This review describes the isolation, activities and synthetic approaches of the naturally occurring cyclic peptides containing biaryl and/or biaryl ether linkages. These compounds range from monocyclic, to bicyclic, to the polycyclic glycopeptide antibiotics, and most of them exhibit significant biological properties such as cytotoxic or antimicrobial activities. Interestingly, vancomycin is used clinically as the antibiotic of last resort for the treatment of methicillin-resistant Staphylococcus aureus. The medicinal significance and the structural complexity of these macrocycles have challenged chemists towards the total synthesis of these compounds and in designing synthetic analogues. Non-natural macrocycles reported from 1999 to 2004 are also covered.

Cyclic Peptides Containing Biaryl and Biaryl Ether Linkages

Publisher Summary This chapter discusses the isolation, structure, physicochemical and spectral data of all bromotyrosine derivatives isolated from marine organisms. The biosynthesis, total synthesis, and bioactivity of the bromotyrosine derivatives are also discussed followed by cyclopeptides containing halogenated tyrosine units. The bromotyrosine derivatives are divided into six categories: simple bromotyrosine derivatives, spirocyclohexadienylisoxazolines, spirooxepinisoxazolines, oximes, bastadins, and other structural classes. The simple bromotyrosine derivatives are products of one bromotyrosine undergoing degradation, reduction, hydroxylation, alkylation, or esterification with simple functional groups. In spirocyclohexadienylisoxazoline bromotyrosine derivatives, one or two bromotyrosine units are transformed into a spirocyclohexadienylisoxazoline undergoing an arene oxide biosynthetic pathway. This class of alkaloids generally consists of one to three bromotyrosinederived units, as well as other functional groups, such as histamine. Bromotyrosine alkaloids provide a unique diversity in chemical structure and in bioactivity. As the first bromotyrosine derivative, the dienone, was isolated as an antibiotic, a large number of bromotyrosine derivatives have been found to have diverse activities, which include antibacterial, antifungal, anticancer, antiviral, antifouling, etc. The majority of the dibromotyrosine-derived natural products from Verongida have been reported to possess significant antimicrobial and cytotoxic activity. The presence of antibacterial compounds in marine sponges has been reported as a general phenomenon, and has been suggested to reflect a defensive strategy of these sedentary, filter-feeding animals.

The Marine Bromotyrosine Derivatives

Efficient total synthesis of bastadin 6, an anti-angiogenic brominated tyrosine-derived metabolite from marine sponge

A general strategy for the synthesis of twenty naturally occurring bastadins (all but bastadin 3) is presented. A key retrosynthetic disconnection of the two amide bonds, common in all target molecules, bisects the macrocyclic core into two diaryl ether fragments, an α,ω-diamine (western part) and an α,ω-dicarboxylic acid (eastern part). Efficient preparation of the synthetically challenging o-mono or dibromo-substituted diaryl ether linkages was achieved employing the diaryl iodonium salt method. Regarding the western part, variations of the aliphatic chain were more efficiently secured by the preparation of two different α,ω-aminonitrile moieties. Cobalt boride mediated reduction of the nitrile functionality established the required diamines and, at the same time, provided the necessary variation of the aromatic-ring bromination pattern. Regarding the eastern part, two different dicarboxyl precursors had to be prepared in order to accommodate bromination-pattern variations. Coupling and subsequent macrolactamization of different combinations of these key intermediates may lead at will to any member of this family of marine natural products. Four bastaranes (bastadins 5, 10, 12 and 16) and two isobastaranes (bastadins 20 and 21) were synthesized as a demonstration of the flexibility and efficiency of the approach presented.

http://www.chm.bris.ac.uk/sillymolecules/bastarane.pdf

A General Method for the Synthesis of Bastaranes and Isobastaranes: First Total Synthesis of Bastadins 5, 10, 12, 16, 20, and 21

A new cytotoxic bastadin, bastadin 24 (1), and the previously reported bastadins 4, 5, 6, 7, 12, 13, and 21 (2−8) were isolated from a polar extract of the Australian marine sponge Ianthella quadrangulata. The planar structure of bastadin 24 (1) was elucidated as the 25-hydroxy derivative of bastadin 6 (4) by employing spectroscopic techniques (NMR, MS, UV, and IR). All isolated bastadins were evaluated for their cytotoxicity toward a panel of 36 human tumor cell lines and were found to be moderately cytotoxic. Bastadin 24 (1) exhibited selective cytotoxic activity toward five of the 36 investigated tumor cell lines. Bastadins 7 (5) and 12 (6) significantly inhibited the serum + hEGF-induced (human epithelial growth factor) tubular formation of human umbilical vein endothelial cells (HUVEC) at a concentration of 1 μg/mL.

Cytotoxic bastadin 24 from the Australian sponge Ianthella quadrangulata.

Bastadin 21, a novel tribrominated bastadin with the uncommon isobastarane skeleton, was isolated from the Great Barrier Reef marine sponge Ianthella quadrangulata. The structure was elucidated on the basis of the 1D and 2D NMR and MS data of bastadin 21 and its tetramethyl ether.

Vani Sankar

Papers

Bastadin 21, a novel isobastarane metabolite from the Great Barrier Reef marine sponge Ianthella quadrangulata.