Thio diketopiperazines

The smallest cyclic peptides built from amino acids are the so-called diketopiperazines (DKP). In recent research, the DKPs and higher functionalized analogs - the thiodiketopiperazines (TDKP) - have become attractive due to their broad biological activity (390). The DKP or TDKP moiety can be found in a great variety of mycotoxins. Both DKPs and TDKPs can, for example, be isolated from Aspergillus, Candida, Chaetomium, Gliocladium, Penicillium, and Verticillium species (7, 390). The most common structural motifs A-D of this class of compounds are depicted in Fig. 10.1. Many of these natural products show C2 symmetry, which means they consist of two identical amino acids (R = R in Fig. 10.1). 

To date, a large number of different DKPs and TDKPs have been isolated and characterized. Selected examples are shown in Fig. 10.2 (391-399). 

Erase et al.. The Chemistry of Mycotoxins, Progress in the Chemistry of Organic Natural Products, Vol. 97, DOI 10.1007/978-3-7091-1312-7 10, 

Epicoccin A (602) was isolated from Epicoccum nigrum among several other epicoccins (B-P) 397, 401, 402) (Fig. 10.4 403)). This class of mycotoxins is of great interest due to the bis(polysulfide) moiety and due to their antimicrobial effects. 

Exserohilon (603) can be found in Exserohilum rostratum together with rostratins A-D (398) (Fig. 10.5 (404)). These mycotoxins exhibit in vitro cytotoxicity against the HCT-166 human colon cancer cell line (405). 

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Sabilla Zhong was bom in 1987. She studied chemistry at the Karlsmhe Institute of Technology. In April 2011, she received her diploma degree by working on the synthesis of functionalized hexahydroin-doles. In the same year, she started her Ph.D. studies at the Karlsmhe Institute of Technology with Prof. Dr. Stefan Erase. Her scientific work focuses on the total synthesis of (thio)diketopiperazine natural products and their biological evaluation. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Homoserine lactone (XII) easily forms the diketopiperazine (XIII) which is apparently in equilibrium with the tricyclic addition product (XIV) to judge from its chemical transformations and the relative ease of hydrolysis (Fischer, 1907 Snyder, 1942). Even the lower thio analog, the diketopiperazine of cysteine (XV) opens with remarkable case to give the hydrochloride of cysteinylcysteine (Grecnstein, 1937). 

Amauromine, a dimeric indole alkaloid with hypotensive vasodilator properties, was isolated from Amauroascus species (Gymnoascales, Ascomycotina) (267) and Penicillium verrucosum (26S). The structure of this metabolite was determined by chemical and spectroscopic investigations and confirmed by a total synthesis by Takase et aL 268). The symmetrical diketopiperazine made up of two modified tryptophans, each bearing a 1,1-dimethylallyl group at C-3, was synthesized as shown briefly in Scheme 45. The two inverted prenyl groups were introduced simultaneously by a thio-Claisen rearrangement reaction through the sulfonium salt. 

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