POTENT IMMUNOSUPPRESSIVE AGENTS, DERIVATIVES AND USES

• US 20110053994A1
• Filed: 06/11/2010
• Published: 03/03/2011
• Est. Priority Date: 03/13/2002
• Status: Active Grant

• Current Assignee: Johns Hopkins University, Texas A&M University System
• Original Assignee: Johns Hopkins University, Texas A&M University System
• Inventors: Liu, Jun, Schneider-Poetsch, Tilman, Shi, Zonggao, Low, Woon-Kai, Dang, Yongjun, Choi, Nam Song, Romo, Daniel
• Granted Patent: US 8,841,285 B2
• Time in Patent Office: Days
• US Class Current: 514/368
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 513/08 Bridged systems

Abstract

Provided herein include compositions, all related stereoisomers as well as pharmaceutically acceptable salts provided as simplified analogs of pateamine A, in which the analogs generally are devoid of the C3-amino and C5-methyl groups, also referred to as desmethyl, desamino-pateamine A. Suitable analogs provide anticancer and antiproliferative effects in vivo and in vitro by a novel drugs mechanism of action described herein for pateamine A, including inhibition of eIF4A-dependent translation initiation. As with pateamine A, as described herein, suitable analogs cause cell cycle arrest or induce apoptosis in transformed cells. However, toxicity of such compounds to slow growing normal cells is low. In addition, such analogs, like pateamine A, target translation initiation factors and are useful as anticancer and antiproliferative agents in subjects in need thereof. Moreover, the analogs, like pateamine A, are valuable molecular probes for evalutaion of eukaryotic translation initiation and as lead compounds for development of improved anticancer agents.

Claims

1. A compositions comprising:

an analog of pateamine A, wherein the analog is devoid of a C3-amino and a C5-methyl group, and wherein the composition is synthesized by macrocyclization.

2. The composition of claim 1 further comprising a dihydro group using a saturated acid as a coupling partner.

3. The composition of claim 1 further comprising a β

-keto group serving as precursor for conjugation with a label.

4. The composition of claim 1 further comprising a hydrozone moiety with a terminal alkyne.

5. The composition of claim 4, wherein the composition undergoes Huisgen-Sharpless cycloaddition.

7. A method using a composition of claim 1, wherein the method identifies compounds that bind the composition of claim 1 to identify compounds that bind pateamine A.

6. A composition comprising:

an analog of pateamine A, wherein the analog is devoid of a C3-amino and a C5-methyl group, wherein the composition is synthesized by macrocyclization, and wherein the composition inhibits translation initiation in eukaryotes.

8. A method using a composition of claim 6, wherein the method identifies compounds that bind the composition of claim 6 to identify compounds that inhibit translation initiation in eukaryotes.

9. A compositions comprising:

an analog of pateamine A, wherein the analog is devoid of a C3-amino and a C5-methyl group, wherein the composition is synthesized by macrocyclization, wherein the composition inhibits translation initiation in eukaryotes, and wherein the composition is provided to a subject in need to inhibit translation initiation in one or more proliferative cells of the subject.

10. The composition of claim 9, wherein the cells are cancer cells

11. The composition of claim 9, wherein the cells are involved in angiogenesis.

12. The composition of claim 9, wherein the composition binds eIF4A in the proliferative cells.

13. The composition of claim 9, wherein the composition stimulates ATPase activity of eIF4A in the proliferative cells.

14. The composition of claim 9, wherein the composition increases ATP-dependent RNA helicase activity of eIF4AI in the proliferative cells.

15. The composition of claim 9, wherein the composition inhibits protein synthesis in the proliferative cells.

16. The composition of claim 9, wherein the composition stalls a 48S complex when in the process of scanning the 5′

-UTR in the proliferative cells.

17. The composition of claim 9, wherein the composition prevents stable binding at a AUG start codon.

18. The composition of claim 9, wherein the composition promotes formation of stress granules in the proliferative cells.