Search

Two different synthetic concepts led to the formation of 17, 19, and 29, the first structural isomeric benzobis[1,3]oxathiins. Hetero-DielsAlder reactions of diethyl mesoxylate 14 and the open valence isomers of the benzobisthietes 12 and 18 yielded the linear benzobis[1,3]oxathiin 17 and its angular isomer 22, respectively. The isomeric angular system 29 could be obtained by a twofold O,S-acetalization reaction of the dihydroxydisulfanyl compound 27 and acetone (28).

Many clinically used protein therapeutics are modified to increase their efficacy. Example modifications include the conjugation of cytotoxic drugs to monoclonal antibodies or poly(ethylene glycol) (PEG) to proteins and peptides. Monothiol-specific conjugation can be efficient and is often accomplished using maleimide-based reagents. However, maleimide derived conjugates are known to be susceptible to exchange reactions with endogenous proteins. To address this limitation in stability, we have developed PEG-mono-sulfone 3, which is a latently reactive, monothiol selective conjugation reagent. Comparative reactions with PEG-maleimide and other common thiol-selective PEGylation reagents including vinyl sulfone, acrylate, and halo-acetamides show that PEG-mono-sulfone 3 undergoes more efficient conjugation under mild reaction conditions. Due to the latent reactivity of PEG-mono-sulfone 3, its reactivity can be tailored and, once conjugated, the electron-withdrawing ketone is easily reduced under mild conditions to prevent undesirable deconjugation and exchange reactions from occurring. We describe a comparative stability study demonstrating a PEG-maleimide conjugate to be more labile to deconjugation than the corresponding conjugate obtained using PEG-mono-sulfone 3.

2-(1H-Benzotriazol-1-ylmethyl)-1-naphthalenol (1) can be transformed in high yields to the corresponding thiol 4. Flash vacuum pyrolysis of 4 leads to 2H-naphtho[1,2-b]thiete (5). The benzotriazolyl group proved to be a good leaving group; however, a subsequent nitrogen extrusion takes place under flash vacuum pyrolysis conditions and cyclopentadienecarbonitriles 6a,b are formed by a ring contraction (Scheme 1). Cycloaddition reactions of 5 and dienophiles or heterodienophiles yield the naphtho-condensed sulfur heterocycles 8, 10, 12 and 14 (Scheme 2).

Naphtothietes and Their Application to the Synthesis of Heterocycles The three isomeric naphthothietes 5, 11, and 16 were prepared according to the reaction sequences shown in Schemes 1–3. The final step was in each case a flash vacuum pyrolysis (FVP) of the corresponding mercaptonaphthalenemethanol 4, 9, and 15, respectively. The thiete rings in 5 and 11 can be opened by gentle heating; the ring opening of the isomer 16 possesses a much higher activation barrier. A MNDO calculation of the ΔHf values of 5, 11, and 16 and the open isomers 5′, 11′, and 16′ provides an explanation for the different behavior. Photochemical ring opening represents a useful alternative. The reaction Schemes 4, 6, and 7 reveal the synthetic potential of the naphtho-condensed thietes. Cycloaddition reactions with CC, CO, or CN double bonds lead into the series of differently condensed thiopyrans 17, 18, 24, 25, 26, 3,1-oxathiine 19 and 1,3-thiazines 20, 21.

Site-specific PEGylation reagents have been developed that undergo thiol-specific bis-alkylation with the two cysteine sulphur atoms from a native accessible disulphide in proteins. The process for this approach of site-specific PEGylation involves two steps: (1) disulphide reduction to release the two thiols and (2) bis-alkylation of the PEG reagent to the two sulphur atoms to give a three-carbon bridge to which PEG is covalently attached. Mechanistically, the conjugation is thought to occur by a sequential, interactive bis-alkylation that requires functionalised PEG reagents that have a α, β-unsaturated β′-mono-sulphone moiety. Competitive reactions can be effectively suppressed to achieve high yield PEGylation with a stoichiometric equivalence of the reagent. The reagents are easily prepared and precursor forms of our PEG reagents can be used to control the rate of formation of the reactive PEG mono-sulphone in situ that undergoes conjugation with the protein. Purification is often a simple process where un PEGylated protein can be easily recycled to further increase yields. Many classes of therapeutically relevant proteins possess accessible native disulphides. Our studies have shown that peptides, proteins, enzymes and antibody fragments can be site-specifically PEGylated by bis-alkylation using a native, accessible disulphide.

Oligo(phenyleneethynylene)s 1 are rod-like compounds with undisturbed conjugation. In supplementation of the previously described members of this series 1a−e, with repeating units of up to n = 5, this work contains the preparation of higher oligomers 1f−i (n = 6, 7, 8, 10) through the use of the Sonogashira−Hagihara reaction. Both the absorption and the fluorescence bands showed convergence for increasing values of n, reaching limiting values at the effective conjugation length of nECL = 10. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)