柔红酮和阿霉酮二肽衍生物的合成

本文报道柔红酮和阿霉酮二肽衍生物的合成。二肽与柔红酮在DCC/DMAP或苯磺酰氯/吡啶存在下反应,得到柔红酮衍生物,继之溴化、水解得到阿霉酮衍生物或直接由二肽与保护阿霉酮酯化,脱保护后得到阿霉酮衍生物。合成的18个化合物对L₁₂₁₀白血病细胞增殖均有抑制作用,并存在一定的构效关系,游离氨基的位置与抗肿瘤活性相关。

SYNTHESIS OF THE DIPEPTIDE DERIVATIVES OF DAUNOMYCINONE AND ADRIAMYCINONE

A number of analogues and derivatives of daunomycin and adriamycin have been studied in our laboratory to increase the activity and decrease the cardiotoxicity of antitumor anthracyclines. Some of them showed antitumor activities, and especially 7-O-(trans-4-aminocyclohexanecarbonyl) adriamycinone hydrochloride (4) as well as its N,N-dimethyl derivatives (5,6) showed significant antitumor properties in preliminary tests. We now report the synthesis of 7-O-or 7,11-0-dipeptide derivatives of daunomycinone and adriamycinonoe. Dipeptides were prepared by treating appropriate N-protected amino acids with ethyl trans-4-amino-cyclohexanecarbonylate hydrochloride in DMF in the presence of diethyl phosphrous cyanidate (DEPC) or N,N-bis-(2-oxo-3-oxazolidinyl) phosphroro diamidie chloride (ClSPO), followed by hydrolysis with 1mol/L NaOH in acetone. The peptides reacted with daunomycinone and 14-protected adriamycinone by using benzenesulfonyl chloride or DCC/DMAP to give the intermediates (27～40). N-Deprotection was carried out with 1.5 mol/L HCl/dioxane and to give the dipeptide derivatives ofdaunomycinone (41～53). Adriamycinone derivatives were obtained by bromination of daunomycinone derivatives and hydrolysis with 10% HCOONa or by deprotection of the compound (40). All compounds showed antitumor activities in the L₁₂₁₀ cell test. Some exhibited comparable activities when compared with compound (4) and adriamycin.