Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-09-13
2001-03-27
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500, C536S018600, C536S124000
Reexamination Certificate
active
06207820
ABSTRACT:
TECHNICAL FIELD
The present invention is for a combinatorial chemical library of compounds structurally related to the moenomycin class of antibiotics, and methods of preparing the compounds. Members of the library comprise disaccharides and trisaccharides covalently bonded to a lipid or lipid mimetic through a phosphorus linkage.
BACKGROUND OF THE INVENTION
The moenomycin antibiotics are naturally-occurring phosphoglycolipids, which have been isolated from several strains of Streptomyces. These antibiotics have a wide range of antimicrobial activity, which is believed due to their ability to inhibit the transglycosylase activities of the bi-functional penicillin binding proteins (PBPs). These proteins catalyze the transfer of a disaccharide unit to a growing peptidoglycan chain during the biosynthesis of bacterial cell walls. To date, the moenomycins are the only known inhibitors of this enzyme activity. The structure of the disaccharide substrate is shown hereinbelow:
The moenomycins are active against several bacterial strains, including those resistant to beta-lactam antibiotics. They are currently marketed under the tradename Flavomycin® as an additive in cattle feed, where the efficacy in promoting animal growth is believed due to their antimicrobial activity. The moenomycins are particularly potent against gram-positive bacteria and less potent against gram-negative microbes.
The potential for moenomycin antibiotics as human therapeutics has not been studied in detail, but is expected to be limited by poor bioavailability and unfavorable pharmacodynamics. The unique mode of action and wide range of activity of this class of antibiotics makes them attractive for the study of related compounds having more favorable pharmacological properties.
At present, moenomycins A, C
1
, C
2
, C
3
, A
12
, and pholipomycin compose the class of moenomycin antibiotics. Of this class, the most studied member is moenomycin A—a pentasaccharide linked to a C
25
lipid group through a phosphate moiety. The structure of moenomycin A is shown hereinbelow. The structural similarity of this compound to the transglycosylase substrate mentioned above is readily apparent and suggests that moenomycin A acts as a competitive inhibitor of transglycosylase activity.
In the above structure, it is known that a disaccharide-phospholipid degradation product of moenomycin A is equipotent (100% minimum inhibitory concentration (MIC) at 1 &mgr;g/mL) to the parent natural product [EP Publn. No. 130327]. In particular, it has been shown that the A, B, C and D units of moenomycin A are unimportant to the inhibition of transglycosylase activity, but that the E, F, G, H, and I groups are essential [Welzel, P., et al., (1984), (1987); Moller, U., et al., (1993); Marzian, S., et al., (1994)]. The lipid moiety I can be fully hydrogenated without substantially affecting its activity. However, a free carboxylic acid function for the glyceric acid unit H appears to be necessary for inhibition. Furthermore, the structural requirements within the F-G-H region appear to be rather strict [Fehlhaber, H-W., et al., (1990); Moller, U., et al., (1993); Luning, J., et al., (1994); Heuer, M., et al., (1994)]. The structure of a fully active disaccharide degradation product of moenomycin A is shown hereinbelow:
The other moenomycin compounds mentioned above differ structurally from moenomycin A principally by the number of sugar residues in the molecule and by the configuration of groups at the C4 position of the F sugar unit. In particular, only moenomycins A and A
12
have a D sugar residue attached to the E unit. Moenomycins C
3
, C
4
and pholipomycin are tetrasaccharide-phospholipids, which differ from each other by the presence or absence of hydroxyl groups at the C6 positions of the C and E sugar units [Hessler-Klintz, M., et al., (1993); Scherkenbeck, J., et al., (1993)].
Moenomycin C
1
also is a tetrasaccharide and, as with moenomycin A
12
, lacks the branching methyl group and has a change of configuration at the C4 position of the F sugar unit, i.e., the F unit is a galactopyranosiduronamide. In contrast to the other moenomycins, degradation studies of moenomycins C
1
and A
12
reveal that the smallest antibiotically active products for these F unit galactopyranosiduronamide compounds are trisaccharide derivatives, which include the C, E and F sugar units. It has been suggested that the additional saccharide unit (C) is required for these compounds in order to achieve the necessary hydrogen bonding environment within the active site, which is otherwise attained with a disaccharide unit in the 4-C-methyl glucopyranosiduronamide compounds [Hessler-Klintz, M., et al., (1993); Donnerstag, A., et al., (1995)]. In a recent series of papers, Welzel and coworkers describe the synthesis and antibiotic properties of some C-E-F trisaccharide derivatives of moenomycin A
12
[Ritzeler, O., et al., (1997a); Ritzeler, O., et al., (1997b); Range, G., et al., (1997)].
The biosynthesis of moenomycin in an aerobic fermentation process is the subject of U.S. Pat. No. 3,992,263, issued to Dietrich et al. Enzymatic methods for degrading moenomycin to defined end products, i.e., pentasaccharide and phospholipid products, are disclosed by U.S. Pat. Nos. 5,206,405, 5,260,206, and 5,506,140, all issued to Aretz et al., which propose that these end products can be used as building blocks in the synthesis of new transglycosylase inhibitors. An enzymatic method of cleaving the phosphate group from the aforementioned phospholipid is described in U.S. Pat. Nos. 5,315,038 and 5,316,929, issued to Aretz et al.
A study of the activities of several moenomycin analogs against the
Helicobacter pylori
bacillus is the subject of EP 655249, issued to Hoechst AG.
It is desired to synthesize and study a library of compounds having several of the basic structural features of the moenomycin degradation products discussed above, which retain anti-microbial activity. Of particular interest are compounds having better pharmacological properties yet retaining the broad spectrum of moenomycin activities. Of particular interest are activities against resistant strains of microorganisms. Generally speaking, it is desired to broaden the spectrum of activities and/or enhance the potencies of moenomycin antibiotics, particularly against clinically relevant microbes.
SUMMARY OF THE INVENTION
The present invention is for a combinatorial chemical library of moenomycin analogs, the members of which are represented by the following formula:
In the formula, “D” represents one or more “donor” saccharide residue(s), as defined hereinafter, and is preferably a mono- or disaccharide. The “A” group in the formula represents an “acceptor” saccharide residue, as defined hereinafter, and is a monosaccharide. The “P—R” group of the formula represents a lipophosphoglycerate mimetic group, as defined hereinafter, and differs from the phospholipid group of moenomycin A and partially or fully saturated forms thereof. Compounds represented by the above formula have a chemical structure analogous to the antibiotically active disaccharide moenomycin fragment discussed hereinabove. Accordingly, compounds represented by this formula are said to belong to a “directed” chemical library of moenomycin analogs.
In a preferred aspect of the invention, the C1 (anomeric) position of donor saccharide residue D is covalently bonded to the C2 position of acceptor saccharide residue A, e.g., through a glycosidic linkage. Also, it is preferred that the C1 (anomeric) position of A is covalently bonded to the lipophosphoglycerate mimetic group P—R through an O atom, which links A to a phosphorus atom of the P—R group.
Typically, the P—R group contains a phosphoester, phosphoanhydride, or phosphonate linkage, which joins an oxidized form of phosphorus to a negatively charged functional group, e.g., a carboxyl or sulfate group. While not wishing to be bound by any particular theory, it is believed that the dianion afforded by the P—R group is at
Allanson Nigel Mark
Chan Tin Yau
Hatzenbuhler Nicole T.
Jain Rakesh K.
Kakarla Ramesh
Hamilton LLP Pepper
Incara Research Laboratories
Peselev Elli
Pouliquen Corinne M.
Villacorta Gilberto M.
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