Bhushana Rao K S, Collard M P, Dejonghe J P, Atassi G, Hannart J A, Trouet A
J Med Chem. 1985 Aug;28(8):1079-88. doi: 10.1021/jm00146a017.
The dimeric alkaloids vinblastine (VLB) and vincristine (VCR) differ structurally only in the functional group on the dihydroindole nitrogen. The semisynthetic derivative vindesine (VDS) differs slightly from VLB by having an amide group instead of an ester group. However, these minor distinctions are responsible for profound differences in the oncolytic spectrum, potency, and toxicity of these compounds. Vinblastin-23-oyl amino acid derivatives were synthesized by linking amino acid carboxylic esters to the vinblastin-23-oyl moiety through an amide linkage. Studies were extended to explore the influence of the nature of the amino acid, the ester alkyl chain lengths, the stereoisomerism of the amino acid, or the reacetylation of the hydroxyl group (position O-4) of the vindoline moiety. The present study deals with the synthesis of 21 vinblastin-23-oyl amino acid derivatives, some of their physicochemical data, the acute toxicity in mice, and therapeutic activities of these derivatives against the P388 and L1210 leukemias in comparison with VDS, VBL, and VCR.
二聚体生物碱长春碱（VLB）和长春新碱（VCR）在结构上仅在二氢吲哚氮上的官能团有所不同。半合成衍生物长春地辛（VDS）与VLB略有不同，其具有酰胺基而非酯基。然而，这些细微差异导致了这些化合物在溶瘤谱、效力和毒性方面的显著差异。通过酰胺键将氨基酸羧酸酯连接到长春碱 - 23 - 酰基部分，合成了长春碱 - 23 - 酰基氨基酸衍生物。研究范围扩大到探索氨基酸的性质、酯烷基链长度、氨基酸的立体异构性或长春多灵部分羟基（O - 4位）的再乙酰化的影响。本研究涉及21种长春碱 - 23 - 酰基氨基酸衍生物的合成、它们的一些物理化学数据、小鼠急性毒性以及与VDS、VBL和VCR相比这些衍生物对P388和L1210白血病的治疗活性。
