US 6,271,384 B1 · Self-assembled taxo-diterpenoid nanostructures

Abstract

Onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes form water soluble self-assembling nanostructures above a critical aggregation concentration. The onium salt of aza-arene includes a delocalized charge which renders derivatized taxo-diterpenoids amphoteric, enhances their solubility in water, and promotes self-assembly of water soluble nanostructures, e.g., helical fibular structures and spherical micellular structures. These same onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes are employed as water soluble prodrugs. For example, taxol-2′-methylpyridinium tosylate (MPT) is characterized by an elevated aqueous solubility, rapid activation by serum protein, good stability in most other aqueous solutions, formation of a protein:taxol intermediate and good retention within the circulatory system. The toxicity of the activated form is comparable or greater than underivatized taxol. Furthermore, taxol-2′-MPT can be synthesized by a simple one step reaction between taxol and 2-fluoro-1-MPT. The invention is applicable to taxol and taxol memetics having hydroxyls that are reactive with onium salts of 2-halogenated-aza-arenes. For example, taxol, C-2 substituted taxol and Taxotere each have reactive hydroxyls at the 2′ and 7 positions. The invention is also applicable to a wide array of 2-halogenated-aza-arenes.

Claims32

Dependent claims

A water soluble self-assembled helical fibrous nanostructure having a diameter of 60-120 Å and a helical twist of 5-10 molecules per turn of an onium salt of a taxo-diterpenoid-2-O-aza-arene produced according to the following method:

Step A:
derivatizing a taxo-diterpenoid having a free hydroxyl with an onium salt of a 2-halogenated aza-arene for producing the taxo-diterpenoid-2-O-aza-arene;
Step B:
forming the water soluble self-assembled helical fibrous nanostructure of the onium salt of the taxo-diterpenoid-2-O-aza-arene by solubilizing the taxo-diteroenoid-2-O-aza-arene of said Step A within an aqueous solution and at concentration suitable for the formation of said water soluble self-assembled helical fibrous nanostructure.

1 more element

A self-assembled helical fibrous nanostructure having a diameter of 60-120 Å and a helical twist of 5-10 molecules per turn of an onium salt of a taxo-diterpenoid-Cn,2-O-aza-arene having an aqueous solubility in excees of 10−3 moles per liter, said onium salt of said taxo-diterpenoid-Cn,2-O-aza-arene represented by the following formula:

wherein:
Cn is selected from the group consisting of C7 and C2′;
Rx is selected from the group consisting of Ph and tBuO;
R10 is selected from the group consisting of OAc and OH;
and
Ry is C-2 substituent selected from the group consisting of benzyl and the following structures:
R2′ and R7 are each selected from the group consisting of OH and an onium salt of a 2-O-aza-arene, with the proviso that at least one of R2′ and R7 is said onium salt of the 2-O-aza-arene, said onium salt of the 2-O-ara-arene, consisting of onium salt I and onium salt II represented by the following formulas:
wherein:
Z1 and Z2 are each selected from the group consisting of C and N;
Z3 is selected from the group consisting of S and O;
R1 is selected from the group consisting of C1-C6 alkyl, allyl, arenxyl, propargyl, and fused aryl;
R2 and R6 are each selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, and fused aryl;
if Z1 is C, then R3 is selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, C1-C6 O-alkyl, OH, halogen, and fused aryl;
if Z1 is N, then R3 is absent;
R4 and R8 are each selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, C1-C6 O-alkyl, OH, halogen, and fused aryl;
and
if Z2 is C, then R5 is selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, C1-C6 O-alkyl, OH, halogen, and fused aryl;
if Z2 is N, then R5 is absent;
and
S− is a counter ion.

17 more elements

A self-assembled helical fibrous nanostructure having a spherical shape with a diameter of 20-120 Å and incorporating an onium salt of a taxo-diterpenoid-Cn,2-O-aza-arene having an aqueous solubility in excees of 10−3 moles per liter, said onium salt of said taxo-diterpenoid-Cn,2-O-aza-arene represented by the following formula:

wherein:
Cn is selected from the group consisting of C7 and C2′;
Rx is selected from the group consisting of Ph and tBuO;
R10 is selected from the group consisting of OAc and OH;
Ry is a C-2 substituent selected from the group consisting of benzyl and the following structures:
R2′ and R7 are each selected from the group consisting of OH and an onium salt of a 2-O-aza-arene, with the proviso that at least 2-O-aza-arene, said onium salt of the 2-O-aza-arene being selected from the group consisting of onium salt I and onium salt II represented by the following formulas:
wherein:
Z1 and Z2 are each selected from the group consisting of C and N;
Z3 is selected from the group consisting of S and O;
R1 is selected from the group consisting of C1-C6 alkyl, allyl, arenxyl, propargyl, and fused aryl;
R2 and R6 are each selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, and fused aryl;
if Z1 is C, then R3 is selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, C1-C6 O-alkyl, OH, halogen, and fused aryl;
if Z1 is N, then R3 is absent;
R4 and R8 are each selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, C1-C6 O-alkyl, OH, halogen, and fused aryl;
and
if Z2 is C, then R5 is selected from the group consisting of H, C1-C6 alkyl, allyl, arenxyl, propargyl, C1-C6 O-alkyl, OH, halogen, and fused aryl;
if Z2 is N, then R5 is absent;
and
S− is a counter ion.

16 more elements

Dependencies are inferred from the claim text.

Self-assembled taxo-diterpenoid nanostructures

Life of this patent

Self-assembled taxo-diterpenoid nanostructures

Life of this patent

Abstract

Claims32