Naito T, Hoshi H, Aburaki S, Abe Y, Okumura J, Tomatsu K, Kawaguchi H
J Antibiot (Tokyo). 1987 Jul;40(7):991-1005. doi: 10.7164/antibiotics.40.991.
The synthesis and structure-activity relationships of 7-[D-alpha-amino-alpha-(4-hydroxyphenyl)-acetamido]-3-[(Z)-1-propenyl]- 3-cephem-4-carboxylic acid (BMY-28100) and its analogs in the 3- and 7-side chains are described. The 3-(substituted-propenyl) groups were introduced by the Wittig reaction of the 3-phosphoniomethyl cephems which were derived from the 3-chloromethyl derivatives. The reaction gave predominantly the cis isomer regarding the 3-side chain. The cis and trans isomers showed characteristic UV and 1H NMR spectra. Most of cephems of this series were well-absorbed orally and more active both in vitro and in vivo than cephalexin and cefaclor against Gram-positive organisms. Their Gram-negative activity varied depending on the 3- and 7-substituents. Compounds with a cis-propenyl group showed the best Gram-negative activity among the 3-alkenyl analogs prepared, whereas the D-4-hydroxyphenylglycyl and D-4-hydroxy-3-methoxyphenylglycyl substitutions in the 7-side chain were found suitable to improve the Gram-negative activity of 3-cis-propenyl series of cephalosporins to the level favorably compared with that of cefaclor. The 3,4-dihydroxyphenyl analog was found to be metabolized in vivo to the 4-hydroxy-3-methoxyphenyl derivative and, therefore, showed nearly the same in vivo activity as that of the latter. BMY-28100 was selected for further evaluation and the results will be reported in the subsequent paper.
描述了7 - [D-α-氨基-α-(4-羟基苯基)-乙酰胺基]-3-[(Z)-1-丙烯基]-3-头孢烯-4-羧酸（BMY-28100）及其3位和7位侧链类似物的合成及构效关系。3-(取代丙烯基)基团是通过由3-氯甲基衍生物衍生而来的3-膦酰甲基头孢烯的维蒂希反应引入的。该反应主要生成3位侧链的顺式异构体。顺式和反式异构体显示出特征性的紫外光谱和¹H核磁共振谱。该系列的大多数头孢烯口服吸收良好，并且在体外和体内对革兰氏阳性菌的活性均比头孢氨苄和头孢克洛更强。它们对革兰氏阴性菌的活性因3位和7位取代基而异。在制备的3-烯基类似物中，具有顺式丙烯基的化合物显示出最佳的革兰氏阴性菌活性，而在7位侧链中发现D-4-羟基苯甘氨酰和D-4-羟基-3-甲氧基苯甘氨酰取代适合将3-顺式丙烯基系列头孢菌素的革兰氏阴性菌活性提高到与头孢克洛相当的水平。发现3,4-二羟基苯基类似物在体内代谢为4-羟基-3-甲氧基苯基衍生物，因此其体内活性与后者几乎相同。选择BMY-28100进行进一步评估，结果将在后续论文中报道。
