Of thiolactone

A range of thiolactones was obtained by virtual screening with the rationale to be covalently cleaved by FabDSer92. Among them, 4 was described as a potent E. coli FabD inhibitor with antibiotic properties although no further biological data was provided [12]. 

Add N-acetyl homocysteine thiolactone (Aldrich) to the bicarbonate reaction mixture to obtain a concentration representing a 10- to 20-fold excess over the amount of amines present. For protein thiolation, add the same molar excess of thiolactone reagent to the water reaction medium, and then slowly add an equivalent molar quantity of silver nitrate (AgNO j). Maintain the pH at 7.0-7.5 with periodic addition of NaOH. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

The problem of oxidative phosphorylation has been approached through model studies that utilize the phosphorylating potential of metaphosphate. In the mitrochondrial process inorganic phosphate and adenosine diphosphate are converted to adenosine triphosphate. Wieland, in a series of papers (e.g. ref. 31), has shown that a variety of thiolactones can activate inorganic phosphate in the presence of bromine for transfer to adenosine diphosphate (ADP). The intermediate may be an acyl phosphate or a sulfonium salt similar to that postulated by Higuchi and Gensch32 and by Lambeth and Lardy33, viz. 

The chemistry of thiolactones is particularly interesting because of the biological activity associated with a number of these derivatives.59 More recently, a method has been pursued51 for the preparation of silylated unsaturated thiolactones 56 having a five- to ten-membered ring (Scheme 37). a-Carboxy acylsilanes 57,... 

For example, treatment of / -thiolactone 110 with Et3N in CDCI3 gives a thermodynamic mixture of two diastereoisomeric S-thiolactones (110 100 = 60 40, equation 23). In comparison, treatment of / -lactam 111 with NaOD in D2O gives the deu-teriated /S-lactam 111 as a single diastereoisomer in quantitative yield with retention of... 

Free radical methods for the synthesis of thiolactones 00MI5. 

Facile synthesis of an intermediate for biotin 53 was achieved through the nonpy-rophoric catalyst Pd(OH)2/C promoted coupling reaction of thiolactone 50 with 4-ethoxycarbonyl-butylzinc iodide (52) [115, 116]. This synthetic route was advantageous over the previously reported method using Pd/C (yield 30%) [117]. 

Puri and co-workers [128,129] found that sulfur is introduced to the carbon matrix by interactions with oxygen-containing functional groups or by addition to unsaturated sites. Thus, the substitution reactions with quinone and phenolic groups lead to thioquinone and thiophenol structures, and the addition reactions result in the formation of sulfide and sulfoxide groups. Moreover, Chang showed the evidence of thiolactones in a number of carbonaceous materials after reaction with various sulfur-containing materials [126]. 

Amine ring opening polymerization of thiolactone to polythioesters [20]. 

In the presence of physiological concentrations of homocysteine, methionine, and folic acid, human umbilical vein endothelial cells efficiently convert homocysteine to thiolactone (Jakubowski et al. 2000). The extent of this conversion is directly proportional to homocysteine concentration and inversely proportional to methionine concentration, suggesting involvement of methionyl-tRNA synthetase. FoHc add inhibited the synthesis of thiolactone by lowering homocysteine and increasing methionine concentrations in endotheUal cells. The extent of post-translational protein homocystei-nylation increased with increasing homocysteine levels but decreased with increasing folic acid and HDL levels in endotheUal cell cultures. 

As mentioned in the introduction to this chapter, the recent discovery of thiolactone peptides as potential antimicrobial agents, based on flieir ability to act as antagonists of natural auto-inducing peptides (AIP), prompted the new synthetic achievements, which permitted the synthesis of these cyclic peptide inhibitors. Here, we discuss the most recent achievement in the synthesis of AIP mimics, based on an original linker for the Fmoc-based solid-phase methodology. 

Scheme 12-5 Schematic presentation of the synthesis of thiolactone peptide Xni with N-Boc protected amino acids (modified fi-om [36])...

Alkenation. Alkenation of thiolactones can be achieved by rhodium(II) acetate-catalyzed reaction with dimethyl diazomalonate (eq 12). Recently, an efficient alternative alkenation protocol has been demonstrated to be applicable to a variety of ketones and aldehydes by reaction with tributylstibine and dimethyl diazomalonate in the presence of copperfT) bromide (eq 13). This process is proposed to occur via tributylstibonium bis(methoxycarbonyl)methylide. 

These polymers, obtained by ring-opening polymerization of thiolactones, have been extensively studied (as illustrated here by Dr Fles) more especially the optically active a-substitued ]3-propiothiolactones (LIV). 

A series of thiolactones (CIII) has been obtained in yields of 58-81 % by treatment of complex XCVI with ceric ammonium nitrate in acetone (Alper and Chan, 1973). This complex exhibits a great propensity towards carbonyl insertion, and these thiolactones may also be prepared by other means such as treatment with FeClj, heating in ethanol, photochemical irradiation at 2537 A, or by reaction with amines, phosphines, alcohols, or thiocyanate ion (Alper et ai, 1974). Note that these thiolactones are dihydro derivatives of isobenzothiophenes, little-known heterocycles (Albert, 1959 Katritzky and Lagowsky, 1968), whose synthesis in two steps may now be facilitated. 

Site-Specific Double PPM of Thiolactone-Containing Polymers. 114... 

---