Precise delivery of therapeutic agents to cell mitochondria for anti-cancer therapy

Patent metadata

Field	Value
Publication number	US-2016339106-A1
Application number	US-201414902514-A
Country	US
Kind code	A1
Filing date	Jul 1, 2014
Priority date	Jul 1, 2013
Publication date	Nov 24, 2016
Grant date	—

Abstract

Described is a targeted molecular scaffold for construction of a metabolic inhibitor loaded with cancer-cell specific activity and anti-tumor immunity. Incorporation of a mitochondria targeting moiety such as triphenylphosphonium cation through a biodegradable linker in allowed for mitochondria targeting of certain metabolic inhibitors like dichloroacetic acid (DCA).

First claim

1 . A compounds having Formula I:

where
TC is a mitochondria targeting moiety;
IM is an inhibitor moiety;
l is from 1 to 10;
m is from 1 to 3;
n is from 0 to 20;
p is from 1 to 64;
X 1 is —CO 2 —, —CO 2 CH 2 —, —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—;
X 2 is —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—;
X 3 is a linker; and
R 1 , R 2 , and R 3 are, independently of one another, —H, —F, —Cl, —Br, —OH, —C 1-6 alkyl, or —OC(O)C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein m is 1, 2, or 3, X 1 is —CO 2 — or —CHR 3 —; X 2 is —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—; X 3 is —CO 2 —; R 1 , R 2 , and R 3 are each —H; p is 1; 1 is 1 to 5; and n is 0 to 3.

3 . The compound of claim 1 , wherein p is 1, 2, or 3, X 1 is —CO 2 — or —CHR 3 —; X 2 is —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—; X 3 is —CO 2 —; R 1 , R 2 , and R 3 are each —H; m is 1; 1 is 1 to 5; and n is 0 to 3.

4 . The compound of claim 1 , wherein TC is a cationic rhodamine moiety or a Szeto-Shiller peptide.

5 . The compound of claim 1 , wherein TC is a triphenyphosphonium moiety.

6 . The compound of claim 1 , wherein IM is lonidamine, dichloroacetate, alpha-tocopheryl succinate, methyl jasmonate, betulinic acid, and resveratrol, A-385358, ABT-263, ABT-737, AT-101, 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), LDH-A shRNA, orlistat, SB-204990, soraphen A, 4-(N-(s-glutathionylacetate)aminophenylarsenoxide (GSAO), clodronate, PK11195, menadione, beta-lapachone, CD437, gamitrinibs, 8-(2-chloro-3,4,5-trimethoxybenzyl)-2-fluoro-9-(pent-4-nyl)-9H-purin-6-amine (PU24Fcl), (8-(6-bromobenzo[d][1,3,]dioxyl-5-ylthio)-9-(pent-4-nyl)-9H-purin-6-amine (PUH58), 8-(6-iodobenzo[d][1,3,]dioxyl-5-ylthio)-9-(3-isopropylamino)propyl-9H-purin-6-amine (PUH71), shepherdin, 2-methoxyestradiol, tetrathiomolybdate, buthionine sulphoximine, dimethylamino-parthenolide, parthenolide, imexons, magafodipir, menadione, motexafin gadolinium, PEITCs, elescomol (STA-4783), all trans-retinoic acid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid, E-3-(4′-hydroxy-3′-adamantylbiphenyl-4yl)acrylic acid, 3-bromopyruvate, butyric acid, 2-deoxyD-glucose, arsenite trioxide, or betulinic acid.

7 . The compound of claim 1 , wherein IM is dichloroacetyl.

8 . The compound of claim 1 , wherein the compound has Formula II:

where
l is from 1 to 10;
m is from 1 to 3;
n is from 0 to 20;
p is from 1 to 64;
X 1 is —CO 2 —, —CO 2 CH 2 —, —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—;
X 2 is —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—; and
R 1 , R 2 , and R 3 are, independently of one another, —H, —F, —Cl, —Br, —OH, —C 1-6 alkyl, or —OC(O)C 1-6 alkyl.

9 . The compound of claim 8 , wherein m is 1, 2, or 3, X 1 is —CO 2 — or —CHR 3 — and X 2 is —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—; R 1 , R 2 , and R 3 are each —H; p is 1; 1 is 1 to 5; and n is 0 to 3.

10 . The compound of claim 8 , wherein p is 1, 2, or 3, X 1 is —CO 2 — or —CHR 3 — and X 2 is —CONR 3 —, —SO 2 NR 3 —, —CHR 3 —, —NHR 3 —, —CO—, or —O—; and R 1 , R 2 , and R 3 are each —H; m is 1; 1 is 1 to 5; and n is 0 to 3.

11 . The compound of claim 8 , wherein m is 1, 2, or 3, X 1 is —CH 2 — and X 2 is —CONH—, and R 1 and R 2 are each —H; p is 1; 1 is 1 to 3; and n is 0.

12 . The compound of claim 8 , wherein p is 1, 2, or 3, X 1 is —CH 2 — and X 2 is —CONH—, and R 1 and R 2 are each —H; m is 1; 1 is 1 to 3; and n is 0.

13 . The compound of claim 1 , wherein the compound has Formula IV or V:

where p is 1 to 64, and R 1 is C 1-3 alkyl or H.

14 . The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable sa thereof.

15 . A compound comprising from 4 to 64 triphenyl phosphenyl moieties and from 4 to 64 dichloroacetyl moieties.

16 . The compound of claim 15 having the structure

17 . The compound of claim 15 having the structure

18 . The compound of claim 15 having the structure

19 . A composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

20 . A nanoparticle comprising a hydrophobic core, a hydrophilic outer layer surrounding the core, and a compound of claim 1 .

21 . The nanoparticle of claim 20 , wherein the core comprises poly(lactic-co-glycolic) acid.

22 . The nanoparticle of claim 20 , wherein the hydrophilic outer layer comprises polyethylene glycol and is attached to the core.

23 . A method of treating or preventing cancer in a subject, comprising administering to the subject an effective amount of a compound or composition of claim 1 .

24 . The method of claim 23 , wherein the cancer is prostate cancer lung, breast, brain, ovarian, lymphoma, leukemia, head and neck, pancreatic, and cervical, colon and rectum, endrometrial, esophagous, liver, penile, skin-melanoma, skin-nonmelanoma, stomach, testicular, vaginal, uterine, vulvar, paranasal cancer, oropharyngeal and laryngeal cancers.

25 . The method of claim 23 , further comprising administering a second compound or composition, wherein the second compound or composition includes an anticancer agent.

26 . The method of claim 23 , further comprising administering an effective amount of ionizing radiation to the subject.

27 . A method of killing a tumor cell in a subject, comprising contacting the tumor cell with an effective amount of a compound or composition of claim 1 .

28 . The compound of claim 1 , wherein X 3 is CH 2 .

Assignees

• Univ Georgia

Inventors

• Shanta Ohar

Classifications

• C07F9/6518

  Five-membered rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07F9/5442

  Aromatic phosphonium compounds (P-C aromatic linkage) · CPC title

• A61K9/5184

  Virus capsids or envelopes enclosing drugs (liposomes with additional exogenous lipids A61K9/127) · CPC title

• A61K47/54 Primary

  the modifying agent being an organic compound · CPC title