Other Cyclic Hexapeptides

A number of cydic hexapeptides ha been synthesized and sutgected to detailed investigations, the reason for whidi is summarized by the followii points  

Synthesis is fairly ea in spite of many amino add residues. 

A trend for a particular amino add residue to take a cific position in the cycle can be assessed. 

Suffident flexibility is given by the isomerization of peptide bond. 

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The steric bulk of the thioamide sulfur results in conformational changes that have been documented in cyclopentapeptide and cyclohexapeptide model systems (for more details see Vol. E22b, Section 6.8.5.2.1). For example, in c[-Proi(>[C(=S)-NH]Gly-Pro-Gly-D-Phe-], the first synthetic cyclic thiopeptide, an intramolecular y-turn seen in the all-amide parent compound by NMR methods was perturbed by the putative interaction of sulfur with the adjacent Pro s (3-protons.[9 On the other hand, in a cyclic hexapeptide, the enhanced H-bond donor capacity of the thioamide NH led to the formation of a relatively strong intramolecular H-bond stabilized (3-turn, which was frame shifted compared to that found in its all-amide parent peptide. 10 ... 

Comprehensive investigations have been carried out with synthetic Qrdic dipeptides and cyclic hexapeptides because they are sjynthesized more easily than others. Under suitable reaction conditions, cydic peptides with the requisite number of amino acid residues and a known sequence can be nthesized without racemiza-tion. A review article for the nthesis of cydic peptides has been publidied recently (32). 

Other cyclic peptides including konbamide (31), from the keramamide derivatives containing Theonella [27], and mozamides A (32) and B (33), from a Theonellid collected in the southern Mozambique [28], incorporate an ureido linkage. In the cyclic hexapeptides 32 and 33 an... 

Chloptosin (190, Scheme 8.19), a dimeric cyclohexapeptide, was isolated from Streptomyces strain M K498-98F14 [183]. It exhibits apoptotic activity in the apoptosis-resistant human pancreatic adenocarcinoma ceU line AsPC-1 along with few other apoptosis-sensitive cancer cell Hnes. Structurally, two identical cyclic hexapeptide subunits are hnked to form chloptosin 190. These cychc hexapeptides consist of two characteristic fragments (R)- and (S)-piperazic acids that are unusual cychc amino acids with a hydrazine unit and a 6-chloropyrroloindole residue. The first total synthesis of chloptosin was pubhshed recently after 10 years from disclosure of its structure [184]. In this report, Yao and coworkers centered their hypothesis around dimeric bis-pyrroloindole amino acid present in the... 

Figure 38 Representation of the equilibrium between the cyclic and acyclic forms of a hexapeptide. The N- and C-terminal blocking groups, CH3CO— and —NHCH3, respectively, are not shown.233 The standard free energy change for this process depends on the intrinsic chemistry to form a disulfide bond from two sulfhydryl groups, the tendency of Pro-Giy (or any other dipeptide in this position) to form a P turn, and the tendencies of residues X and Y to adopt the extended conformation (and interact with each other). Table 5 of Reference 234 illustrates the range of standard free energy changes for a family of such hexapeptides.

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