1.3-Dimethylphosphinothioyl-2(3H)-oxazolone (MPTO), a promising new reagent for racemization-free couplings.
Katoh T1, Ueki M. Int J Pept Protein Res. 1993 Sep;42(3):264-9.
3-Dimethylphosphinothioyl-2(3H)-oxazolone (MPTO) was synthesized, and its ability to effect racemization-free couplings and cyclization of a peptide and its C-terminal epimer was examined. MPTO showed good reactivity in aprotic polar solvents such as N,N-dimethylformamide (DMF) and N-methylpyrrolidone. In reactivity MPTO resembles DPPA and dimethylphosphinothioyl azide (MPTA) previously developed by us, but it is much better than these reagents because the side reactions specific to the azide method could be avoided. In coupling of Z-Gly-Val-OH with H-Val-OMe in DMF at 0 degree C, no racemization was observed without use of racemization-suppressing additives. Slight racemization observed at room temperature could be completely suppressed by addition of HOBt but not by HOSu. The utility of MPTO was demonstrated by the synthesis of cyclo-(D-Trp-D-Glu(OBzl)-Ala-D-Val-Leu), an intermediate for an endothelin-binding inhibitor BE 18257A. In a comparative study using DPPA, MPTA and MPTO, no racemization was observed for MPTA or MPTO, while DPPA caused considerable racemization.
2.Relationship between enantioselectivity of alternative molecularly imprinted polymeric membranes and species of amino acid residues composing chiral recognition sites.
Yoshikawa M1, Kondo Y, Morita Y. Bioseparation. 2001;10(6):323-30.
Molecularly imprinted polymeric membranes with tetrapeptide residue H-Asp(OcHex)-Asp(OcHex)-Asp(OcHex)-Asp(OcHex)-CH2- (DDDD) or H-Glu(OBzl)-Glu(OBzl)-Glu(OBzl)-Glu(OBzl)-CH2- (EEEE) were prepared during membrane preparation (casting) processing in the presence of print molecules. The Boc-L-Trp imprinted polymeric membranes thus obtained showed adsorption selectivity toward Ac-L-Trp from its racemic mixtures. From adsorption isotherms of Ac-Trp, the chiral recognition site, that had been formed by the presence of print molecules in the membrane preparation process, exclusively recognized Ac-L-Trp that possessed the same configuration of the print molecule. The affinity constants between chiral recognition sites in the membrane and Ac-L-Trp was determined to be 1.00 x 10(4) mol(-1) dm3 and 1.08 x 10(4) mol(-1) dm3 for the DDDD and EEEE membranes, respectively. Enantioselective electrodialysis could be attained by applying an optimum potential difference to give permselectivity, with a value close to its adsorption selectivity.
3.Chemical synthesis of O-thiophosphotyrosyl peptides.
Kitas E1, Küng E, Bannwarth W. Int J Pept Protein Res. 1994 Feb;43(2):146-53.
The synthon for O-thiophosphotyrosine, Fmoc-Tyr[PS(OBzl)2]-OH (1c), was prepared in 63% yield from Fmoc-Tyr-OH by first transient protection as the tBuMe2Si-ester and phosphinylation with (BzlO)2PNiPr2/tetrazole followed by oxidation of P(III) to P(V) with S8 in CS2. Building block 1c was incorporated in the Fmoc solid-phase synthesis of two O-thiophosphotyrosine-containing peptides H-Thr-Glu-Pro-Gln-Tyr(PS)-Gln-Pro-Gly-Glu-OH (2) and H-Thr-Arg-Asp-Ile-Tyr(PS)-Glu-Thr-Asp-Phe-Phe-Arg-Lys-OH (3), corresponding to sequences of the p60src (523-531) protein and an insulin receptor (IR) (1142-1153) analogue, respectively. An alternative approach of synthesis, the global phosphorylation of a resin-bound peptide, also proved useful. Thus, the free tyrosyl side-chain containing-peptide IR (1142-1153) on support was phosphinylated with the above phosphoramidite reagent followed by oxidation with either S8/CS2 or tetraethylthiuram disulfide/CH3CN solutions.
4.Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter.
Lepist EI1, Kusk T, Larsen DH, Andersen D, Frokjaer S, Taub ME, Veski P, Lennernäs H, Friedrichsen G, Steffansen B. Eur J Pharm Sci. 2000 Jul;11(1):43-50.
One approach to increase drug stability and to facilitate oral absorption of low bioavailability drugs may be to design oligopeptide ester prodrugs which are stable in the gastrointestinal tract, are transported via the oligopeptide transporter, and finally release the parent drug molecule into the blood circulation and/or by its site of action. In these kinds of prodrugs the ester linkage may be broken by pH dependent and/or enzyme catalyzed hydrolysis. The objective of the present study was to investigate the degradation mechanism and rate of the model compounds Glu(OBzl)-Sar, D-Glu(OBzl)-Ala and Asp(OBzl)-Sar in aqueous solution and in relevant biological media and to compare these results with those of our previous study of D-Asp(OBzl)-Ala. Furthermore, the resulting aqueous stability and in vitro metabolism data are related to our previous affinity data to evaluate if Glu-Sar, D-Glu-Ala, and Asp-Sar have potential as pro-moieties in these kinds of prodrugs.
