STRUCTURE-ACTIVITY-RELATIONSHIPS OF DIMERIC CATHARANTHUS ALKALOIDS .1. DEACETYLVINBLASTINE AMIDE (VINDESINE) SULFATE
STRUCTURE-ACTIVITY-RELATIONSHIPS OF DIMERIC CATHARANTHUS ALKALOIDS .1. DEACETYLVINBLASTINE AMIDE (VINDESINE) SULFATE
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DOI：
10.1021/jm00199a016
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发表时间：
1978-01-01
影响因子：
7.3
通讯作者：
NELSON, RL
中科院分区：
文献类型：
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作者：
BARNETT, CJ;CULLINAN, GJ;NELSON, RL
以长春花碱（VLB）和去乙酰长春花碱为原料制备去乙酰长春花碱酰胺（vindesine， VDS），探讨其结构差异对二聚长春花生物碱抗肿瘤活性和毒性的影响。通过优先肼水解VLB中vindoline部分的c23 -酯，然后氢解得到去乙酰长春花碱肼，制备出足够量的长春花碱用于生物试验。Vindesine对啮齿动物肿瘤系统的活性谱类似于长春新碱（VCR），而不是其母体VLB，而其神经毒性潜力似乎小于VCR。为估计这种可能性而开发的实验模型包括猫坐骨神经轴浆运输效应的体外测量，以及与VCR相比，vindesine对鸡和猴子神经肌肉紊乱的估计。用去乙酰长春花碱酸叠氮化物建立的放射免疫分析法研究长春花碱在人体内的药动学。长春地辛的临床研究正在进行中。与先前的报道相反，去乙酰长春花碱显示出对几种小鼠肿瘤系统的活性。
Exploration of the effects of minor structural differences on the antitumor activity and toxicity of dimeric Catharanthus alkaloids resulted in the preparation of deacetylvinblastine amide (vindesine, VDS) from vinblastine (VLB) or deacetylvinblastine. Adequate amounts of vindesine for biological testing were prepared by preferential hydrazinolysis of the C23-ester in the vindoline moiety of VLB followed by hydrogenolysis of the resulting deacetylvinblastine hydrazide. Vindesine in its activity spectrum against rodent tumor systems resembles vincristine (VCR) rather than its parent VLB, while ite neurotoxic potential appears to be less than that of VCR. The experimental models developed to estimate this potential include in vitro measurements of axoplasmic transport effects in the cat sciatic nerve and the estimation of neuromuscular disturbances in chickens and monkeys by vindesine in comparison with VCR. A radioimmunoassay for VLB, VCR and VDS, developed by deacetylvinblastine acid azide was used to study the pharmacokinetcs of vindesine in man. The clinical investigation of vindesine is in progress. Deacetylvinblastine, in contrast to earlier reports, showed activity against several murine tumor systems.