1. A compound represented by C:
wherein
Z represents C(R3)2, C(O), O, NR, NC(O)OR, S, SO, or SO2;
m is 1, 2, 3, 4 or 5;
p is 0, 1, 2, or 3;
y is 0, 1 or 2;
R represents alkyl, cycloalkyl, aryl, or aralkyl;
R1 represents alkyl, aryl, or aralkyl;
R and R1 may be connected through a covalent bond;
R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, or cycloalkyl;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
R4 represents independently for each occurrence H, alkyl, cycloalkyl, aryl, alkenyl, or OR;
R5 and R6 are selected independently for each occurrence from the group consisting of H, alkyl, (CH2)pY, aryl, F, OR2, and OC(O)R2; or an instance of CR5R6 taken together is C(O);
R8 and R9 are selected independently for each occurrence from the group consisting of H, alkyl, (CH2)pY, aryl, F, OR2, and OC(O)R2; or an instance of CR8R9 taken together is C(O);
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
any two instances of R2 may be connected through a covalent bond;
a covalent bond may connect R4 and an instance of R5 or R6;
any two instances of R5 and R6 may be connected through a covalent bond;
any two geminal or vicinal instances of R8 and R9 may be connected through a covalent bond; and
the stereochemical configuration at any stereocenter of a compound represented by C is R or S, or a mixture of these configurations.
2. The compound of claim 1, wherein Z is O or NR.
3. The compound of claim 1, wherein m is 3.
4. The compound of claim 1, wherein y is 1.
5. The compound of claim 1, wherein R1 represents aryl.
6. The compound of claim 1, wherein R3 represents independently for each occurrence H or alkyl.
7. The compound of claim 1, wherein R4 represents cycloalkyl, or aryl.
8. The compound of claim 1, wherein R5 and R6 are selected independently for each occurrence from the group consisting of H, alkyl, OR2, aryl, and F.
9. The compound of claim 1, wherein R8 and R9 are selected independently for each occurrence from the group consisting of H, alkyl, OR2, aryl, and F.
10. The compound of claim 1, wherein Z is O or NR; and m is 3.
11. The compound of claim 1, wherein Z is O or NR; and y is 1.
12. The compound of claim 1, wherein Z is O or NR; m is 3; and y is 1.
13. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; and R1 is aryl.
14. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R1 is aryl; and R3 is H or alkyl.
15. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R1 is aryl; R3 is H or alkyl; and R4 is cycloalkyl, or aryl.
16. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R1 is aryl; R3 is H or alkyl; R4 is cycloalkyl, or aryl; and R5 and R6 are selected independently for each occurrence from the group consisting of H, alkyl, OR2, aryl, and F.
17. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R1 is aryl; R3 is H or alkyl; R4 is cycloalkyl, or aryl; R5 and R6 are selected independently for each occurrence from the group consisting of H, alkyl, OR2, aryl, and F; and R8 and R9 are selected independently for each occurrence from the group consisting of H, alkyl, OR2, aryl, and F.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound comprising a water soluble derivative of buckministerfullerene (C60) with virucidal properties, and water soluble salts thereof.
2. The compound of claim 1 wherein the compound has virucidal properties against a human retrovirus.
3. The compound of claim 2 wherein the retrovirus is a strain of HIV.
4. The compound of claim 3 wherein the fullerene is a methanofullerene and is substituted with a polar organic moiety comprising from 1 to 20 carbon atoms.
5. The compound of claim 4 wherein the organic moiety further comprises a heteroatom selected from the group consisting of oxygen and nitrogen.
6. The compound of claim 1 having the formula 4,4-Bis( X) diphenyl C61, wherein X is an organic moiety comprising from 1 to 20 carbon atoms.
7. The compound of claim 6 wherein X further comprises a heteroatom selected from the group consisting of oxygen and nitrogen.
8. The compound of claim 1 wherein the structure of the fullerene is selected from the group consisting of:
5
23
a.
24
b.
25
c.
26
d.
27
e.
28
f.
29
g.
30
h.
31
i.
32
j.
33
k.
34
l.
35
m.
36
n.;
and,
wherein R is an organic moiety comprising from 1 to 10 carbon atoms.
