Relative and absolute stereochemistries and total synthesis of (+)-macrosphelides A and B, potent, orally bioavailable inhibitors of cell-cell adhesion
Relative and absolute stereochemistries and total synthesis of (+)-macrosphelides A and B, potent, orally bioavailable inhibitors of cell-cell adhesion
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DOI：
10.1021/ja971657w
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发表时间：
1997-10-22
影响因子：
15
通讯作者：
Smith, AB
中科院分区：
文献类型：
--
作者：
Sunazuka, T;Hirose, T;Smith, AB
炎症的关键早期事件，1-3过敏反应，4-6和肿瘤转移7-9涉及白细胞和内皮细胞之间的相互作用。多种细胞分裂素和相关的化学介质通过调节细胞粘附分子的表达来控制白细胞粘附和随后的细胞间侵袭。10,11抑制细胞-细胞粘附因此有望治疗多种病理。最近，我们报道了(+)-macrosphelides A和B的分离、平面结构和初步生物学评价（1和2）。这些新型大环内酯类化合物由Microsphaeropsis sp. FO-5050产生，是第一个包含三个内酯键的16元环抗生素（即大环内酯类）。巨球磷脂对人白血病HL-60细胞粘附人脐静脉内皮细胞（HUVEC）的抑制作用呈剂量依赖性（IC50分别为3.5µM和36µM）。初步研究表明，1和2通过抑制sialyl Lewis x与e -选择素的结合来阻止细胞-细胞粘附。13巨球内酯A也被证明对小鼠B16/BL6黑色素瘤的肺转移具有口服活性（50 mg/kg）。重要的是，1在体外没有抑制各种哺乳动物细胞系（0.2 mg/mL）或微生物（1 mg/mL）的生长。腹腔注射BDF1小鼠（200 mg/kg，连续5天）未见急性毒性。巨球磷脂对花生四烯酸诱导的啮齿动物耳水肿反应也显示出显著的活性，因此，可能为脂氧合酶抑制剂的开发提供有价值的线索。配合我们的持续
Critical early events in inflammation, 1-3 the allergic response, 4-6 and tumor metastasis7-9 involve interactions between leukocytes and endothelial cells. A variety of cytokinins and related chemical mediators control both leukocyte adhesion and subsequent intercellular invasion by regulating the expression of cellular adhesion molecules. 10, 11 Inhibition of cell-cell adhesion thus holds promise for the treatment of diverse pathologies.Recently we reported the isolation, planar structures, and preliminary biological evaluation of (+)-macrosphelides A and B (1 and 2). 12 These novel macrolides, produced by Microsphaeropsis sp. FO-5050, are the first 16-membered-ring antibiotics embodying three lactone linkages (ie, macrotriolides). The macrosphelides strongly inhibit the adhesion of human-leukemia HL-60 cells to human-umbilical-vein endothelial cells (HUVEC) in dose-dependent fashion (IC50 3.5 and 36 µM, respectively). 12 Preliminary studies suggest that 1 and 2 prevent cell-cell adhesion by inhibiting the binding of sialyl Lewis x to E-selectin. 13 Macrosphelide A also proved to be orally active against lung metastasis of B16/BL6 melanoma in mice (50 mg/kg). Importantly, 1 did not inhibit the growth of various mammalian cell lines (0.2 mg/mL) or microorganisms (1 mg/mL) in vitro. No acute toxicity was observed upon intraperitoneal injection into BDF1 mice (200 mg/kg for 5 days). 13 The macrosphelides also display significant activity against the rodent-ear edema reaction induced by arachidonic acid and, thus, may serve as valuable leads for the development of lipoxygenase inhibitors. 13 In conjunction with our continuing