Macrocyclic depsipeptide

The most prominent application of the Ru-arene chemistry has been for the preparation of biaryl ethers in the syntheses of portions of vancomycin,467 ristocetin (Equation (127)),462,468-473 and teicoplanin (see also Section 10.14.1.2).474-476 Additional applications477-479 have included the syntheses of the macrocyclic biaryl ether-containing compounds K-13480,481 and OF4949-III,481,482 several macrocyclic depsipeptides,483,484 and poly(phenylene oxide) polymers.485... 

R. S. Al-Anwar C. Shih, The Isolation, Characterization, and Development of a Novel Class of Potent Antimitotic Macrocyclic Depsipeptides The Cryptophycins. n Anticancer Agents from Natural Products] G. M. Cragg, D. G. I. Kingston, D. J. Newman, Eds. Taylor Francis Boca Raton, FL, 2005 pp 151-169. 

Somamide A, a 19-membered macrocyclic depsipeptide isolated from assemblages of the marine cyanobacteria Lyngbya ma-juscula and Schizothrix sp. from the Fijian Islands. The stmcture is characterized by a 3-amino-6-hydroxy-2-piperidone (Ahp) unit, a (Z)-2-amino-2-butenoic acid building block, and a sulfoxide function was confirmed by total synthesis in 2002 [L. M. Nogle et al., J. Nat. Prod. 2001, 64, 716 ... 

The synthesis of 16-membered macrocyclic depsipeptides, cryptophycins 06S3747. 

Sansalvamide A is an antineoplastic macrocyclic depsipeptide isolated from the marine fungus Fusarium by William Fenical in 1999. Studies have shown potent cytotoxicity against NCI s 60 cell line panel for the natural product and ten-fold inhibition over the depsipeptide for the pentapeptide derivative. A library of over 100 derivatives of the compound have been synthesized and the Structural Activity Relationships (SARs) show promising bio-potency against pancreatic, colon, breast, prostate and melanoma cancer cell-lines. Six derivatives show over 100-fold differential selectivity for cancer cell lines over normal cell lines and are over 100 times more active against pancreatic cancer cell lines than compounds used clinically to treat these cancers (e.g., 5-FU). Through use of inhibition assays and analysis of trends emerge that can be used to modify the scaffold to produce more potent compounds. 

KahalalideF(KHF) Phase II Elysia/Bryopsis Anticancer, antiviral Macrocyclic depsipeptide... 

Jasplaklnolide Jaspis sp. (Sponge) Macrocyclic depsipeptide Inducer ofactin polymerization (for study of cytoskeleton) 527/1 mg... 

In another type of tandem sequence, Zhu and co-workers have reported the synthesis of macrocyclic depsipeptides 192 that starts with the SCR of a,cx-disubstituted a-isocyanoacetamides, amino alcohols and aldehydes in the presence of ammonium chloride (Scheme 11.25, building block contributions to the molecule and cyclization site indicated). The 14- to 16-membered target compounds are then formed from acid treatment of the intermediate 5-iminoisoxazolines. Evaluation of the scope indicated this sequence was quite general, and so has the potential to be applicable to the construction of macrodepsipeptide libraries. 

Macrocyclic peptides and depsipeptides ( macrocyciic peptides with amide and ester linkages) are important natural compounds. They have been synthesized in low yield from open-chain precursors by DCC treatment at high dilution (E. SchrSder, 1963 M.M. Shemyakin,... 

TE-catalyzed cyclization is not limited to the synthesis of macrocyclic peptides by catalyzing the formation of aC N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a di-domain excised from fengycin synthase was... 

Keywords Cyclopeptides Depsipeptides Peptoids Macrocycles Diketopiper-azines Benzodiazepines Ugi-reaction Polycyclic compounds Orthogonal reactivity Sequential reactions Iteration Bifunctional building blocks Medium sized rings Beta-turn motif... 

A host of carriers, with a wide variety of ion selectivities, have been proposed for this task. Most of them have been used for the recognition of alkali and alkaline metal cations (e.g., clinically relevant electrolytes). A classical example is the cyclic depsipeptide valinomycin (Fig. 5.13), used as the basis for the widely used ISE for potassium ion (38). This doughnut-shaped molecule has an electron-rich pocket in the center into which potassium ions are selectively extracted. For example, the electrode exhibits a selectivity for K+ over Na+ of approximately 30,000. The basis for the selectivity seems to be the fit between the size of the potassium ion (radius 1.33 A) and the volume of the internal cavity of the macrocyclic molecule. The hydrophobic sidechains of valinomycin stretch into the lipophilic part of the membrane. In addition to its excellent selectivity, such an electrode is well behaved and has a wide working pH range. Strongly acidic media can be employed because the electrode is 18,000 times more responsive to K+ than to H+. A Nernstian response to potassium ion activities, with a slope of 59mV/pK+, is commonly observed... 

