Thiostreptons

Thiostrepton and Related Antibiotics. Thiostrepton [1393-48-2] (thiactin, bryamycin), C.72Hg5N O gS, shown in Figure 4, is a large (mol... 

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

Nicolaou in his model system for an approach to the thiopeptide antibiotic thiostrepton, in particular, the elaboration of the quinaldic acid moiety. The tetrahydroquinoline 21 was converted to the A-oxide by /n-CPBA oxidation. Subsequent treatment with TFAA, to carry out the Boekelheide reaction, was followed by hydrolysis of the resultant ester to produce 22 as a mixture of alcohols. 

Vancomycin was the first macrocyclic antibiotic evaluated as selector for the synthesis of HPLC chiral stationary phases (CSPs) [7], along with rifamycin B (among ansamycins) and thiostrepton (among polypeptides). 

Macrocyclic antibiotics also include a family of thiopeptides, of which thiostrepton (Figure 2.11) is the parent compound and the most complex member. Produced by Streptomyces azureus [59], thiostrepton includes 10 rings, 11 peptide bonds, extensive unsaturation, an imine functionality, a secondary amine, and 17 stereogenic centers [60] it also contains five thiazole rings and one quinoline nucleus. 

Carboxylic acid-terminated organosilanes were used in the early studies on chemically bonded glycopeptides to immobilize vancomycin and thiostrepton via then-amino groups, leading to the formation of stable amide bonds between antibiotics and modified silica [7]. In a typical reaction, 4 g of dry silica gel is slurried on 50 mL of dry toluene. Two grams of [l-(carbomethoxy)ethyl]methyldichlorosilane or [2-(carbomethoxy)ethyl]trichlorosilane is dissolved in 15 mL of dry toluene contained in a dropping flask. The organosilane solution is added dropwise over 30 min... 

Another factor that remarkably affects the enantioresolution of given enantiomeric pairs has been shown to be the binding chemistry used for the silica immobilization of glycopeptides (see Section 2.2). This was illustrated in the case of ristocetin A, which was covalently bonded to silica microparticles by immobilization onto epoxy-activated silica under mild conditions [22], and compared with the corresponding commercially available CSP, where the macrocycle was immobilized as previously reported for vancomycin, rifamycin B, thiostrepton [7], and teicoplanin [30]. The comparison proved that immobilization of ristocetin A onto epoxy-activated silica could significantly improve the enantioselectivity and the resolution of the corresponding CSP in the separation of a-amino acids under RP conditions [22]. 

Nicolaou, K.C. et al., Total synthesis of thiostrepton, Part 1 construction of the dehydropiperidine/thiazoline-containing macrocycle, Angew. Chem. Int. Ed., 43, 5087, 2004. 

Armstrong et al. ° first introduced chiral stationary phases based on macrocyclic antibiotics. Vancomycin, ristocetin A, teicoplanin, avoparcin, rifamycin B and thiostrepton are used as chiral selectors. They posses a broad enantiorecognition range, similar to protein based CSPs. However, CSPs based on macrocyclic antibiotics show higher stability and capacities.Underivatized amino acids, N-derivatized amino-acids, acidic compounds, neutrals, amides, esters and amines can be separated.The first four of the above-mentioned chiral selectors appear to have the largest enantiorecognition range.The selectors can also be derivatized to obtain different enantioselectivities. 

Fig. 10.3 (M-8H) charge state of the 58merA1061 RNA construct (see text) in the presence of an excess of thiostrepton. The buffer solution contains 20% MeOH and 25 mM NH4OAC. In the absence of adequate ion, the A1061 construct is denatured and does not bind thiostrepton. At increasing Mg concentration, the A1061 adopts a...

Fig. 10.4 A1061 folding in the presence of MeOH. In a solution containing 25 mM NH4OAC and a molar excess of thiostrepton, the A1061-thiostrepton complex is not observed at significant abundance with less than 25% MeOH. The spectrum acquired...

Fig. 10.5 Proper folding of A1061 RNA construct (as measured by thiostrepton binding) as a function of MeOH composition of the buffer.

For biosynthetic studies of the formation of the macrocyclic peptide antibiotic thiostrepton, isotopically labeled [ C]-AAs were employed. The quinaldic acid moiety 97 of this antibiotic was shown to be biosynthesized from 3-methyltryptophan, and a mechanism has been proposed (93JA7992). 

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