DNA glycosylase inhibitors, and uses related thereto

• US 6,369,237 B1
• Filed: 03/07/1997
• Issued: 04/09/2002
• Est. Priority Date: 03/07/1997
• Status: Expired due to Term

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Deng, Li, Verdine, Gregory L.
• Primary Examiner(s): Geist, Gary
• Assistant Examiner(s): Owens, Jr., Howard V.
• Application Number:
  US08/812,653
• Time in Patent Office: 1,859 Days
• Field of Search: 536/24.3, 536/24.5, 536/26.7, 536/28.1, 547/400
• US Class Current: 548/400
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

The present invention pertains to novel inhibitors of DNA glycosylases. The invention is based at least in part on the observation that specific substituted pyrrolidines, and analogs thereof, are capable of specifically inhibiting DNA glycosylases, e.g., as transition state analogs, and consequently are useful for modulation of DNA repair. Such compounds can, for example, be used for treating subjects having a disorder associated with excessive cell proliferation, such as in the treatment of various cancers. Furthermore, these glycosylase inhibitors can be used as anti-bacterial, anti-viral and anti-fungal agents.

Claims

1. A compound represented by the formula, or a pharmaceutically acceptable salt thereof:

wherein

B is a nucleoside purine or pyrimidine base, or a heterocyclic analog thereof;

X is O, N, S or CH₂;

R1, independently for each occurrence, is absent or is a hydrogen, or an amino protecting group;

R2 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbarnate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R3 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R4, R5, R6 and R7 are each, independently, as valence and stability permit, hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8;

R8 is, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocycle, a carbonyl, a sulfonyl or a phosphoryl; and

p is 1 or 2, and n and m are independently for each occurrence zero or an integer in the range of 1 to 6,

which compound inhibits an N-glycosidic activity of a DNA glycosylase.

6. A glycosylase inhibitor, comprising a compound of claim 1 or 2.

7. The compound of claim 1 or 2, the nucleic acid of claim 3 or 4, or the inhibitor of claim 5 or 6, wherein the DNA glycosylase is a member of the EC category EC 3.2.2.

8. The compound of claim 1 or 2, wherein the DNA glycosylase is selected from the group consisting of a purine nucleosidase (EC 3.2.2.1), an inosine nucleosidase (EC 3.2.2.2), a uridine nucleosidase/uracil deglycosylase (EC 3.2.2.3), a ribosylpyrimidine nucleosidase (EC 3.2.2.8), an inosinate nucleosidase (EC 3.2.2.12), a 1-methyladenosine nucleosidase (3.2.2.13), a dna-deoxyinosine glycosidase (EC 3.2.2.15), a methylthioadenosine nucleosidase (EC 3.2.2.16), a DNA-3-methyladenine glycosidase (I) (EC 3.2.2.20), a DNA-3-methyladenine glycosidase (II) (EC 3.2.2.21), and a formamidopyrimidine-DNA glycosidase (EC 3.2.2.23).

9. The compound of claim 1 or 2, wherein the DNA glycosylase is a mammalian DNA glycosylase selected from the group of MYH, Mpg, 3 Mg, Ung1 and Ung2.

10. The compound of claim 1 or 2, wherein the DNA glycosylase is a bacterial DNA glycosylase selected from the group of MutM, MutT, fpg4 and MutY.

11. The compound of claim 1 or 2, wherein the DNA glycosylase is a viral DNA glycosylase from an Epstein Barr Virus or Herpes Simplex Virus.

12. The compound of claim 1 or 2, which inhibits a glycosylase activity of a bacterial, fungal or viral DNA glycosylase with a Ki at least one order of magnitude less than a human DNA glycosylase of similar specificity.

13. The compound of claim 1 or 2, wherein B is selected from the group consisting of adenine, guanine, thymine, cytosine, uracil and hypoxanthine, or a derivative thereof.

14. The compound of claim 1 or 2, wherein B is a purine or pyrmidine base analog selected from the group consisting of N⁶-benzoyladenine, N²-isobutyrylguanine, N⁴-benzoylcytosine, N⁶-di-n-butylformamidinyladenine, N⁶-(N-methyl-2-pyrrolidineamidinyl)-adenine, N⁶-succinyladenine, N⁶-phthaloyladenine, N⁶-dimethylacetamidinyladenine, N²-di-n-butylformamidinylguanine, isocytosine, xanthine (3,7-dihydro-1H-purine-2,6-dione), 6-chloropurine, 6-chloro-2-fluoropurine, 2,6-diaminopurine, 2-fluoro-N⁶-hydroxyadenine, 2,6-dihydroxyaminopurine, 8-bromoadenine, 2-chloroadenine, 8-azidoadenine, 8-mercaptoadenine, 8-aminoadenine, 6-thioguanine, 2,6-dichloropurine, N,N-dimethyl-6-aminopurine, N⁶-benzyladenine, 1,3-dimethylxanthine, 2-amino-6,8-dihydroxypurine, 6-methoxypurine, 6-mercaptopurine, 6-(2-hydroxyethyl)-aminopurine, N⁶-(2-isopentyl)-adenine, N⁶-furfuryladenine (kinetin), 5-bromomethyluracil, 5-dibromomethyluracil, 5-hydroxymethyluracil, 5-formyluracil, 5-fluorouracil, 5-bromouracil, 6-methyl-2-thiouracil, 5-hydroxymethyl-6-methyluracil, 5-hydroxyuracil (isobarbituric acid), 5-methoxyuracil, 5-methylcytosine, 5-trifluoromethyluracil, 5-nitrouracil, 5-aminouracil, 2-thiocytosine, 2-amino-4,6-dihydroxypyrimdine, 4-amino-2,6-dihydroxypyrimidine, 2-amino-4-hydroxy-6-methylpyrimidine, 4-amino-6-hydroxy-2-mercaptopyrimidine.