Durette et al. [74] have achieved the total synthesis of the hexadepsipeptide antibiotic L-156,602 128) using the mixed phosphonic anhydride method as key macrolactamization step. As shown in Scheme 43, treatment of the linear depsipeptide 126 with n-propylphosphonic anhydride and DMAP in dichloro-methane at high dilution afforded the macrocycle 127 in more than 57% yield. 

Enantiomerically pure non-proteinogenic amino acids have attracted recent attention due to their antibiotic [1], antifungal [2], cytotoxic [3], and other important pharmacological properties [4]. Frequently, they also occur incorporated in natural products, such as peptides, depsipeptides, and other macrocyclic compounds. Other important applications are to serve as building blocks in asymmetric synthesis. A specifically prominent class of them are cyclic 3- and y-amino acids, the subject to which the present chapter is dedicated. 

Figure 12 A solid-phase total synthesis of the antimycobacterial cyclodepsipeptide kaha-lalide A. The synthesis relies on the Kenner safety-catch linker for attachment to the peptide backbone, followed by macrocyclative cleavage of the linear depsipeptide...

Synthesis of macrocyclic peptides and depsipeptides with cytotoxic activity 88YZ1115. 

To achieve selectivity in a classical metal-binding HDAC inhibitor, the cap needs to contain functionality for additional interactions with the rim . Of the inhibitors described above, the cyclic tetrapeptides have this potential due to their large macrocyclic scaffold, but have yet to result in clinical candidates. Structurally, the most complex HDAC inhibitors are the depsipeptide natural products exemplified by FK228. These compounds, which are treated separately in the next section, have even more elaborate caps , and are the best-documented example of selective HDAC inhibitors. 

Total Synthesis of Depsipeptide HDAC Inhibitors - Macrocyclizations and Completion of the Synthesis... 

Interestingly, all the depsipeptide total syntheses to date have chosen to form the macrocyclic ring by disconnecting the same ester bond. 

Guidelines for the synthesis of cyclopeptides have it that pendant groups should be connected to the cyclic scaffold after ring closure. Moreover, peptide bond formation is generally preferred to ester bond formation as a means to accomplish macrocyclization of depsipeptide frameworks, and it is also well established that primary amino groups react more efficiently than secondary ones in peptide bond forming reactions i.e., secondary amides are more readily formed than tertiary ones. Retrosynthetic dissection of the only pair of secondary amide bonds in luzopeptin A-C precursor 11 leads to pentadepsipeptide 12 (Scheme 3). 

Papuamides, a family of cyclodepsipep-tides depsipeptides) isolated from the sponges Theonella mirahilis and Theonella swinhoei collected near Papua New Guinea. The papuamides A-D are 22-membered macrocycles containing a number of unusual amino acids, such as 3,4-dimethylglutamine, /5-methoxytyrosine, 3-methoxyalanine, 2,3-diaminobutanoic acid, 2-amino-2-butenoic acid, 3-hydroxyleucine, homoproline, and... 

DCC-DMAP has been used in the synthesis of depsipeptides. Macrocyclic lactones have been prepared by cyclization of hydroxy carboxylic acids with DCC-DMAP. The presence of salts of DMAP, such as its trifluoroacetate, is beneficial in such cyclizations, as shown for the synthesis of a (9. -dihydroerythronolide. Other macrolactonizations have been achieved using 2,4,6-Trichlorobenzoyl Chloride and DMAP in Triethylamine at rt or Di-2-pyridyl Carbonate (6 equiv) with 2 equiv of DMAP at 73 °C. ... 

Peptide antibiotics. Antibiotics with linear or cyclic oligopeptide structures containing not only L- amino acids but often also unusual, non-proteinogenic amino acids. Homopeptides are built up exclusively of amino acids (e.g., gramicidins), the so-called heteropeptides also contain other structural elements, e.g., hydroxamic acids. Macrocyclic Ra. containing one or more ester bonds in the ring are known as peptide lactones (e.g., hormaomycin) or depsipeptides (e.g., valinomycin). 

It was not until 1986 that a new interest was shown in the synthesis of streptogramin depsipeptides when the problems associated with racemisation at particular amino-acid residues during the coupling procedures were reinvestigated and the possibility of replacing certain amino-acid functions to provide water soluble derivatives related to the natural antibiotic was considered. In all these studies formation of the macrocycle was restricted to ring closure at one of the amide bonds in a linear hexapeptide intermediate. 

Several fungal metabolites have been found which enhance the passive uptake of potassium. Some, like nonactin and monactin 14.6), are macro-tetrolides others, like valinomycin, are depsipeptides. Valinomycin 14.7) (from Streptomycesfulvissimus) is a macrocycle composed of three residues of each of L-valine, D-valine, L-lactic acid, and D-a-hydroxy-isovaleric acid, linked alternatively by ester and amide bonds to form a 36-membered ring (Shemyakin... 

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