Blickenstaff R T, Hanson W R, Reddy S, Witt R
Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
Bioorg Med Chem. 1995 Jul;3(7):917-22. doi: 10.1016/0968-0896(95)00076-s.
There is an interest and need for new compounds that protect tissues from radiation injury. In cancer therapy, the protection of normal tissue without protecting tumors is one way to increase the therapeutic gain. Thiol compounds are currently in clinical trials, but are limited to some extent by their human toxicities including hypotension, nausea, and emesis. Several new aminochalcones and aminobenzophenones were synthesized and tested for radioprotective activity in mice. All were less active than p-aminobenzophenone itself. Several acid hydrazides were synthesized and tested similarly, but none exhibited significant activity. The high radioprotective activity of 4-nitroaniline was confirmed, but other nitro amines were substantially less active. 4-Chloro-N-methylaniline is as active as 4-chloroaniline, but other chloro aromatics are devoid of significant activity. When compared with the phosphorothioate amyfostine (WR-2721) using the intestinal clonogenic cell survival assay, 1-(p-aminophenyl)-1-propanol (15), p-aminopropiophenone (16), its ethylene ketal (14), and a mixture of the two (17) protected to a great extent, though slightly less than WR-2721. These results suggest that there is direct cellular radioprotection by these non-thiol compounds. The studies further suggest that preclinical toxicity testing of the most protective agents is warranted.
人们对能够保护组织免受辐射损伤的新化合物存在兴趣和需求。在癌症治疗中，保护正常组织而不保护肿瘤是提高治疗增益的一种方法。硫醇化合物目前正在进行临床试验，但在一定程度上受到其人体毒性的限制，包括低血压、恶心和呕吐。合成了几种新的氨基查耳酮和氨基二苯甲酮，并在小鼠中测试其辐射防护活性。所有这些化合物的活性均低于对氨基二苯甲酮本身。合成了几种酰肼并进行了类似的测试，但均未表现出显著活性。4-硝基苯胺的高辐射防护活性得到了证实，但其他硝基胺的活性则显著较低。4-氯-N-甲基苯胺与4-氯苯胺活性相当，但其他氯代芳烃没有显著活性。使用肠道克隆形成细胞存活试验与磷硫代酯氨磷汀（WR-2721）相比，1-（对氨基苯基）-1-丙醇（15）、对氨基苯丙酮（16）、其乙烯缩酮（14）以及两者的混合物（17）具有很大程度的保护作用，尽管略低于WR-2721。这些结果表明这些非硫醇化合物具有直接的细胞辐射防护作用。研究进一步表明，对最具保护作用的药物进行临床前毒性测试是有必要的。