15. The compound of claim 1 or 2, whrein B is an substituted or unsubstituted heterocycle selected from the group consisting of imidazole, indole, benzimidazole, indazole, pyrazole, benzotriazole, 8-azaadenine, 8-azaguanin, 6-azathymin, 6-azauracil, 5-azacytosine, 8-azahypoxanthine, pyrazolopyrimidine, 3-deazauracil, orotic acid (2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidine carboxylic acid), barbituric acid, uric acid, ethenoadenine, and allopurinol (4-hydroxy-pyrazolo [3,4-d]pyrimidine).

16. The compound of claim 1 or 2, wherein B is a heterocyclic analogue of a nucleoside base.

17. The compound of claim 1 or 2, wherein R1 is a protecting group selected from the group consisting of aromatic urethane-type protecting groups, aliphatic urethane-type protecting groups, and cycloalkyl urethane-type protecting groups.

18. The compound of claim 1 or 2, wherein one or both of R2 and R3 are hydroxyl-protecting groups selected from the group consisting of a lower alkylsilyl group, a lower alkoxymethyl group, a tetrahydropyranyl group, an aralkyl group, and an acyl group.

22. A pharmaceutical preparation, comprising the compound of claim 1 or 2;

and a pharmaceutically acceptable carrier.

23. A solid support derivatized with a compound of claim 1 or 2, or the nucleic acid of claim 3 or 4.

2. A compound represented by the formula, or a pharmaceutically acceptable salt thereof:

wherein

B is a nucleoside purine or pyrimidine base, or a heterocyclic analog thereof;

X is O, N, S or CH₂;

R1, independently for each occurrence, is absent or is a hydrogen, or an amino protecting group;

R2 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R3 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R4, R5, R6 and R7 are each, independently, as valence and stability permit, hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8;

R8 is, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocycle, a carbonyl, a sulfonyl or a phosphoryl; and

p is 1 or 2, and n and m are independently for each occurrence zero or an integer in the range of 1 to 6,

which compound inhibits an N-glycosidic activity of a DNA glycosylase.

3. A nucleic acid comprising at least one analog represented by the formula:

wherein

B is a nucleoside purine or pyrimidine base, or a heterocyclic analog thereof;

X is O, N, S or CH₂;

R1, independently for each occurrence, is absent or is a hydrogen, or an amino protecting group;

R2 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R3 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R4, R5, R6 and R7 are each, independently, as valence and stability permit, hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8;

R8 is, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocycle, a carbonyl, a sulfonyl or a phosphoryl; and

p is 1 or 2, and n and m are independently for each occurrence zero or an integer in the range of 1 to 6,

which nucleic acid inhibits an N-glycosidic activity of a DNA glycosylase.

19. The nucleic acid of claims 3 or 4, which inhibits an N-glycosidic activity of a DNA glycosylase.

20. The nucleic acid of claim 3 or 4, wherein the nucleic acid is at least 4 nucleotide units in length.

21. The nucleic acid of claim 3 or 4, wherein the nucleic acid is at least 10 nucleotide units in length.

24. A pharmaceutical preparation, comprising the nucleic acid of claim 3 or 4;

and a pharmaceutically acceptable carrier.

4. A nucleic acid comprising at least one analog represented by the formula:

wherein

B is a nucleoside purine or pyrimidine base, or a heterocyclic analog thereof;

X is O, N, S or CH₂;

R1, independently for each occurrence, is absent or is a hydrogen, or an amino protecting group;

R2 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonarnido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R3 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R4, R5, R6 and R7 are each, independently, as valence and stability permit, hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8;

R8 is, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocycle, a carbonyl, a sulfonyl or a phosphoryl; and

p is 1 or 2, and n and m are independently for each occurrence zero or an integer in the range of 1 to 6,

which nucleic acid inhibits an N-glycosidic activity of a DNA glycosylase.

5. A glycosylase inhibitor comprising a analog represented by the formula:

wherein

B is a nucleoside purine or pyrimidine base, or a heterocyclic analog thereof;

X is O, N, S or CH₂;

R1, independently for each occurrence, is absent or is a hydrogen, or an amino protecting group;

R2 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R3 is a hydrogen, a nucleotide or oligonucleotide, a phosphoryl, a phosphonate, a phosphoramidate, a carbamate, a phosphorothioate, a phosphorodithioate, a hydroxyl blocking group, or as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylarmino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8, or a solid or polymeric support;

R4, R5, R6 and R7 are each, independently, as valence and stability permit, hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, —

(CH₂)_m—

R8, —

(CH₂)_m—

OH, —

(CH₂)_m—

O-lower alkyl, —

(CH₂)_m—

O-lower alkenyl, —

(CH₂)_m—

O—

(CH₂)_n—

R8, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-lower alkyl, —

(CH₂)_m—

S-lower alkenyl, —

(CH₂)_m—

S—

(CH₂)_n—

R8;

R8 is, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocycle, a carbonyl, a sulfonyl or a phosphoryl; and

p is 1 or 2, and n and m are independently for each occurrence zero or an integer in the range of 1 to 6,

which inhibitor inhibits an N-glycosidic activity of a DNA glycosylase.

25. A pharmaceutical preparation, comprising the inhibitor of claim 5 or 6;

and a pharmaceutically acceptable carrier.