Baumann H, Faust V
ITMC, Macromolecular Chemistry and Textile Chemistry, Hemocompatible and Biocompatible Biomaterials, University of Technology Aachen, Germany.
Carbohydr Res. 2001 Mar 9;331(1):43-57. doi: 10.1016/s0008-6215(01)00009-x.
In the present paper a new strategy has been studied to introduce solely or in combination N-sulfo, O-sulfo, N-acetyl, and N-carboxymethyl groups into chitosan with highest possible regioselectivity and completeness and defined distribution along the polymer chain. The aim was to generate compounds having lowest toxicity for determining the pharmacological structure function relationships among different backbone structures and differently arranged functional groups compared to those of heparin and heparan sulfate. The water-soluble starting material, chitosan, with a degree of acetylation (DA) of 0.14 and a molecular weight of 29 kD, allows one to apply most of the known reactions of chitosan as well as some reactions of heparin chemistry successfully and with improved regioselectivity and completeness. On the other hand, a number of these reactions were not successful by application to water-soluble high-molecular-weight chitosan (DA 0.45 and 150 kD). The starting material showed statistical N-acetyl (N-Ac) distribution along the polymer chain according to the rules of Bernoulli, with highest abundance of the GlcNAc-GlcNAc diad along with a lower abundance of triads, tetrads, and pentads. The space between the N-Ac groups was filled up in homogeneous reactions by N-sulfo and/or N-carboxymethyl groups, which also resulted in a Bernoulli statistical distribution. The N-substitution reaction showed highest regioselectivity and completeness with up to three combined different functional groups. The regioselectivity of the 3-O-sulfo groups was improved by regioselective 6-desulfation of nearly completely sulfated 3,6-di-O-sulfochitosan. By means of desulfation reactions, all of the possible intermediate sulfated products are possible. 6-O-Sulfo groups can also be introduced with highest regioselectivity and completeness, and a number of partially 6-desulfated products are possible.
在本论文中，研究了一种新策略，以尽可能高的区域选择性、完整性以及聚合物链上明确的分布，将N-磺基、O-磺基、N-乙酰基和N-羧甲基基团单独或组合引入壳聚糖中。目的是生成毒性最低的化合物，以便与肝素和硫酸乙酰肝素相比，确定不同主链结构和不同排列的官能团之间的药理结构-功能关系。水溶性起始原料壳聚糖，乙酰化度（DA）为0.14，分子量为29 kD，使得人们能够成功应用壳聚糖的大多数已知反应以及肝素化学的一些反应，并且具有更高的区域选择性和完整性。另一方面，将其中一些反应应用于水溶性高分子量壳聚糖（DA 0.45和150 kD）时并不成功。起始原料根据伯努利规则在聚合物链上呈现统计性的N-乙酰基（N-Ac）分布，GlcNAc-GlcNAc二联体的丰度最高，三联体、四联体和五联体的丰度较低。在均相反应中，N-磺基和/或N-羧甲基基团填充了N-Ac基团之间的空间，这也导致了伯努利统计分布。N-取代反应在引入多达三种不同官能团组合时表现出最高的区域选择性和完整性。通过对几乎完全硫酸化的3,6-二-O-磺基壳聚糖进行区域选择性6-脱硫酸反应，提高了3-O-磺基基团的区域选择性。通过脱硫酸反应，可以得到所有可能的中间硫酸化产物。6-O-磺基基团也可以以最高的区域选择性和完整性引入，并且可以得到许多部分6-脱硫酸的产物。
