# US 2014/0155339 A1 · Hydroxytyrosol and oleuropein compositions for induction of dna damage, cell death and lsd1 inhibition

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- Number: US 2014/0155339 A1
- Document ID: US20140155339A1
- Status: Published application
- Kind: A1
- Application number: 14/091,742
- Filed: 2013-11-27
- Published: 2014-06-05
- Earliest claimed: 2012-11-30
- Inventors: Darlene E. McCord; Thomas Karagiannis
- Web page: https://patentgrep.com/patent/US20140155339A1

## CPC

- A61K 31/05: Phenols {(cannabinoids A61K31/658)}
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C12Q 1/26: involving oxidoreductase
- C12Q 1/6876: Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- G01N 33/575: for cancer
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Compositions comprising hydroxytyrosol-containing formulations and treatment regiments comprising hydroxytyrosol and/or oleuropein and chemotherapeutic agents are disclosed. Compositions and/or regiments may optionally include the administration of vitamins, minerals, and anti-oxidants. Methods for using these compositions and treatment regimens for treating subjects for diseases, such as a malignancy, and for inducing or enhancing angiogenesis, treating or preventing oxidative stress, for treating or preventing high glucose-induced dysfunction, treating or preventing chemotherapy-induced dysfunction, and for improving cell viability are provided. Various methods for use of the hydroxytyrosol compositions for inhibition of lysine specific demethylase 1 (LSD1) in various cancers are also provided.

## Claims

### Claim 1

A pharmaceutical composition for treatment, suppression and/or amelioration of a condition or disease currently treated with chemotoxic compounds, wherein said composition comprises hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite.

### Claim 2 (depends on 1)

The composition of claim 1 further comprising a chemotherapeutic agent.

### Claim 3 (depends on 1)

The composition of claim 1 wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol is present at a concentration of about 1 μM to about 100 μM, and is selected from the group consisting of:
(a) hydroxytyrosol that is isolated, purified and/or synthesized and has the following formula:
(b) a hydroxytyrosol acyl derivative according to the following structure:
and
(c) hydroxytyrosol derived and/or substituted compound and/or hydroxytyrosol metabolite has the following formula:
wherein R1, R2, and R2 provide a pharmaceutically acceptable salt, solvate, prodrug and/or isomer of hydroxytyrosol;
wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite has an inhibitory efficacy against the LSD1 protein.

### Claim 4 (depends on 3)

The composition of claim 3 wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like having inhibitory efficacy against the LSD1 protein; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein).

### Claim 5

A method of treating a condition of disease currently treated with chemotoxic compounds, comprising:
administering to an individual in need thereof a composition comprising hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite selected from the group consisting of:
(a) hydroxytyrosol that is isolated, purified and/or synthesized and has the following formula:
(b) a hydroxytyrosol acyl derivative according to the following structure:
and
(c) hydroxytyrosol derived and/or substituted compound and/or hydroxytyrosol metabolite has the following formula:
wherein R1, R2, and R2 provide a pharmaceutically acceptable salt, solvate, prodrug and/or isomer of hydroxytyrosol;
wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite has an inhibitory efficacy against the LSD1 protein.

### Claim 6 (depends on 5)

The method of claim 5 further comprising administering to said individual a chemotherapeutic agent.

### Claim 7 (depends on 5)

The method of claim 5 wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like having inhibitory efficacy against the LSD1 protein; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein).

### Claim 8

A method for detecting cancer or pre-cancer cells in an individual comprising:
contacting a sample from said individual with or administering to an individual in need thereof a composition comprising hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite to a particular site of said individual followed by detection of genetic and epigenetic effects; and
detecting cancerous or pre-cancerous cells.

### Claim 9 (depends on 8)

The method of claim 8 wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite is selected from the group consisting of:
(a) hydroxytyrosol that is isolated, purified and/or synthesized and has the following formula:
(b) a hydroxytyrosol acyl derivative according to the following structure:
and
(c) hydroxytyrosol derived and/or substituted compound and/or hydroxytyrosol metabolite has the following formula:
wherein R1, R2, and R2 provide a pharmaceutically acceptable salt, solvate, prodrug and/or isomer of hydroxytyrosol;
wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite has an inhibitory efficacy against the LSD1 protein.

