Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-06-07
2001-05-15
Lee, Howard C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S061000, C514S317000, C514S326000, C514S336000, C514S352000, C536S017300, C536S017400, C536S123130, C546S207000, C546S282100, C546S283100, C546S329000
Reexamination Certificate
active
06232450
ABSTRACT:
TECHNICAL FIELD
The present invention relates to fucosyltransferase inhibitors, including fucosyltransferase inhibitors having antiinflammatory and antitumor activity. In addition, the present invention relates to a method for synthesizing a new class of Lewis and LacNAc analogues having an iminocyclitol moiety linked through a 2 carbon spacer to a LacNAc mimetic and having inhibitory activity with respect to fucosyltransferases.
BACKGROUND
Many complex oligosaccharides on the cell surface are fucosylate (Varki, A. Glycobiology 1993, 3, 97-130; Hakomori et al. Adv. Cancer Res. 1989, 52, 257; Hakomori et al. J. Biol. Chem. 1984, 259, 4672; Feizi, T. Nature, 1985, 314, 53). These fucose containing structures are involved in cell-cell interactions which mediate inflammation, tumor development, and blood clotting (Ichikawa et al. 1994, Chem. Br. 117; Parekh et al. TIBTECH, 1994, 12, 339). The biosynthesis of these structures requires the action of several glycosyltransferases, of which fucosylation by a class of fucosyltransferases (FucT) is the last and critical step (Natsuka et al. Curr. Opin. Struct. Biol. 1994, 4, 683; Holme et al. J. Biol. Chem. 1986, 261, 3737; Kornfeld et al. Annu. Rev. Biochem. 1985, 54, 631-664). Therefore inhibitors of FucT are potentially useful as anti-inflammatory and anti-tumor drugs. To date only limited success has been achieved in the development of potent inhibitors of this important class of enzymes. Besides the production of unreactive analogs of GDP-fucose (Cai et al. J. Org. Chem. 1992, 57, 6693; Luengo et al. Tetrahedron Lett. 1992, 33, 6911) a bisubstrate inhibitor for &agr;-1,2-fucosyltransferase has also been reported (Palcic et al. J. Biol. Chem. 1989, 264, 17174). Very recently, we and others have synthesized trisubstrate analogs, of &agr;-1,3-fucosyltransferase (Heskamp et al. Tetrahedron, 1995, 51, 8397; Heskamp et al. J. Carbohydr. Chem. 1995, 14, 1265; Qiao et al. J. Am. Chem. Soc. 1996, 118, 7653). Although FucT V has been shown to have a catalytic residue with pKa=4.1, presumably an active site carboxylate, it has never been considered in the design of inhibitors until recently (Murray et al. Biochemistry, 1996, 34, 11183). Product inhibition studies with human &agr;-1,3-fucosyltransferase (FucT V) have been used to establish that FucT V has an ordered, sequential, bi-bi mechanism with guanosine 5′-diphospho-&bgr;-1-fucose (GDP-Fuc) binding first and the product releasing last (Qiao et al. J. Am. Chem. Soc. 1996, 118, 7653; Murray et al. Biochemistry, 1997, 36, 823). Our past approach to the construction of fucosyltransferase inhibitors has been based on mimicking the proposed transition state by covalently linking an iminocyclitol to the 3-position of the acceptor substrate. Besides the fact the trisaccharide should form a complex with GDP and provide synergistic inhibition, it is assumed that a basic two carbon spacer could block the catalytic residue and improve the inhibition by additional hydrogen bonding (For synergistic inhibition see: (Wong et al. J. Am. Chem. Soc. 1992, 114, 7321; Ichikawa et al. J. Am. Chem. Soc. 1992, 114, 9283).
What is needed are improved fucosyltransferase inhibitors. Furthermore, what is needed is an efficient and general method for the synthesis of improved fucosyltransferase inhibitors.
SUMMARY OF THE INVENTION
The invention is directed to fucosyltransferase inhibitors and the synthesis of improved compounds. More particularly, the invention relates to an improved class of fucosyltransferase inhibitors Lewis and LacNAc analogues having an iminocyclitol moiety linked to an amino group of a LacNAc mimetic through a two carbon spacer moiety, as potential inhibitors of fucosyltransferases (
FIG. 1
; c).
One aspect of the invention is directed to a first type of fucosyltransferase inhibitor. This first type of fucosyltransferase inhibitor is represented by the following structure:
In the above structure, R and R
1
may be either hydrogen or benzyl. R
2
may be either hydrogen or methyl.
Another aspect of the invention is directed to a second type of fucosyltransferase inhibitor. This second type of fucosyltransferase inhibitor is represented by the following structure:
In the above structure, R and R
1
may be either hydrogen or benzyl. R
2
may be either hydrogen or methyl.
