Medical School, Dimokrition University of Thrace, Alexandroupolis, Greece.
Mutat Res. 2012 Jul 4;746(1):1-6. doi: 10.1016/j.mrgentox.2011.12.032. Epub 2012 Mar 21.
New compounds with potential antitumour activity were synthesised by combining nitrogen mustard with the steroidal skeleton, in an effort to improve specificity and at the same time reduce systemic toxicity. The steroidal part is aimed to serve as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties. The purpose of the present investigation was to evaluate these compounds for anti-neoplastic activity. The compounds tested have as alkylators either para-NN-bis(2-chloroethyl)-aminophenyl-butyrate (CHL) or para-N,N-bis(2-chloroethyl)-aminophenyl-acetate (PHE) esterified with a differently modified steroidal nucleus. The eight newly synthesised compounds were compared on a molar basis with respect to their ability to induce sister chromatid exchanges (SCEs) and to modify proliferation rate indices (PRI) in lymphocytic leukaemia P388 cells in mice in vivo. The life span of BDF1 mice inoculated with P388 leukaemia cells was also estimated (anti-leukaemic activity). The compounds that were effective in inducing cytogenetic effects in lymphocytic leukaemia cells in vivo were also effective in inducing antineoplastic effects in BDF1 mice inoculated with P388 leukaemia cells. These results suggest that the in vivo cytogenetic effects in conjunction with the antineoplastic activity of modified steroidal alkylators depend on the configuration of the whole molecule and on the appropriate combination of the alkylator with the steroidal molecule: a pronounced cytogenetic and anti-neoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with either a steroidal nucleus that carries a cholesten group in the 17 position of the D-ring, or with a steroidal nucleus having an exocyclic NHCO-group in the D-ring. In contrast, a ketone group or an NHCO-group in the D-ring inserted endocyclically in the steroidal nucleus esterified with either CHL or PHE failed to induce cytogenetic or anti-neoplastic effects.
新型具有潜在抗肿瘤活性的化合物通过将氮芥与甾体骨架结合来合成，旨在提高特异性，同时降低全身毒性。甾体部分旨在作为一个生物平台，通过改变其理化性质，使烷化部分能够接近其作用部位。本研究旨在评估这些化合物的抗肿瘤活性。测试的化合物的烷化剂为对-NN-双（2-氯乙基）-氨基苯丁酸酯（CHL）或对-N，N-双（2-氯乙基）-氨基苯乙酸酯（PHE），它们与不同修饰的甾体核酯化。在体内比较了这 8 种新合成的化合物在诱导姐妹染色单体交换（SCE）和改变小鼠体内淋巴细胞白血病 P388 细胞增殖率指数（PRI）方面的能力。还估计了接种 P388 白血病细胞的 BDF1 小鼠的寿命（抗白血病活性）。在体内诱导淋巴细胞白血病细胞细胞遗传学效应有效的化合物也有效地诱导接种 P388 白血病细胞的 BDF1 小鼠的抗肿瘤效应。这些结果表明，修饰甾体烷化剂的体内细胞遗传学效应与抗肿瘤活性取决于整个分子的构型以及烷化剂与甾体分子的适当结合：含有 PHE 或 CHL 作为烷化剂并与甾体核酯化的化合物表现出明显的细胞遗传学和抗肿瘤作用在 D 环 17 位携带胆固醇基团的甾体核或在 D 环中具有外环 NHCO 基团的甾体核上，或者在 D 环中插入内环的酮基团或 NHCO 基团与 CHL 或 PHE 酯化的甾体核未能诱导细胞遗传学或抗肿瘤作用。
