Tubulin binding agents and corresponding prodrug constructs
A diverse set of tubulin binding agents have been discovered which are structurally characterized, in a general sense, by a semi-rigid molecular framework capable of maintaining aryl-aryl, pseudo pi stacking distances appropriate for molecular recognition of tubulin. In phenolic or amino form, these ligands may be further functionalized to prepare phosphate esters, phosphate salts, phosphoramidates, and other prodrugs capable of demonstrating selective targeting and destruction of tumor cell vasculature.
1 . A method for treating a vascular proliferative disorder in an animal comprising administering to an animal an effective amount of a compound of formula I:
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, OH, amine, lower alkoxy, phosphate, phosphoramidate, or amino acid acyl group;
is optionally a single covalent bond or a double covalent bond;
X is a single covalent bond or a carbonyl group, and
Y is optionally H or OH.
2 . The method of claim 1 , wherein the vascular proliferative disorder is characterized by the presence of nonmalignant proliferating vasculature.
3 . The method of claim 2 , wherein the malignant proliferating vasculature is associated with a tumor or other neoplastic disease.
4 . The method of claim 2 , wherein the vascular proliferative disorder is characterized by the presence of nonmalignant proliferating vasculature.
5 . The method of claim 4 , wherein the nonmalignant proliferating vasculature is associated with an ocular disease selected from the group comprising wet or age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, diabetic macular edema, uveitis, or corneal neovascularization.
6 . The method of claim 4 , wherein the nonmalignant proliferating vasculature is associated with a nonocular disease state such as psoriasis, rheumatoid arthritis, atheroma, restenosis, Kaposi's sarcoma, haemangioma, and in general, inflammatory diseases characterized by vascular proliferation.
7 . The method of claim 1 , wherein at least one of R 2 , R 3 , R4, R 5 , R 6 , R 7 , or R 8 is lower alkoxy.
8 . The method of claim 1 , wherein R 4 is OMe.
9 . The method of claim 1 , wherein X is a single bond.
10 . The method of claim 1 , wherein X is a carbonyl.
11 . The method of claim 1 , wherein at least one of R 2 , R 3 , R4, R 5 , R 6 , R 7 , or R 8 is phosphate.
12 . The method of claim 1 , wherein the compound is selected from:
13 . A method for selectively reducing the flow of blood to at least a portion of a neoplastic region thereby causing substantial necrosis of tissue in the neoplastic region without substantial necrosis of tissue in adjoining regions by administering a compound of formula I:
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, OH, amine, lower alkoxy, phosphate, phosphoramidate, or amino acid acyl group;
is optionally a single covalent bond or a double covalent bond;
X is a single covalent bond or a carbonyl, and
Y is optionally H or OH.
14 . The method of claim 13 , wherein the reduction in tumor blood flow is reversible such that normal tumor blood flow is restored following cessation of treatment.
15 . The method of claim 13 , wherein at least one of R 2 , R 3 , R4, R 5 , R 6 , R 7 , or R 8 is alkoxy.
16 . The method of claim 13 , wherein R 4 is OMe.
17 . The method of claim 13 , wherein X is a single bond.
18 . The method of claim 13 , wherein X is a carbonyl.
19 . The method of claim 13 , wherein at least one of R 2 , R 3 , R4, R 5 , R 6 , R 7 , or R 8 is phosphate.
20 . The method of claim 13 , wherein the compound is selected from:
21 . A method for treating neoplastic disease in an animal comprising administering to an animal an antiproliferative amount of a compound of formula I:
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, OH, amine, lower alkoxy, phosphate, phosphoramidate, or amino acid acyl group;
is optionally a single covalent bond or a double covalent bond;
X is a single covalent bond or a carbonyl, and
Y is optionally H or OH.
22 . The method of claim 21 , wherein the reduction in tumor blood flow is reversible such that normal tumor blood flow is restored following cessation of treatment.
23 . The method of claim 21 , wherein at least one of R 2 , R 3 , R4, R 5 , R 6 , R 7 , or R 8 is lower alkoxy.
24 . The method of claim 21 , wherein R 4 is OMe.
25 . The method of claim 21 , wherein X is a single bond.
26 . The method of claim 21 , wherein X is a carbonyl.
27 . The method of claim 21 , wherein at least one of R 2 , R 3 , R4, R 5 , R 6 , R 7 , or R 8 is phosphate.
28 . The method of claim 21 , wherein the compound is selected from:
29 . A method for inhibiting tubulin polymerization by contacting a tubulin-containing system with a compound of formula I:
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, OH, amine, lower alkoxy, phosphate, phosphoramidate, or amino acid acyl group;
is optionally a single covalent bond or a double covalent bond;
X is single covalent bond or a carbonyl group, and
Y is optionally H or OH.
30 . The method of claim 29 , wherein said system is a tumor cell.
31 . The method of claim 29 , wherein at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 is lower alkoxy.
32 . The method of claim 29 , wherein R 4 is OMe.
33 . The method of claim 29 , wherein X is a single bond.
34 . The method of claim 29 , wherein X is a carbonyl.
35 . The method of claim 29 , wherein at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 is phosphate.
36 . The method of claim 29 , wherein the compound is selected from:
37 . A pharmaceutical formulation containing a compound of formula I in a pharmaceutically suitable carrier:
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, OH, amine, lower alkoxy, phosphate, phosphoramidate, or amino acid acyl group;
is optionally a single covalent bond or a double covalent bond;
X is a single covalent bond or a carbonyl, and
Y is optionally H or OH.
38 . The method of claim 37 , wherein at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 is lower alkoxy.
39 . The method of claim 37 , wherein R 4 is OMe.
40 . The method of claim 37 , wherein X is a single bond.
41 . The method of claim 37 , wherein X is a carbonyl.
42 . The method of claim 37 , wherein at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 is phosphate.
43 . The method of claim 37 , wherein the compound is selected from: