Müller K, Reindl H, Breu K
Institut für Pharmazeutische Chemie, Westfälische Wilhelms--Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
J Med Chem. 2001 Mar 1;44(5):814-21. doi: 10.1021/jm001073w.
The synthesis and structure-activity relationships (SARs) of a series of novel 10-arylacetyl-1,8-dihydroxy-9(10H)-anthracenones are described. Acylation of anthralin with either the appropriate arylacetyl chlorides or arylacetic acids in the presence of pyridine or via the coupling agent dicyclohexylcarbodiimide (DCC), respectively, furnished this structural class of antipsoriatic agents. Potential antipsoriatic activity was evaluated in complementary assays specifically addressed to three important aspects of psoriasis. First, several compounds were identified which are equally potent as inhibitors of human keratinocyte growth as the antipsoriatic agent anthralin. Furthermore, improved ratio of antiproliferative activity to cytotoxicity is demonstrated by the reduced potential of the novel analogues to induce membrane damage, which is a benefit of their reduced ability to generate oxygen radicals as documented by deoxyribose degradation. Second, analogue 3o bearing a hydroxamate functional group was also a highly potent inhibitor of LTB(4) biosynthesis in addition to its excellent antiproliferative activity. SARs of these inhibitors of both keratinocyte growth and LTB(4) biosynthesis with respect to the nature of the para-substitution in the 10-phenylacetyl side chain are discussed. Third, the compounds were also evaluated for their ability to induce the formation of cornified envelope protein in keratinocytes. Cross-linking of cellular protein as a marker of terminal differentiation of keratinocytes was observed for many 10-arylacetyl analogues at concentrations required to arrest cell growth. This newly uncovered activity of the novel anthracenones suggests antipsoriatic potential with respect to disturbance of keratinocyte differentiation, in addition to hyperproliferative and inflammatory aspects of psoriasis.
描述了一系列新型10-芳基乙酰基-1,8-二羟基-9(10H)-蒽酮的合成及其构效关系（SARs）。分别在吡啶存在下或通过偶联剂二环己基碳二亚胺（DCC），用适当的芳基乙酰氯或芳基乙酸对蒽林进行酰化反应，得到了这一类抗银屑病药物。通过针对银屑病三个重要方面的互补试验评估了潜在的抗银屑病活性。首先，鉴定出几种化合物，它们作为人角质形成细胞生长抑制剂的效力与抗银屑病药物蒽林相当。此外，新型类似物诱导膜损伤的潜力降低，证明了抗增殖活性与细胞毒性的比例得到改善，这得益于其产生氧自由基能力的降低，脱氧核糖降解实验证明了这一点。其次，带有异羟肟酸酯官能团的类似物3o除了具有出色的抗增殖活性外，还是白三烯B4（LTB4）生物合成的高效抑制剂。讨论了这些角质形成细胞生长和LTB4生物合成抑制剂在10-苯基乙酰基侧链对位取代基性质方面的构效关系。第三，还评估了这些化合物诱导角质形成细胞中角质化包膜蛋白形成的能力。在许多10-芳基乙酰基类似物中，在抑制细胞生长所需的浓度下观察到细胞蛋白交联，这是角质形成细胞终末分化的标志。这种新型蒽酮新发现的活性表明，除了银屑病的过度增殖和炎症方面外，其在干扰角质形成细胞分化方面具有抗银屑病潜力。
