Molecular cyclopeptides

Molecular modeling studies toward the structural optimization of new cyclopeptide-based HDAC inhibitors modeled on the natural product FR235222. Bioorganic and Medicinal Chemistry, 16, 8635-8642. 

Kubik, S., Kirchner, R., Nolting, D., and Seidel, J. (2002) A molecular oyster A neutral anion receptor containing two cyclopeptide subunits with a remarkable sulfate affinity in aqueous solution, J. Am. Chem. Soc. 124, 12752-12760. 

In another attempt, cyclopeptide SOs and SO libraries, respectively, for CE enan-tioseparations have been developed by combinatorial chemistry approaches [378,379], and recently also molecularly imprinted polymer combinatorial libraries have been prepared [ 191 ]. 

Cyclopeptidic alkaloids (molecular mass 600 Da), a class of important alkaloids which present biological activity, were analyzed by HT-HRGC without derivati-zation [16]. Figure 1 illustrates the separation of cyclopeptidic alkaloids in the chloroform fraction. The following selected compounds were identified (1) Franganine, (2) Miriantine-A, (3) Discarine-C, and (4) Discarine-D. 

The elucidation of the structure of cyclopeptidic indoles in a mixture could be determined by analyzing the B/E/CAD spectra of molecular ions. The FD spectra of this mixture indicated the presence of high-molecular-weight ions, including m/z 593 and 573. It was impossible to separate this mixture, even with liquid chromatography, as a result of the similar structures of these molecules and the mixture had to be studied as it was (about 1 pg of sample). Collisions on these ions led to side-chain cleavage, which led to an interesting approach to molecular structure. Table 23 lists the principal ions observed in B/E/CAD spectra from the M molecular ions produced in FD conditions. 

In this section, we wish to discuss the results of recent studies on cyclopeptides carried out by our group [97-99]. Cyclopeptides as molecular receptors have been immobilized on different sensor surfaces, and can be prepared in high diversity by parallel solid-phase peptide synthesis (SPPS) [100], However, functional groups for the attachment to the surface must be available. On the other hand, the interaction with the analyte should be as specific as possible, and for this reason appropriate side chains must be selected. 

J. M. Garda Fernandez, C. Ortiz Mellel, J. L. Jimenez Blanco, J. Fuenles, M. Martin-Paster, and J. Jimenez-Barbero, Macrocyelic sugar thioureas Cyclocligosaecliarides mimicking cyclopeptides, in Molecular Recognition and Inclusion. A. W. Coleman (Ed.), Kluwer, Dordrecht, 1998. 103-108. 

The main tools for structure elucidation nowadays are MS and NMR spectroscopy. MS is extensively used as an important tool for identification. Besides determining the molecular weight, it provides substantial information about the structure of the alkaloids since the various groups of cyclopeptide alkaloids fragment in a predicted and well described way. In recent years use of high field NMR spectroscopy has made structure elucidation of the cyclopeptide alkaloids considerably easier. 

A molecular ion of high m/z ( 650) with a fragmentation typical of 4(14)-cyclopeptide alkaloids and a fragment of m/z 70 (q ) reveal a 5(14)-scutianine-A-type alkaloid, further supported by the presence of two fragments (c-d) differing by 26 amu. 

Celenamides are the cyclopeptide alkaloids with the highest molecular weight (around 1000) and are isolated from sponges. The universal presence of fragment e, with m/z 319 is quite characteristic. The occurrence of fragments differing by 2 amu is due to the presence of Br in the R side chain. 

Table 7. Cyclopeptide Alkaloids and Related Compounds in Order of Increasing Molecular Weight, Including Type, Molecular Formula and Molecular Weight...

Cyclopeptidic alkaloids (molecular mass 600 Da), a class of important alkaloids which present biological... 

One also has to consider that not aU amino add-based natural ligands are structurally so complex as a protein. There are a number of relatively low-molecular-weight natural peptides, for example, cyclopeptides, that very efQciendy and selectively interact with a complementary substrate. Notable examples are the antibiotics vaUnomycin, 1, and vancomycin, 2, as weU as the natural macrocyclic ligand patellamide A, 3 (Scheme 1). 

Figure 4 Molecular structures of cyclopeptides 22a (a) and 22b (b). Nonacidic protons are omitted for clarity.

The 2 1 complexes formed by 23 were subsequently converted into 1 1 complexes by covalently linking two peptide units together. Examples of bis(cyclopeptides) prepared in this context are compounds 24a,b and 25a,b, all of which possess substantially unproved anion affinity with respect to 23. While 24a,b resulted from molecular modeling studies, " bis(cyclopeptides) 25a,b were identified by using dynamic combinatorial chemistry. With a log of almost 7 in 33% water/CHsCN, the latter two compounds... 

Figure 7 Structure of 31 (a) and molecular stracture of the dicopper(II) complex of this cyclopeptide (b). Hydrogen atoms and valine and isoleucine side chains are omitted for clarity.

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