Oxidation of dextrans

Detailed studies of the periodate oxidation of dextran and inulin (4-6) have shown evidence for the occurrence of hemiacetal structures formed by reaction of aldehydes with hydroxyl groups of either the same unit (intra-residual) or a neighbouring unit (inter-residual). Inter-residual hemiacetal formation reduces the number of diol struc-... 

Oxo derivatives of dextrans result from the oxidation of dextran or dex-tran 2,4-benzeneboronate with methyl sulfoxide-acetic anhydride. " ... 

M. F. Ishak and T. J. Painter, Kinetic evidence for hemiacetal formation during the oxidation of dextran in aqueous periodate, Carbohydr. Res., 64 (1978) 189-197. 

More recently, camptothecin (CPT) was conjugated to poly(l-hydroxymethylethylene hydroxymethylformyl) (PHF or Eleximer ) and the conjugate 11 (XMT-1001) is currently in clinical development [72,73]. The polyacetal is derived from the exhaustive oxidation of dextran [74]. CPT is poorly soluble and prone to rapid inactivation through lactone ring hydrolysis in vivo [75]. As a cytotoxic compound, CPT has been used in many efforts to develop other CPT-polymer conjugates [45,76,77]. The sodium salt of CPT has also been examined in phase I trials, but only modest responses were observed while severe toxicities remain. 

Kinetic evidence for hemiacetal formation during the oxidation of dextran by aqueous sodium periodate has been interpreted in terms of intra-residual hemiacetal formation by singly oxidized residues, and inter-residual hemiacetal formation between doubly oxidized residues and intact adjacent d-glucose residues. ... 

Figure 2. Influence of branching on the periodate oxidation of dextran.

Periodate activation. Partial periodate oxidation of dextran leads to the formation of aldehydes that are suitable for chemical coupling with the drug of interest. The concentration of aldehyde functions in oxidized dextran (D-CHO) was determined from the iodine numberThe results obtained for varying amounts of periodate are summarized in table 2. 

Table 2. Partial oxidation of dextran with sodium periodate.

Oxidation of dextran with periodate gave the dialdehydo-derivative, which was used to label antibodies for examination by electron microscopy. Covalent linkages were formed when dialdehydodextran reacted with a solution of rabbit immunoglobulin IgG anti-(human type-0) antibodies and with rabbit anti-(human type-0) red-blood cells. 

The presence of three hydroxyl groups per glucose unit was shown by the preparation of a triacetate and a tribenzoate. Six or seven methyla-tions (using dimethyl sulfate and concentrated alkali) of dextran did not raise the methoxyl content above 41% (theoretical maximum 45.6%). Also, Purdie methylations (using methyl iodide and silver oxide) and methylation with thallium ethoxide and methyl iodide were ineffective in raising the methoxyl content of methylated dextran above 43.5%. The maximum theoretical methoxyl content was eventually attained by modified Muskat methylations. 6 Partially methylated dextran suspended in anisole solution was treated with sodium in liquid ammonia, and the sodium salt of methylated dextran thus formed was allowed to react with methyl iodide. The methoxyl content of the partially methylated dextran was raised by three such methylations from 42% to 45.5% and by five such methylations from 30% to 45.4%. 

The linear dextran has also been used in investigating the mechanism of the periodate oxidation of polysaccharides. The results support the proposal that inter-residue, hemiacetal formation is a general occurrence in the later stages of the oxidation.128... 

The two polymers most often used in these applications are dextran and PEG. Both polymers consist of repeating units of a single monomer—glucose in the case of dextran and an ethylene oxide basic unit in the case of PEG. The polymers may be composed of linear strands (PEG or dextran) or branched constructs (dextran). An additional similarity is that both of them possess hydroxyl and ether linkages, lending hydrophilicity and water solubility to the molecules. Dextran and PEG can be activated through their hydroxyl groups by a number of chemical methods to allow... 

Hydrazide derivatives of dextran also may be prepared from the periodate-oxidized polymer or from a carboxyl derivative by reaction with fcfs-hydrazide compounds (Chapter 4, Section 8). A hydrazide terminal spacer provides reactivity toward al-... 

Preliminary examinations of dextran structures were conducted by optical rotation, infrared spectroscopy and periodate-oxidation reactions. More detailed results can be achieved by methylation analysis [19]. The hydroxyl groups are methylated with methyl iodide after activation with sodium methylsulfinyl carbanion (Fig. 2). The methyl dextran is hydrolysed to the corresponding different methylated monosaccharides, which are furthermore reduced and peracetylated. The resulting alditol acetates of methylated sugars are separated by gas chromatography and identified by their retention times. In particular, a combined capillary gas-liquid chromatography/mass... 

These reagents have a number of drawbacks. First of all, they are toxic especially via contact with skin. The LD50 (dermal, rat) of DCC is 71 mg kg. This should always be considered if the reaction is used for the preparation of materials for biological applications. Moreover, the N.N -dialkylurea formed during the reaction is hard to remove from the polymer except for preparation in DMF and DMSO, where it can be filtered off. In case of esterification of polysaccharides in DMSO in the presence of these reagents, oxidation of hydroxyl functions may occur due to a Moffatt type reaction (Fig. 25, [188]). The oxidation products formed can be detected with the aid of 2,4-dinitrophenylhydrazine, e.g. in case of the conversion of dextran with DCC in DMSO [189],... 

---