Guo J, Wu Y Q, Rattendi D, Bacchi C J, Woster P M
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202.
J Med Chem. 1995 May 12;38(10):1770-7. doi: 10.1021/jm00010a021.
The S-adenosylmethionine (AdoMet) analogue S-(5'-deoxy-5'-adenosyl)-1-aminoxy-4-(methylsulfonio)-2-cycl opentene (AdoMao) was synthesized in two of its four possible diastereomeric forms using a facile chemoenzymatic route. The trans-1R,4R- and trans-1S,4S-diastereomers of AdoMao, as well as the corresponding diastereomers of the unmethylated precursor molecule nor-AdoMao, were then evaluated as inhibitors of S-adenosylmethionine decarboxylase (AdoMet-DC) from both bacterial and human sources. All four of the analogues acted as time-dependent, irreversible inhibitors of AdoMet-DC from Escherichia coli, exhibiting remarkably constant Ki values ranging between 20.6 and 23.7 microM. These analogues also inhibited the human form of AdoMet-DC, although this form of the enzyme was able to discriminate between AdoMao (Ki values of 21.2 microM for the trans-1R,4R form and 19.6 microM for the trans-1S,4S form) and nor AdoMao (Ki values of 95.2 microM for the trans-1R,4R form and 30.9 microM for the trans-1S,4S form). The trans diastereomers of AdoMao and nor-AdoMao were next evaluated for their ability to inhibit trypanosomal growth in vitro against cultured Trypanosoma brucei brucei bloodforms. All four of these analogues were effective growth inhibitors, with IC50 values ranging between 0.9 and 10.1 microM. The two most effective analogues, trans-1S,4S-AdoMao (IC50 0.9 microM) and trans-1S,4S-AdoMao (IC50 3.0 microM) were also effective against two clinical isolates of the pathogenic organism Trypanosoma brucei rhodesiense, KETRI 243 and KETRI 269. The most promising analogue in all respects was trans-1S,4S-AdoMao, which was subsequently found to have minimal effects on cell growth, AdoMet-DC activity, and intracellular polyamine levels in the sensitive human promyelocytic leukemia cell line HL60. Thus, the S-adenosylmethionine analogue trans-1S,4S-AdoMao acts as an effective inhibitor of AdoMet-DC and appears to serve as a parasite-specific trypanocidal agent in vitro.
使用简便的化学酶促路线合成了S-腺苷甲硫氨酸（AdoMet）类似物S-(5'-脱氧-5'-腺苷基)-1-氨基氧基-4-(甲基硫代)-2-环戊烯（AdoMao）的四种可能非对映异构体形式中的两种。然后评估了AdoMao的反式-1R,4R-和反式-1S,4S-非对映异构体，以及未甲基化前体分子去甲-AdoMao的相应非对映异构体，作为来自细菌和人类来源的S-腺苷甲硫氨酸脱羧酶（AdoMet-DC）的抑制剂。所有四种类似物均作为大肠杆菌AdoMet-DC的时间依赖性不可逆抑制剂，表现出非常恒定的Ki值，范围在20.6至23.7微摩尔之间。这些类似物也抑制人源形式的AdoMet-DC，尽管这种酶能够区分AdoMao（反式-1R,4R形式的Ki值为21.2微摩尔，反式-1S,4S形式的Ki值为19.6微摩尔）和去甲-AdoMao（反式-1R,4R形式的Ki值为95.2微摩尔，反式-1S,4S形式的Ki值为30.9微摩尔）。接下来评估了AdoMao和去甲-AdoMao的反式非对映异构体对体外培养的布氏布氏锥虫血鞭毛体抑制锥虫生长的能力。所有这四种类似物都是有效的生长抑制剂，IC50值范围在0.9至10.1微摩尔之间。两种最有效的类似物，反式-1S,4S-AdoMao（IC50为0.9微摩尔）和反式-1S,4S-AdoMao（IC50为3.0微摩尔）对致病生物罗德西亚锥虫的两种临床分离株KETRI 243和KETRI 269也有效。在所有方面最有前景的类似物是反式-1S,4S-AdoMao，随后发现它对敏感的人早幼粒细胞白血病细胞系HL60中的细胞生长、AdoMet-DC活性和细胞内多胺水平影响最小。因此，S-腺苷甲硫氨酸类似物反式-1S,4S-AdoMao作为AdoMet-DC的有效抑制剂，并且在体外似乎作为一种寄生虫特异性杀锥虫剂。
