To probe the substrate specificity of the human metalloproteinase stromelysin (SLN), we determined values of kc/Km for the SLN-catalyzed hydrolysis of substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH2; SP; kc/Km = 1790 +/- 140 M-1 s-1), 15 analogues of SP, and 17 other peptides. We found a remarkably narrow substrate specificity for SLN: while SP and its analogues could serve as substrates for SLN (hydrolysis occurred exclusively at the Gln6-Phe7 bond), peptides that were not direct analogues could not (kc/Km less than 3 M-1 s-1). From the study of the SLN-catalyzed hydrolysis of SP and its analogues, the following findings emerged: (1) Decreasing the length of SP results in decreases in kc/Km. (2) Conservative amino acid replacements near the scissle bond of SP decrease kc/Km. (3) The SP analogue in which Gly9 is replaced with sarcosine (N-methylglycine) is not hydrolyzed by SLN (kc/Km less than 3 M-1 s-1). (4) Several SP analogues that are not hydrolyzed by SLN are inhibitors of the enzyme. The complexes formed from interaction of SLN with these peptides have dissociation constants that are similar to the Km value for the complex of SLN and SP. Combined, these results suggest that SLN uses the energy that is available from favorable interactions with its substrate to stabilize catalytic transition states but not the Michaelis complex or other stable-state complexes.

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Abstract-The regioselective alkylation of pyridinium-N-(2 H -azinil)aminides with alkyl halides under mild conditions is described. The alkylation, combined with a reduction of the N-N bond, allows an easy preparation of 2-alkylaminoazines. ᭧

Abstract-A regioselective Suzuki-Miyaura cross-coupling reaction on 3 0 ,5 0 -dibromo pyridinium N-(2 0 -azinyl)aminides is reported. A series of 3 0 -aryl(or heteroaryl)-5 0 -bromo-pyridinium N-(2 0 -pirazinyl)aminides were obtained in good yields. Two isomeric 3 0 ,5 0 -diaryl pyridinium N-(2 0 -azinyl)aminides were also prepared. Ó 2006 Elsevier Ltd. All rights reserved.Functionalization of heterocycles through SuzukiMiyaura palladium-catalyzed cross-coupling has been established as a standard method for the synthesis of biaryl and heterobiaryl systems. 1 Substituted pyridines and pyrazines are valuable intermediates in the pharmaceutical and flavour fields, so development of regioselective processes over both systems has an indubitable interest. In the past years, our research programme has been related with the synthetic utility of pyridinium N-(2 0 -azinyl)aminides 1 2 ( Fig. 1) as building blocks in the synthesis of azine derivatives, 3 and we recently reported preliminary results obtained in the crosscoupling reaction between arylboronic acids and pyridinium N-(5 0 -bromoheteroar-2 0 -yl)aminides 1a-c 4 (Fig. 1).The promising results obtained from ylides 1a,b justified broadening of the process over other aminides, such as N-(3 0 ,5 0 -dibromopyrid-2 0 -yl)pyridinium aminide 1c. 3c On this substrate, a double Suzuki reaction was performed, and different 3,5-disubstituted azines were obtained. 4 The same double coupling methodology on 1c, employing 3-pyridylboronic acid (Scheme 1), produced a low yield (18%) of the expected bis-heteroaryl aminide 2a, while the monosubstituted ylide 3a appeared as the main reaction product (48%), in addition to 28% of starting material 1c that was recovered. Neither the use of a large excess of 3-pyridylboronic acid and/or palladium catalyst, nor longer reaction times, improved the yields of compound 2a.The structure elucidation of 3a was solved by comparison of its 1 H NMR spectra with those of related compounds. H6 0 of the 2-aminopyridine ring appears more shielded when a bromine atom is in position 5 0 -, than when an arene is placed in the same position. 3b,4 The following data were obtained for dH6 0 (CD 3 OD) in compounds 1c, 2a and 3a: 7.74 ppm, 8.03 ppm and 7.71 ppm, respectively. This result pointed out a considerable degree of regioselectivity in the Suzuki process, when N-(3 0 ,5 0 -dibromo-2 0 -pyridin-2 0 -yl)pyridinium aminide 1c was reacted with pyridyl-3-boronic acid.Regioselectivity in palladium cross-coupling reactions of di-haloazines, having two identical halogen atoms in different positions of the ring, has not been often described in the literature. 5a On uncharged systems, 2,5-dibromopyridine undergoes a regioselective palladium-catalyzed coupling with terminal acetylenes and arylzinc halides, 5b and 2,5-dichloropyridine selectively reacts at 2-position with phenylboronic acid. 5c,d Moreover, the synthesis of 2-aryl-6-chloronicotinamides via Suzuki coupling of 2,6-dichloronicotinamide with aryl boronic acids has also been described, and in this case...

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