Tubulin binding agents and corresponding prodrug constructs

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 R2, R3, R4, R5, R6, R7, and R8 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.

A method for treating neoplastic disease in an animal comprising administering to an animal an antiproliferative amount of a compound of formula I:

• wherein R2, R3, R4, R5, R6, R7, and R8 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.

A method for inhibiting tubulin polymerization by contacting a tubulin-containing system with a compound of formula I:

• wherein R2, R3, R4, R5, R6, R7, and R8 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.

A pharmaceutical formulation containing a compound of formula I in a pharmaceutically suitable carrier:

• wherein R2, R3, R4, R5, R6, R7, and R8 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.