A further aspect of the invention is directed to processes for inhibiting a fucosyltransferase. In one mode of this aspect of the invention, the fucosyltransferase is inhibited by contact with a solution containing an inhibiting concentration of an inhibitor represented by the following structure:
In a second mode of this aspect of the invention, the fucosyltransferase is inhibited by contact with a solution containing an inhibiting concentration of an inhibitor represented by the following structure:
In both of the above structures, R and R
1
may be either hydrogen or benzyl; and R
2
may be either hydrogen or methyl.
Another aspect of the invention is directed to a process for synthesizing an inhibitor of fucosyltransferase represented by the following structure:
In the above structure, R and R
1
may be either hydrogen or benzyl; and R
2
may be either hydrogen or methyl. In the first step of this process, three reactants are admixed, i.e., an aldehyde, a disaccharaide, and NaCNBH
3
for producing a reductive amination intermediate. Preferred aldehydes are represented by the following structure:
Preferred disaccharides are represented by the following structure:
In the above disaccharide, R
3
may be either -benzoyl or —OH. R
4
may be either -benzyl or —OH. R
5
is n-propyl. X is —NH
2
. Then the reductive amination intermediate is hydrogenated for producing said inhibitor of fucosyltransferase.
REFERENCES:
patent: 5620864 (1997-04-01), Matta et al.
Wishnat et al., “Synthesis of a New Class of N-Linked Lewis and LacNAc Analogues as Potential Inhibitors of Human Fucosyltransferases . . . ”, J. Org. Chem., vol. 63, No. 23, pp. 8361-8365, Oct. 1998.*
Beacham et al., “Inhibition of Fucosyl Transferase and Fucosidase by a Rigid Bicyclic Mimic of alpha-L-fucose”, Tetrahedron Letters, vol. 39 (1-2): 151-154, Jan. 1998.*
Qiao et al., “Synergistic Inhibition of Human alpha-1,3-Fucosyltransferase V”, J. Amer. Chem. Soc., vol. 118, pp. 7653-7662, Aug. 1996.*
Hokke et al., “Identification of an alpha 3-fucosyltransferase and a novel alpha 2-fucosyltransferase activity in cercariae of the schistosomeTrichobilharzia ocellata. . . ”, Glycobiology, vol. 8(4): 393-406, 1998.*
Hanada et al., “The alpha 1—>3 fucosylation at the penultimate GlcNAc catalyzed by fucosyltransferase VII is blocked by internally fucosylated residue . . . ”, Biochem. Biophys. Res. Commun., vol. 243(1): 199-204, 1998.*
Murray et al., “Mechanism and specificity of human alpha 1,3-fucosyltransferase V”, Biochemistry, vol. 35(34): 11183-111995, Aug. 1996.*
Holmes, et al., “Biosynthesis of the Sialyl-LexDeterminant Carried by Type 2 Chain Glycosphingolipids (IV3NeuAcIII3FucnLc4,VI3Neu-AcV3FucnLc6,and VI3NeuAcIII3V3Fuc2nLc6) in Human Lung Carcinoma PC9 cells”,J. Biol. Chem. 261, 3737-3743 (1986).
Palcic, et al., “A Bisubstrate Analog Inhibitor for &agr;(1→2)-Fucosyltransferase”,J. Biol. Chem. 264: 17174-17181 (1989).
Luengo, et al., “Synthesis of C-Fucopyranosyl Analogs of GDP-L-Fucose as Inhibitors of Fucosyltransferases”,Tet. Lett. 33: 6911-6914 (1992).
Wong, et al., “Specificity, Inhibition, and Synthetic Utility of a Recombinant Human &agr;-1,3-Fucosyltransferase”,J. Am. Chem. Soc. 114: 7321-73222 (1992).
Ichikawa, et al., “Chemical-Enzymatic Synthesis and Conformational Analysis of Sialyl Lewis x and Derivatives”,J. Am. Chem. Soc. 114: 9283-9298 (1992).
Cai, et al., “Synthesis of Carbocyclic Analogues of Guanosine 5 ′-(&bgr;-L-Fucopyranosyl diphosphate) (GDP-Fucose) as Potential Inhibitors of Fucosyltransferases”,J. Org. Chem. 57: 6693-6696 (1992).
Natsuka, et al., “Enzymes Involved in Mammalian Oligosaccharide Biosynthesis”,Curr. Opin. Struct. Biol. 4: 683-691 (1994).
Heskamp, et al., “Design and Synthesis of a Trisubstrate Analogue
Lee Howard C.
Lewis Donald G.
The Scripps Research Institute
LandOfFree
Inhibition of human fucosyltransferases with N-linked... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Inhibition of human fucosyltransferases with N-linked..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibition of human fucosyltransferases with N-linked... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2462176