Synthesis And Performance Of Novel β-cyclodextrin Derivatives

It has attracted significant interest of research to construct artificial enzymes, molecule recognition sensors and other functional models utilizing the cone-shaped cyclodextrins (CDs, includingα,β,γ-CD etc), which process a hydrophobic cavity and a hydrophilic outside. As a multi-functional molecule,β-CD was proved to be a useful auxiliary in agriculture, industry and pharmacy. However, the inherent defects of naturalβ-CD restrict its practical applications. For instance,β-CD lacks the chromophores or auxochromes in UV-inertness, which limits the application of UV-Fluorescence analysis to its supramolecular activities (Host-Guest interaction). Moreover, poor water-solubility and deficiency of active functional groups restrict its bioavailability and molecular recognition ability. In the past 10 years, it has showed great progress that cyclodextrins and their derivatives were used as chiral selectors for the separation of the enantiomers of drugs by capillary electrophoresis (CE). The separation mechanics was that the enantiomers of drugs could selectively enter the hydrophobic cavity of cyclodextrins to form Host-Guest complexes according to the chiral internal environment of cyclodextrins, and then achieve resolution via the increment of difference of the electrophoretic migration velocity. The previous scientists have developed a series of cyclodextrin derivatives, neutral, cationic, anionic, amphoteric, asymmetrical di-modified cyclodextrins and binary cyclodextrin systems. In addition, amphiphilic cyclodextrins could form the supermolecular assemblage such as monolayers, multilayers, capsule and vesicles in specific system based on their special structures. The self-assembly of amphiphilic cyclodextrins has been changed into the important method to construct the nano supermolecular system, which has manifested the potential application in the field of material, medicine and biology.The focus of our research was directed to the chemical-selective modification ofβ-CD, aiming to produce novel enzyme-like functional molecules with enhanced properties. The content of the paper was showed as follows:1. Hydroxybutyl-β-cyclodextrin (HB-β-CD): preparation and its application for the separation of enantiomers of drugs by capillary electrophoresisSix different degree of substitution and substituent position of neutral hydroxybutyl-β-cyclodextrin were prepared, and the hydroxybutyl group was first introduced to the C-2 and C-6 of theβ-cyclodextrin. When 2-HB-β-CD (DS～3.0) was used as chiral selector in CE, it was found that the enantiomers of Ketoconazole, Promethazine, Anisodamine, Chlorphenamine, Propranolol, Adrenaline, Ethambutol, Benzhexol and Fenfluramine could be separated effectively. Results showed that 2-HB-β-CD (DS～3.0) could provide higher separating capability than that ofβ-cyclodextrin (β-CD), 2-O-(2-hydroxypropyl)-β-cyclodextrin (2-HP-β-CD DS～4.0), 2-O-(2-hydroxybutyl)-β-cyclodextrin (2-HB-β-CD DS～4.0), 6-O-(2-hydroxy)-β-cyclode-xtrin (6-HB-β-CD DS～3.0) and 6-O-(2-hydroxybutyl)-β-cyclodextrin (6-HB-β-CD DS～4.0), which testify 2-HB-β-CD (DS～3.0) was a better chiral selector. The enanti-oselectivity for the enantiomers of Ketoconazole, Promethazine, Anisodamine, Chlorphenamine, Propranolol, Adrenaline in CE was also influenced by the degree of substitution of 2-HB-β-CD. The chiral selectivity of 2-HB-β-CD (DS～3.0) with low degree of substitution about 3.0 was more sensitive than that of 2-HB-β-CD (DS～4.0) with relatively high degree of substitution about 4.0. This might be related to more complication of the interior chiral environment of 2-HB-β-CD with relatively high degree of substitution than that with low degree of substitution. In addition, the enantiomers of Ketoconazole, Promethazine, Anisodamine, Chlorphenamine, Propranolol, Adrenaline, Benzhexol and Warfarin were even showed no separation information when using 6-HB-β-CD (DS～3.0) and 6-HB-β-CD (DS～4.0) as the chiral selector, which testify 6-HB-β-CD (DS～3.0) and 6-HB-β-CD (DS～4.0) was not a satisfied chiral selector for the above drugs.2. Cationicβ-cyclodextrin derivative, 6-O-(hydroxypropyltrimethylammonia)-β-cy-clodextrin and 6-O-(hydroxypropyltriethylammonia)-β-cyclodextrin with low degree of substitution: convenient preparation and its application as a chiral selector in capillary electrophoresisA cationic cyclodextrin derivative 6-O-(hydroxypropyltrimethylammonia)-β-cyclod-extrin (6-O-HPTMA-β-CD, Avg. DS～1.5) with low degree of substitution was prepared through a convenient method in solid phase. The product could be used as a valuable chiral selector in the capillary electrophoresis (CE) separation of some acidic drug enanttom- ers such as Naproxen, Ofloxacin, Ibuprofen and Warfarin. Results showed that 6-O-HPT-MA-β-CD could provide higher separating capability than that ofβ-cyclodextrin (β-CD), 2-O-(2-hydroxypropyl)-β-cyclodextrin (2-HP-β-CD DS～4.0), and 6-O-HP-T MA-β-CD (DS GT～3.5) with high degree of substitution, which testify 6-O-HPTMA-β-CD was a valuable chiral selector.6-O-(hydroxypropyltriethylammonia)-β-cyclodextrin could be used as chiral selector in the capillary electrophoresis (CE) separation of the enantiomers such as Anisodamine, Propranolol, Ibuprofen and Maleic acid. The enantioselectivity for the above drugs in CE was influenced by the buffer pH and the concentration of 6-O-HPTEA-β-CD. In addition, the electrolyte solution effect on the resolution was also discussed for the separation of Naproxen, Ofloxacin, Ibuprofen and Warfarin.3. Di-functional group modified cyclodextrin deivatives: synthesis and its application as a chiral selector in capillary electrophoresisEleven water soluble di-functional group modified and two carboxylalkyl cyclodextrin deivatives were synthesized via the control of reaction conditions: 6-O-(2'-hydroxypropyltrimethylammonia)-2-O-(2"-hydroxypropyl)-β-cyclodextrin(6-O-HPTMA-2-OHP-β-CD),6-O-(2'-hydroxypropyltrimethyIammonia)-2-O-(2"-hydroxybutyl)-β-cycl-odextrin(6-O-HPTMA-2-O-HB-β-CD), 6-O-(carboxylmethyl)-2-O-(2-hydroxypropyltri methylammonia)-β-cycIodextrin(6-O-CM-2-O-HPTMA-β-CD), 6-O-(α-methylcarboxy-lmethyl)-2-O-(2-hydroxypropyltriethylammonia)-β-cyclodextrin(6-O-MCM-2-O-HPTEA -β-CD), 6-O-(2'-hydroxybutyl)-2-O-(2"-hydroxypropyltrimethyIammonia)-β-cyclodextr in(6-O-HB-2-O-HPTMA-β-CD),6-O-(2-hydroxypropyltrimethylammonia)-2-O-methyl-β-cyclodextrin(6-O-HPTMA-2-O-Me-β-CD),6-O-(2-hydroxypropyltriethylammonia)-2-O-methyl-β-cycIodextrin(6-O-HPTEA-2-O-Me-β-CD),6-O-(5-sulfobutyl)-2-O-(2-hydro-xypropyltrimethylammonia)-β-cyclodextrin(6-O-SBE-2-O-HPTMA-β-CD),6-O-(5-sulf-obutyl)-2-O-(2-hydoxypropyltriethylammonia)-β-cycIodextrin(6-O-SBE-2-O-HPTEA-β-CD), 6-O-(2'-hydroxypropyl)-2-O-(2"-hydroxypropyltrimethylammonia)-β-cyclodextrin (6-O-HP-2-O-HPTMA-β-CD),6-O-(2'-hydropropyl)-2-O-(2"-hydroxypropyltriethylam-monia)-β-cyclodextrin (6-O-HP-2-O-HPTEA-β-CD) and 6-O-(α-methylcarboxylmethyl)-β-cyclodextrin (6-MCM-β-CD). The aboveβ-cyclodextrin derivatives are ail novel compound including 4 amphotericβ-cyclodextrin derivatives, which can be used as drug carries, potential chiral selector, molecular recognition. In addition, the enantiomers of Naproxen, Ofloxacin, Ibuprofen and Warfarin were showed satisfied separation information when using 6-O-HPTMA-2-O-HP-β-CD and 6-O-HPTMA-2-O-Me-β-CD as the chiral selector. This might be related to the structure complexity and high degree of substitution of cyclodextrin, which change the chiral internal environment of cyclodextrin to more complexity.4. Synthesis novel amphiphilic cyclodextrin deivatives and their capsuleTwelve amphiphilic cyclodextrin deivatives were synthesized via the control of reaction conditions: 6-O-(lauryloxy-2-hydroxypropyl)-2-O-(2-hydroxypropyl)-β-cyclod-extrin (6-O-12C-HP-2-O-HP-β-CD), 6-O-(tetradecyloxy-2-hydroxypropyl)-2-O-(2-hydr-oxypropyl)-β-cyclodextrin(6-O-14C-HP-2-O-HP-β-CD), 6-O-(hexadecyloxy-2-hydroxy-propyl)-2-O-(2-hydroxypropyl)-β-cyclodextrin (6-O-16C-HP-2-O-HP-β-CD),6-O-(octad-ececyloxy-2-hydroxypropyl)-2-O-(2-hydroxypropyl)-β-cyclodextrin(6-O-18C-HP-2-O-H P-β-CD), 6-O-(lauryloxy-2-hydroxypropyl)-2-O-(2-hydroxybutyl)-β-cyclodextrin(6-O-12 C-HP-2-O-HB-β-CD), 6-O-(tetradecyloxy-2-hydroxypropyl)-2-O-(2-hydroxybutyl)-β-C-yclodextrin (6-O-14C -HP-2-O-HB-β-CD), 6-O-(hexadecyloxy-2-hydroxypropyl)-2-O-( 2-hydroxybutyl)-β-cyclodextrin(6-O-16C-HP-2-O-HB-β-CD),6-O-(octadecyloxy-2-hyd-roxypropyl)-2-O-(2-hydroxybutyl)-β-cyclodextrin(6-O-18C-HP-2-O-HB-β-CD),6-O-(lau ryloxy-2-hydroxypropyl)-2-O-(methyl)-β-cyclodextrin(6-O-12C-HP-2-O-Me-β-CD),6-O-(tetradecyloxy-2-hydroxypropyl)-2-O-(methyl)-β-cyclodextrin(6-O-14C-HP-2-O-Me-β-CD),6-O-(hexadecyloxy-2-hydroxypropyl)-2-O-(methyl)-β-cyclodextrin(6-O-16C -HP-2-O-Me-β-CD), 6-O-(octadecyloxy-2-hydroxypropyl)-2-O-(methyl)-β-cyclodextrin(6-O-18C-HP-2-O-Me-β-CD). In addition, the above novel amphiphilic cyclodextrin deivatives could be dispersed in water to form capsule. Results showed that the capsule made by 6-O-12C-HP-2-O-HB-β-CD and 6-O-14C-HP-2-O-HB-β-CD provide better dispersion degree and uniformity, while 6-O-12C-HP-2-O-Me-β-CD showed no formation of capsule, which might be related to the difference of molecular structure of the amphiphilic cyclodextrin deivatives.Main innovations of the paper: (1) Six different degree of substitution and substituent position of neutral hydroxybutyl-β-cyclodextrin were prepared, and the hydroxybutyl group was first introduced to the C-2 and C-6 of theβ-cyclodextrin, 2-HB-β-CD (Avg. DS～1.0 2),2-HB-β-CD (Avg. DS ~ 3.03),2-HB-β-CD (Avg. DS～4.0 4), 6-HB-β-CD (Avg. DS ~1.0 5), 6-HB-β-CD (Avg. DS ~ 2.82 6) and 6-HB-β-CD (Avg. DS ~ 4.76 7).(2) When 2-HB-β-CD (DS～3.0) was first used as chiral selector in capillary electrophoresis, it was found that the enantiomers of Ketoconazole, Promethazine, Anisodamine, Chlorphenamine, Propranolol, Adrenaline, Ethambutol, Benzhexol and Fenfluramine could be separated effectively. Results showed that 2-HB-β-CD (DS～3.0) could provide higher separating capability than that ofβ-cyclodextrin (β-CD), 2-O-(2-hydroxypropyl)-β-cyclodextrin (2-HP-β-CD DS-4.0), 2-O-(2-hydroxybutyl)-β-Cyclodextrin (2-HB-β-CDDS~4.0), 6-O-(2-hydroxybutyl)-β-cyclodextrin (6-HB-β-CD DS～2.82) and 6-O-(2-hydroxybutyl)-β-cyclodextrin (6-HB-β-CD DS～4.76), which testify 2-HB-β-CD (DS～3.0) was a better chiral selector.