US2004229894A1PendingUtilityA1
Inhibition of human teomerase by a G-quadruplex-interaction compound
Priority: Feb 4, 1998Filed: Feb 10, 2004Published: Nov 18, 2004
Est. expiryFeb 4, 2018(expired)· nominal 20-yr term from priority
C07D 277/64C12Q 2600/136C07D 471/06C12Q 1/6886C12Q 1/68C12Q 2600/154
51
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Claims
Abstract
Certain non-nucleoside compounds that will selectively inhibit telomerase by targeting the nucleic add structures, such as G-quadruplexes, that may be associated with human telomeres or telomerase have been identified. Inhibition of human telomerase by two perylenetetracarboxylic acid diimides and a carbocyanine has been demonstrated. 1 H-NMR studies have evidenced the stabilization of a G-quadruplex by the perylenetetracarboxylic acid diimide compounds and provided evidence that these and structurally related compounds inhibit the telomerase enzyme by a mechanism consistent with interaction with G-quadruplex structures.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of reducing proliferative capacity of a cell comprising contacting said cell with a compound or a salt thereof or a stereoisomer of compound I that has the formula:
where R 1 and R 4 are independently -L-A where L is a linking group having the formula:
where n is 1-3; and each R5 is independently H, Me, OH, or OMe;
where R5 is as before and Y is O, S, SO, SO 2 , NH, NMe, or NCOMe;
where R5 and Y are as before and X is CH 2 , O, S, SO, SO 2 , NH, NMe, or NCOMe;
where R 6 , R 7 , R 8 , and R 9 are independently H, OMe, OEt, halogen, or Me;
and A is a compound of the formula:
where m is 0-5 and R6 is halogen, NH 2 , NO 2 , CN, OMe, SO 2 NH2, amidino, guanidino, or Me;
where o is 0-1; p is 0-2; q is 1-2 provided that when o+q is 2, in which case a pyrrolidine or pyrrole ring is indicated, or 3, in which a piperidine or pyridine ring is indicated; r is 0-3; R 7 is H or Me; R 8 is independently Me, NO 2 , OH, CH 2 OH or halogen, and when r is 2-3, two adjacent R8 substituents are —(CH═CH) 2 — or —(CH2) 4 — to form an annulated six-membered ring;
where R 9 is independently H, Me, and when R9 is O; s is 0-1; Z is CH 2 , O, NH, NMe, NEt, N(Me) 2 , N(Et) 2 , or NCO 2 Et;
where Q is N, CH, NMe, or NEt; X is O, S, NH, NMe or NEt; R 10 and R 11 are independently H, Me, CH 2 CO 2 Et, R 10 and R 11 taken together are —(CH═CH) 2 — or —(CH 2 ) 4 —;
where t is 1-4 4; u is 0-4, and R12 is independently Me, OH,
CO 2 R 13 , CON(R 13 ) 2 , SO 3 H, SO 2 N(R 13 ) 2 , CN, CH(CO 2 R 13 ) 2 , CH(CON(R 13 ) 2 ) 2 , N(R 13 ) 2 , or N(R 13 ) 3 where R 13 is H, Me, Et, or CH 2 CH 2 OH; and
R 2 , R 2′ , R 2″ , R ″ ; R 3 , R 3′ , R 3″ , R 3′″ are each independently H, OMe, halogen, or NO 2 .
2 . The method of claim 1 , wherein the cell is a mammalian cell.
3 . The method of claim 1 , wherein the cell is a human cell.
4 . The method of claim 1 , wherein the cell is a cancer cell.
5 . The method of claim 1 , wherein said malignant cell is a breast cancer cell, a prostate cancer cell, liver cancer cell, a pancreatic cancer cell, a lung cancer cell, a brain cancer cell, an ovarian cancer cell, a uterine cancer cell, a testicular cancer cell, a skin cancer cell, a leukemia cell, a head and neck cancer cell, an esophageal cancer cell, a stomach cancer cell, a colon cancer cell, a retinal cancer cell, a bladder cancer cell, an anal cancer cell and a rectal cancer cell.
6 . A method of reducing telomeric extension comprising administering a compound of claim 1 to a telomerase in the presence of a telomerase substrate.
7 . The method of claim 6 , where the telomerase is in a cell.
8 . The method of claim 1 , wherein said compound further promotes apoptosis.
9 . The method of claim 1 , wherein said compound further promotes apoptosis in a cell.
10 . The method of claim 1 , wherein the compound is a perylene compound.
11 . The method of claim 1 , wherein the compound is N,N′-bis(2-piperdinoethyl)-3,4,9,10-perylenetetracarboxylic acid diimide.
12 . The method of claim 1 , wherein the compound is N,N′-bis(2-dimethylaminoethyl)-3,4,9,10-perylenetetracarboxylic acid diimide.
