Covalent conjugates of topoisomerase I and topoisomerase II inhibitors
AssigneesThe University of North Carolina at Chapel Hill, Yale University
InventorsKuo-Hsiung Lee, Yung-Chi Cheng, Xin Guo, Kenneth F. Bastow, Hui-Kang Wang
Life of this patent
Estimating the term…
Abstract
The present invention provides covalent conjugates of topoisomerase I and topoisomerase II inhibitors. Such compounds have a structure according to formula I: TI—L—TII (I) wherein: TI is a topoisomerase I inhibitor such as a camptothecin group; TII is a topoisomerase II inhibitor such as an amsacrine, ellipticine, epipodophyllotoxin, or anthracycline antibiotic group; and L is a linking group. The compounds are useful for inhibiting topoisomerase I and II enzymes, for promoting cellular differentiation, and for treating cancer.
Claims14
A compound having a structure according to formula II:
- wherein:
- R1 is selected from the group consisting of H, alkyl, alkoxy, alkylaryl, hydroxyalkyl, haloalkyl, aminoalkyl, dialkylamino, dialkylaminoalkyl, cycloaminoalkyl, aryl, aryloxy, C-glycal, CO2R7, nitro, cyano, halo, SR8, NR8R8, O-glycosyl and L—TII;
- and
- R2, R3, R4 and R5 are each independently H, amino, hydroxy, alkyl, alkoxy, alkylthiol, alkylamino, aminoalkyl, di(alkyl)amino, cycloarminoalkyl, aminoalkoxy, aryl, aryloxy, C-glycal, cyano, methylenedioxy, formyl, nitro, halo, azido, amido, hydrazino, any of the twenty standard amino acids bonded to the A ring via the amino-nitogen atom, SR8, N8R8, or O-glycosyl, L—TII;
- or R3 and R4 together form a 5- or 6-member aromatic or dioxolane ring;
- and wherein where methylenedioxy comprises R2 and R3, R3 and R4, or R4 and R5 taken together;
- R7 is ethyl;
- and
- each R8 is independently selected from the group consitsing of H, alkyl, alkylaryl, hydroxyalkyl, aminoalkyl, acyl, or aryl;
- subject to the proviso that one of R1, R2, R3, R4, and R5 is a substitutent of the formula —L—TII,
- or a pharmaceutically acceptable salt thereof;
- wherein
- L is a covalent linking group selected from the group consisting of:
- wherein
- a is a 0-3;
- b is a 0-3;
- and
- R70 is selected from the group consisting of alkylene, alkenyl, and arylenyl;
- and
- TII is selected from the group consisting of
- (i) an epipodophyllotoxin group of formula III-A:
- wherein:
- R10, R11, R12, and R16 are each independently selected from the group consisting of H and halo;
- R13 and R15 are each independently alkoxy;
- and
- R14 is selected from the group consisting of H, hydroxyl, alkyl, and phosphate salt;
- (ii) an amsacrine group of formula III-B
- wherein
- R20 and R21 are each independently selected from the group consisting of alkoxy and alkylhydroxyl;
- (iii) an ellipticine group of formula III-c
- wherein
- R30 is H or aliphatic amine;
- R31 is H or —C(O)—N(R35)—(CH2)n—N(R36)(R37) wherein R35, R36, and R37 are each independently selected from the group consisting of H and alkyl and n is an integer from 1 to 6;
- R32 and R34 are each independently selected from the group consisting of H and alkyl;
- and
- R33 is alkyl;
- (iv) an anthracycline antibiotic group of formula III-D
- wherein
- R40 is H or alkoxy;
- R41 is hydroxyl or O—;
- R42 is alkyl, alkylhydroxyl, or CH2O—;
- and
- R43 and R44 are each independently selected from the group consisting of H and hydroxyl;
- subject to the provisos that if R41 is hydroxyl, then R42 is CH2O—;
- and if R42 is alkyl or alkylhydroxyl, then R41 is O—;
- and
- (v) an mitoxantrone group of formula III-E
- wherein
- R50, R51, R52 and R53 are each independently selected from the group consisting of OH or O—;
- subject to the proviso that one of R50, R51, R52 and R53 is O.
Dependencies are inferred from the claim text.