(3) The enantioselectivity for the enantiomers of chiral drugs in CE was also influenced by the degree of substitution of 2-HB-β-CD. The chiral selectivity of 2-HB-β-CD (DS～3.0) with low degree of substitution about 3.0 was more sensitive than that of 2-HB-β-CD (DS～4.0) with relatively high degree of substitution about 4.0. This might be related to more complication of the interior chiral environment of 2-HB-β-CD with relatively high degree of substitution than that with low degree of substitution(4) When 6-HB-β-CD (DS～2.82 and~4.76) was first used as chiral selector in capillary electrophoresis, it was found that the enantiomers of Ketoconazole, Promethazine, Anisodamine, Chlorphenamine, Propranolol, Adrenaline, Benzhexol, Ibuprofen, Warfarin and Maleic acid were even showed no separation information, which testify 6-HB-β-CD (DS～2.82) and 6-HB-β-CD (DS～4.76) was not a satisfied chiral selector for the above drugs.(5) Two cationic cyclodextrin derivative 6-O-(hydroxypropyltrimethylammonia) -β-cyclodextrin (6-O-HPTMA-β-CD DS-1.5) and 6-O-(hydroxypropyltriethylammonia)-β-cyclodextrin(6-O-HPTEA-β-CD DS～2.35) with low degree of substitution were prepared through a convenient method in solid phase, which inhibited the by-products and give high productivity.(6) 6-O-HPTMA-β-CD could be used as a valuable chiral selector in the capillary electrophoresis (CE) separation of some acidic drug enantiomers such as Naproxen, Ofloxacin, Ibuprofen and Warfarin. Results showed that 6-O-HPTMA-β-CD could provide higher separating capability than that ofβ-CD, 2-HP-β-CD( DS ~4.0), and 6-O-HPTMA-β-CD (DS GT～3.5) with high degree of substitution, which testify 6-O-HPTMA-β-CD was a valuable chiral selector.(7) 6-O-(hydroxypropyltriethylammonia)-β-cyclodextrin could be used as chiral selector in the capillary electrophoresis (CE) separation of the enantiomers such as Anisodamine, Propranolol, Ibuprofen and Maleic acid. The enantioselectivity for the above drugs in CE was influenced by the buffer pH and the concentration of 6-O-HPTEA-β-CD. In addition, the electrolyte solution effect on the resolution was also discussed for the separation of Naproxen, Ofloxacin, Ibuprofen and Warfarin.(8) Eleven water soluble di-functional group modified and two carboxylalkyl cyclodextrin deivatives were devised and synthesized via the control of reaction conditions, including four amphotericβ-cyclodextrin derivatives. the enantiomers of Naproxen, Ofloxacin, Ibuprofen and Warfarin were showed satisfied separation information when using 6-O-HPTMA-2-O-HP-β-CD and 6-O-HPTMA-2-O-Me-β-CD as the chiral selector. This might be related to the structure complexity and high degree of substitution of cyclodextrins, which change the chiral internal environment of cyclodextrin to more complexity.(9) Twelve amphiphilic cyclodextrin deivatives were devised and synthesized via the reaction of 2-O-HP-β-CD, 2-O-HB-β-CD, 2-O-Me-β-CD and long chain alkyl glycidol ether. The above novel amphiphilic cyclodextrin deivatives could be dispersed in water to form capsule. Results showed that the capsule made by 6-O-12C-HP-2-O-HB-β-CD and 6-O-14C-HP-2-O-HB-β-CD provide better dispersion degree and uniformity, while 6-O-12C-HP-2-O-Me-β-CD showed no formation of capsule, which might be related to the difference of molecular structure of the amphiphilic cyclodextrin deivatives.