IP Library › Patent Application 14786331

Patent Application

App. No. 14/786,331

POLYMERASE, ENDONUCLEASE, AND HELICASE INHIBITORS AND METHODS OF USING THEREOF

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Patent No.: US None
App. No.: 14/786,331

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Abstract

Inhibitors of DNA damage polymerases, endonucleases, and helicases are provided. In particular, compounds comprising Formula (I) are described.

Claims (113)

1 . A compound, the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I):

wherein:

X 1 , X 2 , and X 3 are each independently selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and cyano;

R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and

R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, trifluoromethyl, halogen, cyano, nitro, amidine, amino, carboxyl, ester, alkylalkylamino, dialkylamino, hydroxyl, alkoxy, and arylalkoxy.

2 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cyano, and COOCH 3 ;

R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and

3 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cyano, and COOCH 3 ;

R 2 , R 3 , and R 4 are selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 5 and Ware hydrogen; and

R 6 and R 7 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, cyano, nitro, amidine, amino, carboxyl, ester, alkylalkylamino, dialkylamino, hydroxyl, alkoxy, and arylalkoxy.

4 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cyano, and COOCH 3 ;

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 and R 4 are selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 5 and R 8 are hydrogen; and

5 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is sulfur;

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of phenyl, substituted phenyl, biphenyl, substituted biphenyl, naphthyl, substituted naphthyl, cyano, and COOCH 3 ;

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 and R 4 are selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 5 and R 8 are hydrogen; and

R 6 and R 7 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, trifluoromethyl, halogen, cyano, nitro, amidine, amino, carboxyl, ester, alkylalkylamino, dialkylamino, hydroxyl, alkoxy, and arylalkoxy.

6 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cyano, and COOCH 3 ;

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 , R 4 , R 5 , and R 8 are hydrogen; and

7 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is carbonyl;

R 1 is selected from the group consisting of phenyl, substituted phenyl, biphenyl, substituted biphenyl, naphthyl, substituted naphthyl, cyano, and COOCH 3 ;

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 and R 4 are selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 5 and R 8 are hydrogen; and

8 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (I), wherein:

X 1 and X 3 are oxygen;

X 2 is sulfur;

Y is carbonyl;

R 1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cyano, and COOCH 3 ;

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 , R 4 , R 5 , and R 8 are hydrogen; and

9 . The compound of claim 1 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (IV):

wherein:

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 and R 4 are selected from the group consisting of hydrogen and methyl;

R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , and R 13 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, trifluoromethyl, halogen, cyano, nitro, amidine, amino, carboxyl, ester, alkylalkylamino, dialkylamino, hydroxyl, alkoxy, and arylalkoxy.

10 . The compound of claim 9 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (IV), wherein:

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl;

R 3 and R 4 are hydrogen;

11 . The compound of claim 9 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (IV), wherein:

X 2 is selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 2 , R 3 , and R 4 are hydrogen;

12 . The compound of claim 9 , the compound comprising a polymerase inhibitor and/or endonuclease inhibitor of Formula (IV), wherein:

X 2 is sulfur;

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 2 , R 3 , and R 4 are hydrogen;

13 . (canceled)

14 . The compound of claim 1 ,

wherein the IC50 value for the compound comprising Formula (I) against an enzyme chosen from polymerase and endonuclease is below 50 μM.

15 .- 16 . (canceled)

17 . A method of treating a tumor, the method comprising contacting a tumor cell with a composition comprising a polymerase inhibitor of Formula (I):

wherein:

X 1 , X 2 , and X 3 are each independently selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, cyano, and COOCH 3 ;

R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and

18 . The method of claim 17 , wherein the tumor cell is selected from the group consisting of a pancreatic tumor cell, a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, a uterine cancer cell, a prostate cancer cell, a lung cancer cell, a brain cancer cell, and a combination thereof.

19 . The method of claim 17 , wherein Formula (I) is chosen from ITBA-17 or ITBA-3.

20 . (canceled)

21 . The method of claim 22 , wherein the compound comprising Formula (I) is chosen from PNR-3-80 and PNR-3-82.

22 . A method of protecting a cell from death, the method comprising contacting a cell with a composition comprising an endonuclease inhibitor of Formula (I):

wherein:

X 1 , X 2 , and X 3 are each independently selected from the group consisting of oxygen, sulfur, and sulfene (R 2 C═SO 2 );

Y is selected from the group consisting of CH 2 , carbonyl, sulfide (R—S(—O)—R), sulfone (R—S(O 2 )—R), and sulfoxide (R—S(═O)—R);

R 1 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, cyano, and COOCH 3 ;

R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and

23 . The method of claim 22 , wherein the cell expresses endonuclease G.

24 . The method of claim 22 , wherein cell death is induced by a cell injury selected from the group consisting of chemical poisoning, drug poisoning, radiation, hypoxia, physical injury, and chemotherapeutics.

25 .- 30 . (canceled)

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2017

From: BOARD OF TRUSTEES OF THE UNIVERSITY OF ARKANSAS

To: BIOVENTURES, LLC

Reel/Frame 041137/0734 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 23, 2016

From: PENTHALA, NARSIMHA REDDY; CROOKS, PETER; EOFF, ROBERT; COGGINS, GRACE; MADDUKURI, LEENA; HARTMAN, JESSICA H.; JANG, DAE SONG; BASNAKIAN, ALEXEI

To: BOARD OF TRUSTEES OF THE UNIVERSITY OF ARKANSAS

Reel/Frame 037793/0780 →