Relative inhibitory activities of the eluted fractions on the contractile responses to SP (10 nM) and acetylcholine (ACh, 100 nM) of the guinea pig ileum are shown by black bars.

The synthesis of nine 2-substituted taurines (5a-i), including the marine natural product D-cysteinolic acid (5f), are described. These involve the successive conversion of N-t-butoxycarbonyl( Boc) -protected amino acid esters (I) into the N-Boc-2-aminoethanols (2), their 0-mesylated derivatives (3), the deprotected 2-aminoethyl methanesulphonates (4), followed by the replacement of the mesyloxy group by a sulpho group to give the optically active taurines (5a-e,g-i).Hydrogenolysis of 2-benzyloxymethyltaurine (5e) gives o-cysteinolic acid (5f). The structure of another of the products, (5b), is also confirmed by an alternative synthesis from N-Boc-valine methyl ester (1 b) via two P-bromoethylamine derivatives, (6b) and (7b).An optically active taurine derivative, D-cysteinolic acid (5f), has been isolated from marine micro-organisms and its bioactivity has also been r e p~r t e d .~ However, although the enantiomer of (50 has been prepared,' the natural product itself (5f) has not been synthesized before. Further, since there have been no simple and general synthetic routes to 2-substituted taurine derivatives (5), this has limited studies on the structural properties and structure-activity relationships for compounds of type (5).We earlier reported a general synthetic method leading to taurine-containing dipeptides, via an amino acid P-halogenoethylamide without r a~e m i z a t i o n ,~'~ and, more recently, we have shown that C-terminal amino acids in oligopeptides can be converted into taurine derivative^.^^^ We now report the extension of such a process to the synthesis of 2-substituted taurines: thus, a synthetic route represented by formulae (1)-(5) in the Scheme, has been evaluated as a general method: it proved remarkably successful.Syntheses.-2-Substituted taurines (5) were synthesized by two routes, namely through the 2-aminoethyl methanesulphonates (4) and the halogenoethylamine (7). The former shorter method proved better, although in the analogous conversion of a C-terminal amino acid of a peptide into a taurine derivative, the second route proved better.6.7 First, each a-amino acid methyl ester was converted into the corresponding hydroxyethylamide (2) by LiBH4 reduction8" in 80-95% yield. Then each hydroxyethylamide (2) was mesylated in 93-99% yield to give the derivative (3), which was deprotected to give (4) (ca. 90-100%), and subsequently allowed to react with sodium sulphite to give a 2-substituted taurine (5) (ca. 90-100%). Alternatively, the product (5b) was prepared from the substrate (3b) via two bromo intermediates (6b) and (7b) in 54% yield. The products derived from both syntheses proved identical.The natural D-cysteinolic acid (5f) was obtained quantitatively by a conventional hydrogenation of its benzyl derivative (5e), which was synthesized from Boc-L-Ser(Bz1)-OMe (le).

No abstract

No abstract

We have developed a rapid evaluation method, comparative molecular active site analysis (CoMASA), for obtaining 3D QSAR. CoMASA has three major advantages: (1) the CoMASA results would easily transform to pharmacophore and/or queries required for 3D database searches, (2) the CoMASA method is not required to consider orientation and translation of molecules against a lattice, and (3) standard PCs can be used to perform the analysis. The potential of these improvements and possible further enhancements are discussed.