甾醇Sterols Squalamine 1970s Shark cartilage oil (squ nhibits angiogenes mie角 作为新生血管抑制剂类抗塘药物进入山有低床试验 nd ha 自白角Squabus的肝中分 出“n 甾体化合物Steroids -CH 0 ty aa】 A-C U-3 The 甾体化合物Steroids 甾醇二聚体生物碱 subapbo 1010 177 甾 醇 Sterols Sterols Squalamine 角鲨胺 作为新生血管抑制剂类抗癌药物进入II期临床试验 自白斑角鲨 Squalus acanthias的肝中分离 Squalamine is an essential ingredient which may be derived from various sources in nature. One known source of squalamine is predominantly found in the liver tissue (not the "liver oil") of the deep water shark. N H OH OSO3 - N H H2N H H H H 178 Squalamine, isolated from the common dogfish shark, Squalus acanthias collected off the New England coast, was originally reported by Zasloff’s group and collaborators from the University of Pennsylvania in 1993, and was shown to be a fairly simple aminosterol with broad spectrum antibiotic activity. The compound was licensed to Genaera and it entered Phase I, and has progressed into Phase II clinical trials for non-responding solid tumors. Moore, K.S.; Wehrli, S.; Roder, H.; Rogers, M.; Forrest Jr, J.N.; McCrimmon, D.; Zasloff, M. Proc. Natl. Acad. Sci. USA, 1993, 90, 1354. N H OH OSO3 - N H H2N H H H H Squalamine 1970s. Shark cartilage oil (squalamine) inhibits angiogenesis 179 Halistanol from Halichondria mooriei and a hydroxy sterol with unusual features is isolated from Dysidea species. Fusetani, N.; Matsunaga, S.; Konosu, S. Tetrahedron Lett. 1981, 22, 1985. Gunasekera, S. P.; Schmitz, F. J. J. Org. Chem. 1983, 48, 5157. NaO3SO H H H H OSO3Na NaO3SO HO HO H OAc HO O 甾体化合物 Steroids Steroids 180 The deep-water sea star Styracaster caroli, collected at a depth of 2000 m off the coast of New Caledonia, was found to contain three polyhydroxycholanic acid derivatives, designated carolisterol A–C (1–3). These polyhydroxysteroids (PHSs) are unique because they contain a polyhydroxycholanic acid moiety connected to D-cysteinolic acid via an amide linkage. F. De Riccardis, L.Minale, R. Riccio, M. Iorizzi,C. Debitus,D. Duhetand C. Monniot, Tetrahedron Lett., 1993, 34, 4381. NaO3SO H H R H R1 OH OH O SO3Na OH 1 R = OH, R1 = b-OH 2 R = OH, R1 = ketone 3 R = H, R1 = a-OH 181 The sea star Lethasterias nanimensis chelifera collected in the Sea of Okhotsk yielded a variety of sulfated alkaloidosteroid group in which a sulfate group bears an alkaloidal counter ion. O - O3SO H H H OH 17 1 17b, Counter ion : A 2 17a, Counter ion : Na+ 3 17a, Counter ion : B 4 17a, Counter ion : A NH HO HO NH3 HO Counter ion A B 甾体化合物 Steroids Steroids 182 N N O O O O OH H H O H H HO HO OH H H H OH N N O O OH O H H H H H H OH OH O OH OH 1 2 从印度洋蠕虫Cephalodiscus gilchristi和海鞘Ritterella tokiokal 中得到30 余个甾醇二聚体生物碱，对多种肿瘤细胞株都具有很强的抑制活性, 并且作 用 机制独 特。其 中 ritterazine A (1)对 P388肿瘤细胞的 IC50值为 0.018 ng/mL。cephalostatin 1 (2)是NCI筛选的抗癌活性最强的天然产物 之一。 甾醇二聚体生物碱