Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
Compounds represented by the following structure (I) are disclosed: as are methods for making such compounds, wherein said methods comprise reacting a diacyldiketopiperazine with a first aldehyde to produce an intermediate compound; and reacting the intermediate compound with a second aldehyde to produce the class of compounds with the generic structure, where the first aldehyde and the second aldehydes are selected from the group consisting of an oxazolecarboxaldeyhyde, imidazolecarboxaldehyde, a benzaldehyde, imidazolecarboxaldehyde derivatives, and benzaldehyde derivatives, thereby forming the above compound wherein R 1 , R 1 ′, R 1 ″, R 2 , R 3 , R 4 , R 5 , and R 6 , X 1 and X 2 , Y, Z, Z 1 , Z 2 , Z 3 , and Z 4 may each be separately defined in a manner consistent with the accompanying description. Compositions and methods for treating cancer and fungal infection are also disclosed.
1 . A method of inhibiting cell proliferation, comprising administering to a mammal a compound having the structure of Formula (I):
wherein
R 1 and R 6 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or separately selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 4 is a tert-butyl group;
R 7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, andphenyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 1 ′ and R 1 ″ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or independently selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R, R 1 ′ and R 1 ″ are either covalently bound to one another or are not covalently bound to one another;
R 2 , R 3 , and R 5 are each separately selected from the group consisting of a hydrogen atom or a halogen atom, or separately selected from the group consisting of saturated C 1 -C 12 alkyl, unsaturated C 1 -C 12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
X 1 and X 2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, each either unsubstituted or substituted with a R 5 group, as defined above;
Y is selected from the group consisting of a nitrogen atom substituted with R 5 , an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R 5 ;
n is an integer equal to zero, one or two;
Z, for each separate n, if non-zero, and Z 1 , Z 2 , Z 3 and Z 4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and
the dashed bonds may be either single or double-bonds.
2 . The method of claim 1 , wherein said compound is selected from the group consisting of: KPU-11, KPU-35, KPU-66, KPU-80, KPU-81, and KPU-90.
3 . The method of claim 1 , wherein said compound is KPU-2.
4 . A method of promoting microtubule depolymerization, comprising contacting a cell containing the microtubule with an amount of a compound of Formula (I) effective to induce microtubule depolymerization:
wherein
R 1 and R 6 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or separately selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 4 is a tert-butyl group;
R 7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, andphenyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen; bydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 1 ′ and R 1 ″ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or independently selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R, R 1 ′ and R 1 ″ are either covalently bound to one another or are not covalently bound to one another;
R 2 , R 3 , and R 5 are each separately selected from the group consisting of a hydrogen atom or a halogen atom, or separately selected from the group consisting of saturated C 1 -C 12 alkyl, unsaturated C 1 -C 12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
X 1 and X 2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, each either unsubstituted or substituted with a R 5 group, as defined above;
Y is selected from the group consisting of a nitrogen atom substituted with R 5 , an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R 5 ;
n is an integer equal to zero, one or two;
Z, for each separate n, if non-zero, and Z 1 , Z 2 , Z 3 and Z 4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and
the dashed bonds may be either single or double bonds.
5 . The method of claim 4 , wherein said compound is selected from the group consisting of: KPU-11, KPU-35, KPU-66, KPU-80, KPU-81, and KPU-90.
6 . The method of claim 4 , wherein said compound is KPU-2.
7 . A method of inducing vascular collapse in a tumor, comprising contacting the tumor with an amount of a compound of Formula (I) effective to induce vascular collapse:
wherein
R 1 and R 6 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or separately selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 4 is a tert-butyl group;
R 7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, andphenyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 1 ′ and R 1 ″ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or independently selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R, R 1 ′ and R 1 ″ are either covalently bound to one another or are not covalently bound to one another;
R 2 , R 3 , and R 5 are each separately selected from the group consisting of a hydrogen atom or a halogen atom, or separately selected from the group consisting of saturated C 1 -C 12 alkyl, unsaturated C 1 -C 12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
X 1 and X 2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, each either unsubstituted or substituted with a R 5 group, as defined above;
Y is selected from the group consisting of a nitrogen atom substituted with R 5 , an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R 5 ;
n is an integer equal to zero, one or two;
Z, for each separate n, if non-zero, and Z 1 , Z 2 , Z 3 and Z 4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and
the dashed bonds may be either single or double bonds.
8 . The method of claim 7 , wherein said compound is selected from the group consisting of: KPU-11, KPU-35, KPU-66, KPU-80, KPU-81, and KPU-90.
9 . The method of claim 7 , wherein said compound is KPU-2.
10 . A method of treating or preventing cancer, comprising co-administering to a mammal a compound of Formula (I) and a second anti-cancer agent:
wherein
R 1 and R 6 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or separately selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 4 is a tert-butyl group;
R 7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, andphenyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R 1 ′ and R 1 ″ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or independently selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 1 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
R, R 1 ′ and R 1 ″ are either covalently bound to one another or are not covalently bound to one another;
R 2 , R 3 , and R 5 are each separately selected from the group consisting of a hydrogen atom or a halogen atom, or separately selected from the group consisting of saturated C 1 -C 12 alkyl, unsaturated C 1 -C 12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, aclyamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -aryl, and —SO 2 -heteroaryl;
X 1 and X 2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, each either unsubstituted or substituted with a R 5 group, as defined above;
Y is selected from the group consisting of a nitrogen atom substituted with R 5 , an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R 5 ;
n is an integer equal to zero, one or two;
Z, for each separate n, if non-zero, and Z 1 , Z 2 , Z 3 and Z 4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and
the dashed bonds may be either single or double bonds.
11 . The method of claim 10 , wherein the second anti-cancer agent is irinotecan.
12 . The method of claim 11 , wherein the cancer is a colon cancer.
13 . The method of claim 10 , wherein the second anti-cancer agent is taxotere.
14 . The method of claim 13 , wherein the cancer is a prostrate cancer.
15 . The method of claim 13 , wherein the cancer is a breast cancer.
16 . The method of claim 13 , wherein the cancer is a lung cancer.
17 . The method of claim 13 , wherein said compound is selected from the group consisting of: KPU-11, KPU-35, KPU-66, KPU-80, KPU-81, and KPU-90.
18 . The method of claim 13 , wherein said compound is KPU-2.