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 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 seperately 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 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, and phenyl 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 4 is a tert-butyl group;
R 1 ′ and R 1 ″ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or indepently 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 seperately 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 and substituted 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, a nitrogen atom substituted with R 5 , an oxygen atom, a sulfur atom, a oxidized sulfur atom, a methylene group and a substituted 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 compound of claim 1 , wherein each of R 2 , R 3 , R 5 and R 6 is a hydrogen atom.
3. The compound of claim 1 , wherein each of X 1 and X 2 is an oxygen atom.
4. The compound of to claim 1 , wherein R 1 is a phenyl group 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.
5. The compound of claim 4 , wherein the substituted phenyl group is methoxybenzene.
6. The compound according to claim 1 , wherein n is equal to zero or one.
7. The compound according to claim 1 , wherein n is equal to one.
8. The compound according to claim 1 , wherein n is equal to one and Z, Z 1 , Z 2 , Z 3 and Z 4 are each a carbon atom.
9. The compound of claim 1 , wherein said compound is selected from the group consisting of: KPU-2, KPU-11, KPU-35, KPU-66, KPU-80, KPU-81, and KPU-90.