Topoisomerase inhibitors with antibacterial and anticancer activity

Patent metadata

Field	Value
Publication number	US-11274106-B2
Application number	US-201816624335-A
Country	US
Kind code	B2
Filing date	Jun 21, 2018
Priority date	Jun 23, 2017
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

Herein is described the conversion of deoxynybomycin (DNM), a natural product and DNA gyrase inhibitor with minimal cytotoxicity, into a compound (Formula I) that has anticancer activity. Detailed in vitro and cell culture experiments demonstrate that these compounds inhibit Top2 and also act upon topoisomerase I. Similar approaches are applicable to other classes of gyrase inhibitors and other antibacterial targets for discovery of new anticancer drugs.

First claim

What is claimed is:

1. A compound of Formula I:

or a salt or solvate thereof;
wherein
G is a direct bond or CH 2 ;
X is C═O;
R 1 is H, —(C 1 -C 6 )alkyl, —OR A , —SR A , —S(═O) 2 N(R A ) 2 , —N(R A ) 2 , —(C 1 -C 5 )alkyl-OR A , —(C 1 -C 5 )alkyl-SR A , —(C 1 -C 5 )alkyl-S(═O) 2 N(R A ) 2 , —(C 1 -C 5 )—N(R A ) 2 , or —(C 1 -C 5 )alkyl-C(═O)R B ;
R 2 is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl;
R 3 and R 4 are each independently H, —(C 1 -C 6 )alkyl, or R 3 and R 4 taken together form a cycloalkyl or an aryl;
R 5 is H;
R 6 is H or —(C 1 -C 6 )alkyl;
R A is H, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, or —C(═O)R B ; and
R B is H, —(C 1 -C 6 )alkyl, —OH, or —NH 2 ;

wherein each —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl and aryl is optionally substituted with one or more substituents and optionally both R A in the moiety N(R A ) 2 taken together form a 5- or 6-membered heterocycle; and
the compound of Formula I is not the compound:

2. The compound of claim 1 wherein R 1 is H, —CH 2 OH, —CH 2 (C═O)OH, —CH 2 NH 2 , —CH 2 -(pyrrolidine), —CH 2 -(piperidine), —CH 2 -(piperazine), —CH 2 -(morpholine), —CH 2 -(imidazole), —CH 2 -(triazole), or —CH 2 -(tetrazole).

3. A compound of Formula II:

or a salt or solvate thereof,
wherein
R 1 is H, —(C 1 -C 6 )alkyl, —OR A , —SR A , —S(═O) 2 N(R A ) 2 , —N(R A ) 2 , —(C 1 -C 5 )alkyl-OR A , —(C 1 -C 5 )alkyl-SR A , —(C 1 -C 5 )alkyl-S(═O) 2 N(R A ) 2 , —(C 1 -C 5 )—N(R A ) 2 , or —(C 1 -C 5 )alkyl-C(═O)R B ;
R 2 is —(C 3 -C 6 )cycloalkyl;
R 3 and R 4 are each independently H, —(C 1 -C 6 )alkyl, or R 3 and R 4 taken together form a cycloalkyl or an aryl;
R 6 is H, —(C 1 -C 6 )alkyl;
R A is H, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, or —C(═O)R B ; and
R B is H, —(C 1 -C 6 )alkyl, —OH, or —NH 7 ;

wherein each —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl and aryl is optionally substituted with one or more substituents and optionally both R A in the moiety N(R A ) 2 taken together form a 5- or 6-membered heterocycle.

4. The compound of claim 1 wherein the compound is a compound of Formula III:

5. The compound of claim 1 wherein R 1 is not H and the compound is the (R)-enantiomer or the (S)-enantiomer.

6. The compound of claim 1 wherein R 2 and R 6 are —(C 1 -C 6 )alkyl.

7. The compound of claim 6 wherein R 4 is —(C 1 -C 6 )alkyl.

8. The compound of claim 1 wherein R 3 and R 4 taken together form a cycloalkyl or an aryl.

9. The compound of claim 1 wherein the compound is a compound of Formula IV:

wherein each R 7 is independently H, halo, —(C 1 -C 6 )alkyl, —OR A , —SR A , —N(R A ) 2 , —C(═O)R B , —C(═O)N(R A ) 2 , or —S(═O) 2 N(R A ) 2 .

10. The compound of claim 9 wherein the compound is a compound of Formula V:

11. A compound selected from any one of compounds C1-C20:

12. A pharmaceutical composition comprising a compound of claim 11 in combination with a pharmaceutically acceptable diluent, carrier, excipient, or buffer.

13. The compound of claim 1 wherein the compound is a compound of Formula II:

wherein
R 1 is —(C 1 -C 6 )alkyl, —OR A , —SR A , —S(═O) 2 N(R A ) 2 , —N(R A ) 2 , —(C 1 -C 5 )alkyl-OR A , —(C 1 -C 5 )alkyl-SR A , —(C 1 -C 5 )alkyl-S(═O) 2 N(R A ) 2 , or —(C 1 -C 5 )alkyl-C(═O)R B ; and
R 2 is H or —(C 1 -C 6 )alkyl.

Assignees

• Univ Illinois

Inventors

• Hergenrother Paul J
• Riley Andrew P

Classifications

• A61K9/2059

  Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/4858

  Organic compounds · CPC title

• C07D498/16 Primary

  Peri-condensed systems · CPC title