### Claim 10 (depends on 9)

The method of claim 9 wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like having inhibitory efficacy against the LSD1 protein; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein).

### Claim 11

A hydroxytyrosol-based inhibitor of the LDS1 protein comprising: hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite.

### Claim 12 (depends on 11)

The composition of claim 11 wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite is selected from the group consisting of:
(a) hydroxytyrosol that is isolated, purified and/or synthesized and has the following formula:
(b) a hydroxytyrosol acyl derivative according to the following structure:
and
(c) hydroxytyrosol derived and/or substituted compound and/or hydroxytyrosol metabolite has the following formula:
wherein R1, R2, and R2 provide a pharmaceutically acceptable salt, solvate, prodrug and/or isomer of hydroxytyrosol;
wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite has an inhibitory efficacy against the LSD1 protein.

### Claim 13 (depends on 12)

The composition of claim 12 wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like having inhibitory efficacy against the LSD1 protein; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein).

### Claim 14 (depends on 11)

A pharmaceutical composition for treating cancers comprising the hydroxytyrosol-based inhibitor of the LDS1 protein of claim 11, a chemotherapeutic agent and a pharmaceutically acceptable carrier.

### Claim 15

A method of inhibiting LSD1 in a cell comprising contacting said cell with a composition comprising a compound that interacts with LSD1 at either the flavin group of LSD1 or close to the adenosine group of LSD1.

### Claim 16 (depends on 15)

The method of claim 15 wherein said compound interacts with one or more of the residues tryptophan residue at position 807, the phenylalanine at position 560, and/or the histidine at position 812 of LSD1, and wherein said compound that interacts with LSD1 comprises hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite.

### Claim 17 (depends on 15)

The method of claim 15 wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite is selected from the group consisting of:
(a) hydroxytyrosol that is isolated, purified and/or synthesized and has the following formula:
(b) a hydroxytyrosol acyl derivative according to the following structure:
and
(c) hydroxytyrosol derived and/or substituted compound and/or hydroxytyrosol metabolite has the following formula:
wherein R1, R2, and R2 provide a pharmaceutically acceptable salt, solvate, prodrug and/or isomer of hydroxytyrosol;
wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite has an inhibitory efficacy against the LSD1 protein;
wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like having inhibitory efficacy against the LSD1 protein; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein).

### Claim 18 (depends on 15)

The method of claim 15 wherein said cancer is an LSD1-expressing cancer in an individual comprising contacting a sample from said individual with or administering to said individual directly a composition comprising hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite, followed by detection of LSD1 inhibition.

### Claim 19 (depends on 18)

The method of claim 18 wherein the detection of LSD1 inhibition comprises assaying for cell growth, proliferation and/or death; alteration of gene expression and epigenetic effects; cell invasion; cell migration; cell adhesion; and/or expression of cancer cell markers, and wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite is selected from the group consisting of:
(a) hydroxytyrosol that is isolated, purified and/or synthesized and has the following formula:
(b) a hydroxytyrosol acyl derivative according to the following structure:
and
(c) hydroxytyrosol derived and/or substituted compound and/or hydroxytyrosol metabolite has the following formula:
wherein R1, R2, and R2 provide a pharmaceutically acceptable salt, solvate, prodrug and/or isomer of hydroxytyrosol;
wherein said hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite has an inhibitory efficacy against the LSD1 protein.

### Claim 20

A method for increasing lysine methylation of a histone polypeptide or for increasing or decreasing gene expression in a cell, inducing cell death, and/or achieving a protective effect in an individual or cell comprising:
contacting said cell with a composition comprising hydroxytyrosol, a hydroxytyrosol derived and/or substituted compound, and/or a hydroxytyrosol metabolite,
wherein said protective effect is one or more of improving cell viability, treating or p preventing chemotherapy-induced dysfunction, treating or preventing high glucose-induced dysfunction, treating or preventing oxidative stress, and inducing or enhancing angiogenesis.