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1.
Org Lett ; 3(7): 1069-71, 2001 Apr 05.
Article in English | MEDLINE | ID: mdl-11277797

ABSTRACT

[reaction: see text]. S-Trifluoromethyl xanthates efficiently add to unactivated alkenes by a radical mechanism to give adducts with a trifluoromethyl group at the least hindered terminus of the olefin.

3.
Drug Des Discov ; 16(1): 41-8, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10466055

ABSTRACT

We have synthesised a number of analogues of lipid X, a precursor in the biosynthesis of LPS, some of which exhibit marked antagonism of LPS induced TNF production in vivo. These compounds provide new non-polar leads in the search for a therapy for endotoxic shock.


Subject(s)
Acids, Carbocyclic/chemical synthesis , Glycolipids/biosynthesis , Lipopolysaccharides/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , Acids, Carbocyclic/pharmacology , Drug Interactions , Humans , In Vitro Techniques , Lipopolysaccharides/pharmacology , Shock, Septic/drug therapy
4.
J Med Chem ; 35(1): 63-7, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1732534

ABSTRACT

Analogues of sinefungin derivatives 18a and 18b have been prepared from uridine and L-aspartic acid. The key step in the synthesis was the coupling of the radical derived from 14 with the unsaturated amide 13. The latter was produced from the known N-hydroxy-2-thiopyridone ester of L-aspartic acid 12 with the olefin 11. Thus, the essential carbon skeleton was constructed by way of two radical coupling reactions. These analogues as well as 1a and 1b synthesized previously were tested for their antileishmanial effect in vivo and for their inhibitory activity of protein carboxymethylase (protein methylase II). The replacement of the adenine moiety by uracil or dihydrouracil considerably decreases the antiparasitic activity and the affinity for protein methylase II. The synthetic (S)-sinefungin was as active as the natural one. Interestingly, the C-6' epimer 1b was 50% less active in vitro than the natural sinefungin, but both had identical affinities for the target enzyme.


Subject(s)
Adenosine/analogs & derivatives , Antiprotozoal Agents/chemical synthesis , Uracil/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Kinetics , Leishmania donovani/drug effects , Structure-Activity Relationship
5.
Proc Natl Acad Sci U S A ; 89(1): 192-6, 1992 Jan 01.
Article in English | MEDLINE | ID: mdl-1729688

ABSTRACT

We have shown that a Rhizobium meliloti strain overexpressing nodulation genes excreted high amounts of a family of N-acylated and 6-O-sulfated N-acetyl-beta-1,4-D-glucosamine penta-, tetra-, and trisaccharide Nod factors. Either a C(16:2) or a C(16:3) acyl chain is attached to the nonreducing end subunit, whereas the sulfate group is bound to the reducing glucosamine. One of the tetrasaccharides is identical to the previously described NodRm-1 factor. The two pentasaccharides as well as NodRm-1 were purified and tested for biological activity. In the root hair deformation assay the pentasaccharides show similar activities on the host plants Medicago sativa and Melilotus albus and on the non-host plant Vicia sativa at a dilution of up to 0.01-0.001 microM, in contrast to NodRm-1, which displays a much higher specific activity for Medicago and Melilotus than for Vicia. The active concentration range of the pentasaccharides is more narrow on Medicago than on Melilotus and Vicia. In addition to root hair deformation, the different Nod factors were shown to induce nodule formation on M. sativa. We suggest that the production of a series of active signal molecules with different degrees of specificity might be important in controlling the symbiosis of R. meliloti with several different host plants or under different environmental conditions.


Subject(s)
Lipopolysaccharides/physiology , Sinorhizobium meliloti/metabolism , Bacterial Adhesion , Carbohydrate Sequence , Cloning, Molecular , DNA, Bacterial/genetics , Lipopolysaccharides/chemistry , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Recombinant Proteins/genetics , Restriction Mapping , Sinorhizobium meliloti/chemistry , Sinorhizobium meliloti/genetics , Symbiosis
6.
J Antibiot (Tokyo) ; 36(3): 250-5, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6857754

ABSTRACT

The synthesis of 1-deaminogentamicin C2 described here, uses 3,2',6',3"-tetrakis-N-tert-butoxycarbonylgentamicin C2 (2) as intermediate. N-Formylation of 2 followed by per-O-acetylation and dehydration furnished the isocyanide 5. Radical-induced deamination of the latter using tri-n-butylstannane and removal of the protecting groups afforded the target 1-deaminogentamicin C2 (7). Its in vitro antibacterial activity is less than that of the parent gentamicin C2. The behaviour of 7 towards aminoglycoside-inactivating enzymes was also examined; interestingly, it was found to be neither substrate nor inhibitor for such enzymes. These results strongly suggest that the substitution pattern of the 1-position determines the biological properties of the aminoglycoside antibiotics.


Subject(s)
Gentamicins/chemical synthesis , Gentamicins/pharmacology , Microbial Sensitivity Tests , Structure-Activity Relationship
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