ANTITUMOR AND ANTIVIRAL NUCLEOSIDE ANALOGUES

新型核苷类似物的制备和研究 潜在的抗肿瘤和抗病毒药物。这些化合物将 包括：(I)胞苷的类似物，3-羟基碳环； 去氮腺苷、长春花碱和阿糖胞苷，(Ii)不饱和 与奈普罗星A相关的碳环核苷类似物，包括 L-同型半胱氨酰奈普兰菌素A，(Iii)开环戊二醛的膦酸衍生物 链不饱和核苷类似物和(Iv)类似物 腺苷脱氨酶抑制剂。所有化合物都将被获得 通过化学合成。将获得类似物(I)和(II) 由一种新的化学酶以外消旋的形式或光学纯的形式 接近。 活性类似物的抗肿瘤活性及其作用机制 将对小鼠白血病L 1210进行体内外研究， P388和16个实体瘤系统。我们将特别注意 应注意：(一)抑制大分子合成，(二) 对特定代谢物的逆转研究，(Iii) 核苷酸池的大小，以及(Iv)对RNA成熟的影响。 所获得的类似物的抗病毒活性也将 调查过了。 适当的类似物将作为底物(抑制剂)进行研究 腺苷脱氨酶和腺苷同型半胱氨酸水解酶。

Novel nucleoside analogous will be prepared and studied as potential antitumor and antiviral agents. These compounds will include: (i) "Hydroxycarbocyclic" analogous of cytidine, 3- deazaadenosine, vidarabine and cytarabine, (ii) unsaturated carbocyclic nucleoside analogues related to neplanocin A including L-homocysteinylneplanocin A, (iii) phosphonate derivatives of open- chain unsaturated nucleoside analogues and (iv) analogues of adenosine deaminase inhibitor EHNA. All compounds will be obtained by chemical synthesis. Analogues (i) and (ii) will be obtained either in racemic form or optically pure by a new chemico-enzymatic approach. Antitumor activity and mechanism of action of the active analogues will be studied in vitro and in vivo in murine leukemia L 1210, P388, and sixteen solid tumor systems. Particular attention will be paid to: (i) inhibition of macromolecular synthesis, (ii) reversal studies with specific metabolites, (iii) alterations in nucleotide pool sizes, and (iv) effects on RNA maturation. Antiviral activity of the obtained analogues will also be investigated. Suitable analogues will be studied as substrates (inhibitors) of adenosine deaminase and adenosine homocysteine hydrolase.