13 . A compound of the formula
where R 1 and R 4 are independently -L-A where L is a linking group having the formula:
where n is 1-3; and each R5 is independently H, Me, OH, or OMe;
where R5 is as before and Y is O, S, SO, SO 2 , NH, NMe, or NCOMe;
where R5 and Y are as before and X is CH 2 , O, S, SO, SO 2 , NH, NMe, or NCOMe;
where R 6 , R 7 , R 8 , and R 9 are independently H, OMe, OEt, halogen, or Me;
and A is a compound of the formula:
where m is 0-5 and R 6 is halogen, NH 2 , NO 2 , CN, OMe, SO 2 NH 2 , amidino, guanidino, or Me;
where o is 0-1; p is 0-2; q is 1-2 provided that when o+q is 2, in which case a pyrrolidine or pyrrole ring is indicated, or 3, in which a piperidine or pyridine ring is indicated; r is 0-3; R 7 is H or Me; R 8 is independently Me, NO 2 , OH, CH 2 OH or halogen, and when r is 2-3, two adjacent R 8 substituents are —(CH═CH)2- or —(CH2)4- to form an annulated six-membered ring;
where R 9 is independently H, Me, and when R9 is O; s is 0-1; Z is CH 2 , O, NH, NMe, NEt, N(Me) 2 , N(Et) 2 , or NCO 2 Et;
where Q is N, CH, NMe, or NEt; X is O, S, NH, NMe or NEt; R 10 and R 11 are independently H, Me, CH 2 CO 2 Et, R 10 and R 11 taken together are —(CH═CH) 2 — or —(CH 2 ) 4 ;
where t is 1-4 4; u is 0-4, and R 12 is independently Me, OH,
CO 2 R 13 , CON(R 13 ) 2 , SO 3 H, SO 2 N(R 13 ) 2 , CN, CH(CO 2 R 13 ) 2 , CH(CON(R 13 ) 2 ) 2 , N(R 13 ) 2 , or N(R 13 ) 3 where R 13 is H, Me, Et, or CH 2 CH 2 OH; and
R 2 , R 2′ , R 2″ , R 2″ ; R 3 , R 3′ , R 3″, R 3′″ are each independently H, OMe, halogen, or NO 2 .
14 . A method of reducing proliferative capacity of a cell comprising contacting said cell with a compound having the formula II or a salt thereof or a stereoisomer of said compound:
where C is —CH═CH—, —(CH═CH) 2 —, —(CH═CH) 3 —, p-phenylene, o-phenylene, p-phenylene-CH═CH—, or o-phenylene-CH═CH—; B is O, S, or NR, and R is r Me or Et.
15 . The method of claim 14 , wherein the cell is a mammalian cell.
16 . The method of claim 14 , wherein the cell is a human cell.
17 . The method of claim 14 , wherein the cell is a cancer cell.
18 . The method of claim 14 , wherein said cancer cell is a breast cancer cell, a prostate cancer cell, liver cancer cell, a pancreatic cancer cell, a lung cancer cell, a brain cancer cell, an ovarian cancer cell, a uterine cancer cell, a testicular cancer cell, a skin cancer cell, a leukemia cell, a head and neck cancer cell, an esophageal cancer cell, a stomach cancer cell, a colon cancer cell, a retinal cancer cell, a bladder cancer cell, an anal cancer cell and a rectal cancer cell.
19 . A method of reducing telomeric extension comprising administering a compound of claim 14 , to a telomerase in the presence of a telomerase substrate.
20 . The method of claim 19 , where telomerase is in a cell.
21 . The method of claim 14 , wherein said compound further promotes apoptosis in a cell.
22 . The method of claim 14 , wherein the compound is a carbocyanine.
23 . The method of claim 22 , wherein the carbocyanine is 3,3′-diethyloxadicarbocyanine (DODC).
24 . A method for identifying a candidate compound that inhibits telomerase activity, comprising the steps:
a) obtaining the three-dimensional structure of a selected compound; and b) determining the complementarity of the compound to telomere DNA G-quadruplex wherein a compound that exhibits at least 75% of the favourable intermolecular interaction energy of the perylene diimide 2-d(TTAGGG) 4 complex structure is indicated to inhibit telomerase activity.
25 . A method of identifying a telomerase inhibitor comprising:
a) contacting a compound with DNA G-quadruplex; and b) determining the melting point of the DNA G-quadruplex wherein a compound exhibiting an increase in melting point of said quadruplex, relative to unbound DNA G-quadruplex, is indicated to inhibit telomerase activity.
26 . A method of identifying a telomerase inhibitor comprising the steps:
a) preparing a DNA G-quadruplex/dye complex wherein the dye is bound with the G-quadruplex; b) contacting said complex with a candidate compound; and c) determining displacement of said dye in the complex by said candidate, wherein displacement of the dye identifies the candidate as a telomerase inhibitor.
27 . A method of identifying a telomerase inhibitor comprising:
a) contacting a candidate compound to be identified as a telomerase inhibitor with DNA G-quadruplex; and b) determining the fluorescence or UV/VIS spectrum of the compound wherein an increase or decrease of the UV/VIS absorption or fluorescence emission intensity of said compound relative to the UV/VIS absorption or fluorescence emission intensity in the absence of DNA-G-quadruplex indicates telomerase inhibitory activity of the compound.
28 . A compound of the formula:
in which C is —CH═CH—, —(CH═CH) 2 —, —(CH═CH) 3 —, p-phenylene, o-phenylene, p-phenylene-CH═CH—, or o-phenylene-CH═CH—; B is O, S, or NR, and R is Me or Et.
29 . The method of claim 1 , wherein the mitotic division of a cell is inhibited.
30 . The method of claim 14 , wherein the mitotic division of a cell is inhibited.
31 . A compound of claim 28 , having the structure:
32 . The method of claim 14 , having the structure:
33 . A compound of claim 13 , having the formula:
34 . The method of claim 1 , having the formula:
35 . The compound of claim 13 , having the formula:
36 . The method of claim 1 , having the structure:Join the waitlist — get patent alerts
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