Kondo Shin-ichi, Sasai Yasushi, Kuzuya Masayuki, Furukawa Shoei
Laboratory of Pharmaceutical Physical Chemistry, Gifu Pharmaceutical University, Japan.
Chem Pharm Bull (Tokyo). 2002 Nov;50(11):1434-8. doi: 10.1248/cpb.50.1434.
In this study we synthesized the water-soluble polymeric prodrugs possessing a 4-methylcatechol (4MC) derivative as a side chain by mechanochemical solid-state copolymerization. 1-benzoyl-4-methylcatechol (Bz4MC) was selected as a model compound of 4MC, and its methacryloyl derivative (1) was synthesized. 6-O-methacryloyl-D-galactose (2) was also prepared as a water-soluble monomer. The mechanochemical solid-state copolymerization of 1 and 2 was carried out to obtain the water-soluble polymeric prodrug possessing the Bz4MC as a side chain. The mechanochemical copolymerization of 1 and 2 proceeded to completion, and the polymeric prodrug produced possessed a narrow molecular weight distribution. Three kinds of polymeric prodrugs, whose compositions were different from one another, were hydrolyzed in vitro. The hydrolysis of these polymeric prodrugs proceeded to completion. The rate constants of hydrolysis decreased with increasing the mole fraction of 1 in polymeric prodrug. It was suggested that the rate constant of hydrolysis could be controlled by the composition, the mole fraction of 1 in the polymeric prodrug.
在本研究中，我们通过机械化学固态共聚合成了具有4-甲基邻苯二酚（4MC）衍生物作为侧链的水溶性聚合物前药。选择1-苯甲酰基-4-甲基邻苯二酚（Bz4MC）作为4MC的模型化合物，并合成了其甲基丙烯酰基衍生物（1）。还制备了6-O-甲基丙烯酰基-D-半乳糖（2）作为水溶性单体。进行1和2的机械化学固态共聚以获得具有Bz4MC作为侧链的水溶性聚合物前药。1和2的机械化学共聚反应进行完全，所制备的聚合物前药具有窄的分子量分布。三种组成彼此不同的聚合物前药在体外进行了水解。这些聚合物前药的水解反应进行完全。水解速率常数随着聚合物前药中1的摩尔分数增加而降低。表明水解速率常数可通过聚合物前药的组成、1的摩尔分数来控制。
