Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof

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
• R1 and R6 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 C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R7, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R7, 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R4 is a tert-butyl group;
• R7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C1-C24 alkyl, unsaturated C1-C24 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R1′ and R1″ 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 C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R7, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R7, 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R, R1′ and R1″ are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 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 C1-C12 alkyl, unsaturated C1-C12 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• X1 and X2 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 R5 group, as defined above;
• Y is selected from the group consisting of a nitrogen atom substituted with R5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R5;
• n is an integer equal to zero, one or two;
• Z, for each separate n, if non-zero, and Z1, Z2, Z3 and Z4 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.

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
• R1 and R6 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 C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R7, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R7, 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R4 is a tert-butyl group;
• R7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C1-C24 alkyl, unsaturated C1-C24 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R1′ and R1″ 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 C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R7, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R7, 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R, R1′ and R1″ are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 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 C1-C12 alkyl, unsaturated C1-C12 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• X1 and X2 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 R5 group, as defined above;
• Y is selected from the group consisting of a nitrogen atom substituted with R5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R5;
• n is an integer equal to zero, one or two;
• Z, for each separate n, if non-zero, and Z1, Z2, Z3 and Z4 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.

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
• R1 and R6 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 C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R7, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CCO—R7, 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R4 is a tert-butyl group;
• R7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C1-C24 alkyl, unsaturated C1-C24 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R1′ and R1″ 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 C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, —CO—O—R7, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CCO—R7, 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• R, R1′ and R1″ are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 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 C1-C12 alkyl, unsaturated C1-C12 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, —SO2-alkyl, —SO2-aryl, and —SO2-heteroaryl;
• X1 and X2 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 R5 group, as defined above;
• Y is selected from the group consisting of a nitrogen atom substituted with R5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, and a methylene group substituted with one or more R5;
• n is an integer equal to zero, one or two;
• Z, for each separate n, if non-zero, and Z1, Z2, Z3 and Z4 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.