been accomplished by using a [(4+1)+3+3]-peptide fragment-coupling strategy and careful examination and optimization of the multiple dense N-methylated amide-bond formations. The synthetic sample of the proposed coibamide A could not match the natural product in both 1H and 13C NMR spectra, but was found to exhibit low micromolar cytotoxicity against the proliferation of three tested cancer cells.
Various carboxylic esters were obtained in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine in the presence of a catalytic amount of 4-(dimethylamino)pyridine.
A rapid and mild esterification method using carboxylic 2,4,6-trichlorobenzoic anhydrides in the presence of 4-dimethylaminopyridine was developed. The method was also successfully applied to the synthesis of large-ring lactones, including DL-2,4,6-tridemethyl-3-deoxymethynolide.
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We report the solid-phase total synthesis of the antifungal highly modified cyclic depsipeptide petriellin A. The synthesis confirms earlier reports on the absolute configuration of the natural product. The solid-phase approach resulted in a protected linear precursor, which was cleaved from the solid support prior to cyclization and final deprotection. Use of advanced coupling agents for several hindered amides was a feature of the synthesis. The natural product was prepared in overall 5% yield.
Racemization-free coupling of Fmoc-N-methyl amino acids on a solid support is quantitative with a new triphosgene-activation method. With this method, the total synthesis of the nematicidal cyclododecapeptide omphalotin A (see picture) was accomplished, which because of its high content of N-methyl amino acids had not yet been accessible.
A library of peptides required for a project investigating the factors relevant for blood-brain barrier transport was synthesized on solid phase. As a result of the high N-methylamino acid content in the peptides, their syntheses were challenging and form the basis of the work presented here. The coupling of protected N-methylamino acids with N-methylamino acids generally occurs in low yield. (7-azabenzotriazol-1-yloxy)-tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) or PyBOP/1-hydroxy-7-azabenzotriazole (HOAt), are the most promising coupling reagents for these couplings. When a peptide contains an acetylated N-methylamino acid at the N-terminal position, loss of Ac-N-methylamino acid occurs during trifluoroacetic acid (TFA) cleavage of the peptide from the resin. Other side reactions resulting from acidic cleavage are described here, including fragmentation between consecutive N-methylamino acids and formation of diketopiperazines (DKPs). The time of cleavage is shown to greatly influence synthetic results. Finally, high-performance liquid chromatography (HPLC) profiles of N-methyl-rich peptides show multiple peaks because of slow conversion between conformers.
A suitable combination of synthetic design, orthogonal protecting groups and coupling reagents was used to complete the first known synthesis of the natural marine cyclodepsipeptide IB-01212. The cyclic, symmetric octapeptide contains two of each of the following residues: L-N,N-Me2Leu, L-Ser, L-N-MeLeu and L-N-MePhe. IB-01212 also features two symmetric ester bonds between the hydroxyl group of Ser and the carboxyl function of the N-MePhe. Total solid-phase syntheses of the product was performed in parallel via three distinct routes: dimerization of heterodetic fragments, linear synthesis, and convergent synthesis. The convergent strategy gave the best results in terms of product yield and purity and is particularly suitable for the large-scale synthesis of IB-01212 and similar peptides.
Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15N and variable temperature experiments; mass spectrometry included TOF-ESI-MSn and FT-MSn experiments. Chemical degradation followed by chiral HPLC- and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism.
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