INHIBITORY EFFECTS OF TRIPHOSPHATE DERIVATIVES OF OXETANOCIN-G AND RELATED-COMPOUNDS ON EUKARYOTIC AND VIRAL-DNA POLYMERASES AND HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE-TRANSCRIPTASE
INHIBITORY EFFECTS OF TRIPHOSPHATE DERIVATIVES OF OXETANOCIN-G AND RELATED-COMPOUNDS ON EUKARYOTIC AND VIRAL-DNA POLYMERASES AND HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE-TRANSCRIPTASE
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DOI：
10.1093/oxfordjournals.jbchem.a123870
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发表时间：
1992-07-01
影响因子：
2.7
通讯作者：
YOSHIDA, S
中科院分区：
文献类型：
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作者：
IZUTA, S;SHIMADA, N;YOSHIDA, S
为了阐明(-)-氧化苦参素G和(-)-氧化苦参素A及其碳环类似物(-)-羧酸菌素G的生物活性，考察了它们的三磷酸衍生物(OXT-GTP、OXT-ATP和C-OXT-GTP)对真核生物和病毒DNA聚合酶的抑制作用。从小牛胸腺中提纯的DNA聚合酶-α可被oxt-GTP和oxt-ATP弱抑制，而被C-oxt-GTP强烈抑制，K(I)值为0.22-mU·M。另一方面，大鼠DNA聚合酶-β不受这些类似物的影响。从牛睾丸中提纯的DNA聚合酶-γ对oxt-GTP和oxt-ATP的抑制作用很弱，而对C-oxt-GTP的抑制作用不明显。3个类似物对单纯疱疹病毒II型DNA聚合酶均有较强的抑制作用，K(I)值在0.5~1.0-mU-M之间。这三个类似物对人类免疫缺陷病毒编码的逆转录酶(HIV RT)也有很强的抑制作用，C-oxt-GTP的K(I)值略小于oxt-GTP或oxt-ATP。DNA聚合酶-α、单纯疱疹病毒II型DNA聚合酶或HIV RT对单链M13单链DNA合成产物的分析表明，oxt-GTP和C-oxt-GTP被掺入DNA中，并导致链终止主要发生在模板上胞嘧啶碱基以外的一个或两个核苷酸位置。
In order to clarify the biological activities of (-)-oxetanocin G, and (-)-oxetanocin A and its carbocyclic analogue, (-)-carboxetanocin G, the inhibitory effects of triphosphate derivatives of these compounds (OXT-GTP, OXT-ATP, and C-OXT-GTP) on eukaryotic and viral DNA polymerases were examined. DNA polymerase-alpha purified from calf thymus was weakly inhibited by OXT-GTP and OXT-ATP but strongly by C-OXT-GTP, the K(i) value being 0.22-mu-M. On the other hand, rat DNA polymerase-beta was not affected by these analogues. DNA polymerase-gamma purified from bovine testes was very weakly inhibited by OXT-GTP and OXT-ATP, but not by C-OXT-GTP. DNA polymerase from herpes simplex virus type-II (HSV-II) was strongly inhibited by all three analogues, the K(i) values ranging from 0.5 to 1.0-mu-M. Human immunodeficiency virus-encoded reverse transcriptase (HIV RT) was also strongly inhibited by these three analogues, the K(i) value of C-OXT-GTP being slightly smaller than that of OXT-GTP or OXT-ATP. Analysis of products synthesized on singly primed M13 single-stranded DNA by DNA polymerase-alpha, HSV-II DNA polymerase or HIV RT in the presence of the analogues revealed that OXT-GTP and C-OXT-GTP were incorporated into DNA and caused chain termination mainly at sites one or two nucleotides beyond the cytosine bases on the template.