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 for the synthetic preparation of 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 2 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, monohalogenated alkyl, polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CH 2 CO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, 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 2 -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, acylamino, 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 independently selected from the group consisting of saturated C 1 -C 24 alkyl, unsaturated C 2 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R 7 , alkylthio, monohalogenated alkyl, polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CH 9 CO—R 7 , each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, 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 , 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 2 -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, acylamino, 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 sulfur atom, or a nitrogen atom substituted with R 5 ;
Y is selected from the group consisting of (i) a nitrogen atom substituted with R 5 , (ii) an oxygen atom, (iii) a sulfur atom, (iv) an oxidized sulfur atom, and (v) 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;
said method comprising:
reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate; and
reacting said intermediate with a benzaldehyde to produce said compound.
2. The method according to claim 1 , wherein each of R 2 , R 3 , R 5 and R 6 is a hydrogen atom.
3. The method according to claim 1 , wherein each of X 1 and X 2 is an oxygen atom.
4. The method according to claim 1 , wherein R 1 comprises a substituted phenyl.
5. The method according to claim 4 , wherein said substituted phenyl group is methoxybenzene.
6. The method according to claim 1 , wherein n is equal to zero or one.
7. The method according to claim 1 , wherein n is equal to one.
8. The method 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 method of claim 1 , wherein Y is a nitrogen atom substituted with hydrogen.
10. The method of claim 1 , wherein said intermediate has the structure:
11. The method of claim 1 , wherein said imidazolecarboxaldehyde has the structure:
12. The method of claim 1 , wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in the presence of a cesium salt.
13. The method of claim 1 , wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in the presence of cesium carbonate.
14. The method of claim 1 , wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in a deoxygenated atmosphere.
15. The method of claim 1 , wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in the presence of dimethylformamide (DMF).
16. The method of claim 1 , wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed at room temperature.
17. The method of claim 1 , wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in the presence of a cesium salt.
18. The method of claim 1 , wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in the presence of cesium carbonate.
19. The method of claim 1 , wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in a deoxygenated atmosphere.
20. The method of claim 1 , wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in the presence of DMF.
21. The method of claim 1 , wherein reacting said intermediate with a benzaldehyde to produce said compound is performed at 80° C.