Anti-cancer agents and methods of use

Patent metadata

Field	Value
Publication number	US-9821173-B2
Application number	US-201414176848-A
Country	US
Kind code	B2
Filing date	Feb 10, 2014
Priority date	Feb 8, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

An anti-cancer agent includes Au(I) purinyl, indolyl, or azaindolyl analogues encapsulated in sterically hindered phosphine ligands.

First claim

Having described the invention, I claim:

1. A compound having the following formula:
X 1 —Au(I)—Y 1 , wherein

X 1 is a sterically hindered phosphine ligand selected from a triphenylphosphine or a tricyclohexylphosphine;
Y 1 is an indolyl derivative, wherein Au is bound to the 5 carbon of the indolyl; and
pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein Y 1 is an indolyl derivative having the following formula:

where R 1 is hydrogen, or a substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, hydroxyl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, halocarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-substituted carbamoyl, di-(C 1 -C 24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, mono- and di-(C 1 -C 24 alkyl)-substituted amino, mono- and di-(C 5 -C 20 aryl)-substituted amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl.

3. The compound of claim 1 selected from group consisting of 5-(triphenylphosphine-gold(I))-tert-butyl 1H-indole-1-carboxylate, 5-(tricyclohexylphosphine-gold(I))-tert-butyl 1H-indole-1-carboxylate, and pharmaceutically acceptable salts thereof.

4. A method of treating cancer in a subject in need thereof, the method comprising:
administering to a cancer cell of the subject a therapeutically effective amount of a compound having the following formula:
X 1 —Au(I)—Y 1 , wherein

X 1 is a sterically hindered phosphine ligand selected from a triphenylphosphine or a tricyclohexylphosphine;
Y 1 is an indolyl derivative, wherein Au is bound to the 5 carbon of the indolyl; and
pharmaceutically acceptable salts thereof; and
administering ionizing radiation to the cancer cell after or substantially contemporaneous with the administration of the compound.

5. The method of claim 4 , wherein Y 1 is an indolyl derivative having the following formula:

where R 1 is hydrogen, or a substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, hydroxyl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, halocarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-substituted carbamoyl, di-(C 1 -C 24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, mono- and di-(C 1 -C 24 alkyl)-substituted amino, mono- and di-(C 5 -C 20 aryl) substituted amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl.

6. The method of claim 4 , wherein the sterically hindered phosphine ligand reduces the reactivity of the Au(I) with biological thiols and/or selenols when the compound is administered to the cancer cell.

7. The method of claim 4 , wherein the compound is selected from group consisting of 5-(triphenylphosphine-gold(I))-tert-butyl 1H-indole-1-carboxylate, 5-(tricyclohexylphosphine-gold(I))-tert-butyl 1H-indole-1-carboxylate, and pharmaceutically acceptable salts thereof.

8. The method of claim 4 , wherein the compound is administered at an amount effective to chemosensitize the cancer cell to the ionizing radiation.

9. A method of treating cancer of a subject in need thereof, the method comprising:
administering to a cancer cell of the subject
(i) an amount of a compound having the following formula effective to chemosensitize the cancer cells to ionizing radiation:
X 1 —Au(I)—Y 1 , wherein

X 1 is a sterically hindered phosphine ligand selected from a triphenylphosphine or a tricyclohexylphosphine;
Y 1 is a indolyl derivative, wherein Au is bound to the 5 of the indolyl, and
pharmaceutically acceptable salts thereof; and
(ii) a therapeutically effective amount of ionizing radiation.

Assignees

• Univ Case Western Reserve

Inventors

• Berdis Anthony J

Classifications

• A61K41/0038 Primary

  Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10) · CPC title

• A61K31/06

  the aromatic ring being substituted by nitro groups · CPC title

• A61N5/10 Primary

  X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence) · CPC title

• C07F9/5045

  Complexes or chelates of phosphines with metallic compounds or metals · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title