Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding activity. This resulted in compounds with a 6-fold increased potency.
Resu le 16 mai 1966Les produits de r6action entre le di-t-butyl-2,7 naphtalkne d'une part e t I'acide nitrique, le brome, le chlori~re de sulfuryle ou le chlorure d'iode d'autre part ont CtC exaininCs. L a structure des produits obte~lus a CtC Ctablie grLce A la resonance rnagnetique nucleaire. ISTRODUCTIONDans des travaux pritcitdents (1, 2), il a ittit ditmontrit que les ritactions de monosubstitution sur le diinitthoxy-2,7 n a p h t a l h e (I) conduisent aux dbrivits du type 11, alors que la sulfonation du di-t-butyl-2,7 naphtalhe (111), qui est stitriquement plus emp&chit, conduit au produit IVa. Un autre effet stitrique a Ctit not6 au cours de ces travaux; en effet, alors que la dinitration du diinitthoxy-2,7 n a p h t a l h e (I) conduit au dinitro-1,s dimitthoxy-2,7 naphtalPne (V), la ritaction de dibromuration pour sa part conduit au dibromo-1,6 dimitthoxy-2,7 naphtalPne (VI). I1 s'avitrait doilc intitressant d'examiner la nature des produits de monosubstitution sur le di-t-butyl-2,7 naphtakne (111) et I'effet des substituants ditjA pritsents sur les ritactions de di-et de tri-substitution d a m la sitrie d u di-t-butyl-2,7 naphtakne. Les ritsultats rapportits dans le pritsent travail auront donc trait aux ritactions de nitration, chloruration, broinuration et iodation du di-tbutyl-2,7 naphtalitne. De plus, certains ditrivits des produits originaux de substitution seront aussi ditcrits. R B S U L T X~~SLa mononitration de l'hydrocarbure I11 conduit 2I deux isomGres, l'un nitrit en position 1 (VIIa) et l'autre nitr6 en position 4 (IVb). Les proportions relatives de chacun, telles que ditterininites par ritsonailce magnittique nuclitaire sur l'huile du n~itlange ritactionnel, seraient de 56% de produit VIIa et 44% du produit IVb; une dittermination par infrarouge utilisant les bandes A 837 e t 826 cm-I pour les nitro-1 (VIIa) et nitro-4 (IVb) di-t-butyl-2,7 naphtalhe, respectiveinent, conduisent 21 des conclusions semblables. Une nitration plus poussite du di-t-butyl-2,7 n a p h t a l h e (111) conduit A un mClange contenant les dinitro-1,5 (VIII), dinitro-4,5 (IX) et trinitro-1,4,5 (X) di-t-butyl-2,7 naphtalitnes aux c6tits de la dinitro-3,s di-t-butyl-2,7 naphtoquinone-1,4 (XI) ; en plus de ces produits, la chromatographie sur couche mince perinet de dittecter cinq autres produits qui sont prksents en faible quantitit e t qui n'ont pas ittit isolits. I1 est A noter que la nitration d u nitro-4 di-t-butyl-2,7 naphtalitile (IVb) conduit exclusivement aux dinitro-1,5 (VIII) e t dinitro-4,s (IX) di-t-butyl-2,7 naphtalhes, alors que la nitration d u nitro-1 di-t-butyl-2,7ILes risrlltats rapportks dans cette co
A number of carbapenem derivatives were examined to determine the structure-activity relationships required for dependence on porin protein D2 for activity against Pseudomonas aeruginosa. As suggested by J. Trias and H. Nikaido (Antimicrob. Agents Chemother. 34:52-57, 1990), carbapenem derivatives, such as imipenem and meropenem, containing a sole basic group at position 2 of the molecule utilize the D2 channel for permeation through the outer membrane of pseudomonads; they are more active against D2-sufficient strains of P. aeruginosa. Our results indicated that carbapenems with a basic group at position 1 or 6 of the molecule did not depend on the D2 channel for activity; i.e., they were equally active against D2-sufficient and D2-deficient pseudomonal strains. However, addition of a basic group at position 1 or 6 of a carbapenem derivative already containing a basic group at position 2 resulted in its lack of dependency on the D2 pathway.Comparison between meropenem and its 1-guanidinoethyl derivative, BMY 45047, indicated that they differed in their dependence on D2; while meropenem required the D2 channel for uptake, BMY 45047 activity was independent of D2. Meropenem and BMY 45047 had similar affinities for the penicillin-binding proteins of P. aeruginosa. However, BMY 45047 and meropenem differed in the morphological changes that they induced in pseudomonal cells. While meropenem induced filamentation, BMY 45047 induced filaments only in BMS-181139-resistant mutants and not in imipenem-resistant mutants or in carbapenem-susceptible P. aeruginosa strains. These results suggested that in Mueller-Hinton medium the uptake of BMY 45047 through the non-D2 pathway is more rapid than that of meropenem through the D2 porin. In summary, the presence of a basic group at position 2 of a carbapenem is important for its preferential uptake by the D2 channel. However, the addition of a basic group at position 1 or 6 of a carbapenem already containing a basic group at position 2 dissociates its necessity for porin protein D2 for activity.
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