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US 2010/0249175 A1Published application
Dicationic compounds which selectively recognize G-quadruplex DNA
OwnerW. David Wilson, David W. Boykin +5inventors
InventorsW. David Wilson, David W. Boykin, Elizabeth W. White, Mohamed A. Ismail, Arvind Kumar, Rupesh Nanjunda, Richard R. Tidwell
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Abstract
Dicationic compounds that are highly selective for binding G-quadruplex DNA are described. Several compounds exhibit groove binding toward G-quadruplex DNA and in vitro and in vivo activity versus Trypanosoma brucei rhodesiense. The compounds represent novel drugs for the treatment of cancer, malaria, leishmania, and trypanosomiasis.
Claims29
A method of binding quadruplex deoxyribonucleic acid (DNA), the method comprising contacting quadruplex DNA with a compound of Formula (I):
- Am1—Ar1—Ar2—Ar3—(Ar4)m—Am2 (I)
- wherein:
- m is an integer from 0 to 1;
- Ar1, Ar2, Ar3, and Ar4 are independently selected from the group consisting of:
- wherein:
- each X is independently selected from the group consisting of O, S, CH, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each A, B, and D is independently selected from the group consisting of CR6 and N, wherein R6 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Q is independently selected from the group consisting of O, S, Se, Te, and NR7, wherein R7 is selected from selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each E is independently selected from the group consisting of CR18 and N, wherein R18 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Z is independently selected from the group consisting of CR19 and N, wherein R19 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each q is independently an integer from 0 to 2;
- each y is independently an integer from 0 to 3;
- each t is independently an integer from 0 to 3;
- each u is independently an integer from 0 to 3;
- each R2, R3, R4, R5, and R17 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, halo, hydroxyl, alkoxyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- Am1 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and R9 or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and R9 or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16 , wherein R14 is alkyl, and R15 and R16 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
22 more elements
A method of reducing telomeric extension, the method comprising:
- a) providing a compound of Formula (I):
- Am1—Ar1—Ar2—Ar3—(Ar4)m—Am2 (I)
- wherein:
- m is an integer from 0 to 1;
- Ar1, Ar2, Ar3 and Ar4 are independently selected from the group consisting of:
- wherein:
- each X is independently selected from the group consisting of O, S, CH, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each A, B, and D is independently selected from the group consisting of CR6 and N, wherein R6 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Q is independently selected from the group consisting of O, S, Se, Te, and NR7, wherein R7 is selected from selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each E is independently selected from the group consisting of CR18 and N, wherein R18 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Z is independently selected from the group consisting of CR19 and N, wherein R19 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each q is independently an integer from 0 to 2;
- each y is independently an integer from 0 to 3;
- each t is independently an integer from 0 to 3;
- each u is independently an integer from 0 to 3;
- each R2, R3, R4, R5, and R17 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, halo, hydroxyl, alkoxyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- Am4 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and R9 or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and Rg or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16 , wherein R14 is alkyl, and R15 and R16 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof;
- and
- b) contacting the compound of Formula (I) with telomeric DNA in the presence of telomerase, wherein the compound of Formula (I) is in an amount effective to stabilize and maintain the telomeric DNA in a quadruplex secondary structure, wherein the ability of telomerase to bind to the telomeric DNA is inhibited, thereby reducing telomeric extension.
25 more elements
A method of reducing the proliferative capacity in a cell comprising contacting the cell with an effective amount of a compound of Formula (I):
- Am1—Ar1—Ar2—Ar3—(Ar4)m—Am2 (I)
- wherein:
- m is an integer from 0 to 1;
- Ar1, Ar2, Ar3, and Ar4 are independently selected from the group consisting of:
- wherein:
- each X is independently selected from the group consisting of O, S, CH, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each A, B, and D is independently selected from the group consisting of CR6 and N, wherein R6 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Q is independently selected from the group consisting of O, S, Se, Te, and NR7, wherein R7 is selected from selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each E is independently selected from the group consisting of CR18 and N, wherein R18 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Z is independently selected from the group consisting of CR19 and N, wherein R19 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each q is independently an integer from 0 to 2;
- each y is independently an integer from 0 to 3;
- each t is independently an integer from 0 to 3;
- each u is independently an integer from 0 to 3;
- each R2, R3, R4, R5, and R17 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, halo, hydroxyl, alkoxyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- Am1 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and Rg or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and R9 or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16 , wherein R14 is alkyl, and R15 and R16 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
22 more elements
A method of treating a cancer in a subject in need of treatment thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):
- Am1—Ar1—Ar2—Ar3—(Ar4)m—Am2 (I)
- wherein:
- m is an integer from 0 to 1;
- Ar1, Ar2, Ar3, and Ar4 are independently selected from the group consisting of:
- wherein:
- each X is independently selected from the group consisting of O, S, CH, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each A, B, and D is independently selected from the group consisting of CR6 and N, wherein R6 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Q is independently selected from the group consisting of O, S, Se, Te, and NRS, wherein R7 is selected from selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- each E is independently selected from the group consisting of CR18 and N, wherein R18 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each Z is independently selected from the group consisting of CR19 and N, wherein R19 is selected from the group consisting of H, halo, hydroxyl, alkyl, alkoxyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, and substituted aryl;
- each q is independently an integer from 0 to 2;
- each y is independently an integer from 0 to 3;
- each t is independently an integer from 0 to 3;
- each u is independently an integer from 0 to 3;
- each R2, R3, R4, R5, and R17 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, halo, hydroxyl, alkoxyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- Am1 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and R9 or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and R9 or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16, wherein R14 is alkyl, and R15 and R16 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
22 more elements
A compound of the following structure:
- wherein:
- each X is independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl, provided that at least one X is selected from Se, Te, and NR1, wherein R1 is selected from aryl and substituted aryl;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Am1 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and R9 or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and R9 or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16 , wherein R14 is alkyl, and R15 and R16 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
11 more elements
A pharmaceutical formulation comprising a compound of the following Formula:
- wherein:
- each X is independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl, provided that at least one X is selected from Se, Te, and NR1, wherein R1 is selected from aryl and substituted aryl;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Am1 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and R9 or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and R9 or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16, wherein R14 is alkyl, and R15 and R16 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
11 more elements
A method of treating a microbial infection in a subject in need of treatment thereof, the method comprising administering to the subject an effective amount of a compound of Formula (IV):
- wherein:
- each X is independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl, provided that at least one X is selected from Se, Te, and NR1, wherein R1 is selected from aryl and substituted aryl;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Am1 and Am2 are each independently selected from the group consisting of:
- wherein:
- each R8 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl;
- each R9, R10, R11, and R12 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R8 and R9 or R8 and R12 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R8 and R9 or R8 and R12 together are:
- wherein s is an integer from 1 to 4, and R13 is H or —CONHR14NR15R16 , wherein R14 is alkyl, and R15 and R16 are each
- independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
12 more elements
Dependencies are inferred from the claim text.