9. The compound of claim 1 wherein the structure of the fullerene is selected from the group consisting of:
37
wherein R is an organic moiety comprising from about 1 to 10 carbon atoms.
10. A compound of claim 4 further comprising a moiety that binds a bivalent cation.
11. A compound of claim 2 wherein the moiety is an amine adduct.
12. A compound of claim 4 wherein X is CH3C(O)NH(CH2)2.
13. A compound of claim 4 wherein X is (CH2)2NH2.
14. A compound of claim 4 wherein X is HOC(O)(CH2)2C(O)NH(CH2)2.
15. A compound of claim 1 wherein the compound forms a complex with HIV protease.
16. A compound of claim 15 wherein the dissociation constant for the complex is in the range from about 106 to 109 M.
17. A method for inhibiting retrovirus in cells infected therewith comprising contacting the cells with a pharmaceutically effective amount of a water soluble buckminsterfullerene or salt thereof.
18. The method of claim 17 wherein the fullerene is symmetrically substituted with water solubilizing organic moieties comprising from 1 to 20 carbon atoms.
19. The method of claim 18 wherein the moieties further comprise a heteroatom selected from the group consisting of oxygen and nitrogen.
20. The method of claim 18 wherein the compound is a methanofullerene.
21. The method of claim 17 wherein the cells are chronically infected and the compound is the compound of claim 1, 4 or 8.
22. The method of claim 11 wherein the cells are human PBMC infected with HIV and the compound is a compound of claims 1, 4 or 8.
23. The method of claim 22 wherein the HIV is type 1LAI.
24. The method of claim 17 wherein the cells are chronically infected with HIV and the compound is a compound of claims 1, 4 or 8.
25. The method of claim 24 wherein the cells are H9 cells.
26. The method of claim 18 wherein the cells are human PBMC cells acutely infected with HIV-2ROD.
27. A method for therapeutic treatment of HIV infection, AIDS or ARC comprising administering to a subject a pharmaceutically effective amount of a pharmaceutical composition comprising a water soluble buckminsterfullerene, or salt thereof.
28. The method of claim 27 wherein the administering is at an EC50 dose of 7 M and uninfected PBMC cells are free from cytotoxicity.
29. The method of claim 27 wherein the compound is administered intravenously.
30. The method of claim 27 wherein the compound is administered intraparenterally.
31. The method of claim 27 wherein the compound is administered orally.
32. The method of claim 27 wherein the compound is administered extra corporeally.
33. The method of claim 27 wherein the compound is administered topically.
34. A method for assaying compounds capable of inhibiting growth of a retrovirus comprising:
a) activating a cell containing the virus;
b) measuring the production of reverse transcriptase or p24 produced by the activated cell;
c) contacting the cell with an inhibition effective amount of a water soluble buckministerfullerene compound, or salt thereof; and
d) determining the decrease in production of reverse transcriptase or p24 of the contacted cell as compared with that of the activated cell.
35. The method of claim 34 wherein the compound is a methanofullerene, or a dicationic salt thereof.
36. A method for identifying a fullerene compound that inactivates HIV protease comprising:
a) establishing a model of the HIVP molecule having an open active site containing Asp25 and Asp125;
b) establishing a model of a fullerene derivative symmetrically substituted with a polar organic moiety containing from 1 to 20 carbon atoms;
c) comparing the fit of the fullerene model with the active site of the HIV protease model to determine binding therebetween.
37. The method of claim 36 wherein the models are three-dimensional computer models and the comparing calculates a release of energy upon binding.
38. The method of claim 36 wherein the computer models are based upon x-ray diffraction solution of the crystal structures of HIVP and buckministerfullerene.
39. The method of claim 38 wherein binding is determined by release of energy of at least 8 kcalsmol.
40. The method of claim 36 wherein the models are three-dimensional computer models and the comparing calculates a substantial reduction in solvated surface area upon binding.
41. The method of claim 36 wherein binding is between the Asp25 and Asp125 in the active site and the fullerene.
42. The method of claim 36 wherein the fullerene has the formula 4,4-Bis(X) diphenyl C61, wherein X is a polar organic moiety containing from 1 to 20 carbon atoms.
43. The method of claim 36 wherein the fullerene is a methanofullerene.