摘 要：该研究开展了10种海洋生物来源候选药物的成药性评价。主要研究任务包括候选药物的规模化制备及其技术，药理药效学评价，安全性评价和初步药代动力学评价。在10种海洋生物来源候选药物中，6种用于抗恶性肿瘤，2种用于镇痛，1种用于抗糖尿病和1种用于溶栓。建立了10种候选药物的规模化制备工艺，质量标准方法和相关的药学研究。在抗肿瘤药理评价中，红树植物角果木来源的二萜tagasin C为PAPR-1靶向抑制剂，具有膜通透性和选择性抗肿瘤活性，对人白血病细胞，肝癌细胞等有明显的抑制活性，而对正常细胞的毒性低。适用于治疗临床Bcl-2高表达、耐常规化疗的药物或治疗复发癌症的药物；总合草苔虫来源的大环内酯bryostatin 19对人白血病和人肝癌模型有显著的抗肿瘤作用；在治疗剂量时与化疗药相比毒性小，且对免疫功能没有影响；海洋微生物来源生物碱HDN-1为HSP90抑制剂，具有靶向抗白血病功效，诱导HL-60细胞分化并诱导的HL-60细胞分化成成熟粒细胞；微生物来源生物碱WHJ-64为CDK4选择性抑制剂，对胰腺癌具有高效抑制作用；微生物来源的降二萜化合物wbg对非小细胞肺癌和小细胞肺癌均具有显著抑制活性；微生物来源的变构甾体HDZ-137与阿霉素联用可显著抑制对阿霉素耐药肿瘤细胞，作用机制是抑制耐药基因和蛋白的表达。红树海芒果来源的苯并大环内酯GSW-1具有显著盐皮质激素拮抗活性，可发展为对盐皮质激素相关重大疾病（糖尿病等）高效低毒的药物候选物。黑星芋螺来源的寡肽Eb1.6对坐骨神经半切镇痛作用显著，可发展为慢性疼痛镇痛药，其作用靶点为N-型钙通道。而信号芋螺来源的寡肽安诺吉斯肽对多种急性和慢性疼痛模型有显著作用，其机制与体内乙酰胆碱递质系统和阿片系统有关。微生物来源混源生物碱FGFC1对急性肺血栓栓塞具有显著溶栓作用，其作用机制为提高纤溶体系纤溶酶原活性。对10种候选药物的安全性进行评价，包括急性毒性和特殊毒性，结果表明，在有效剂量下，大多数候选药物未表现出毒性，但个别候选药物的安全窗较窄，有待对其给药方式进一步研究。对候选药物进行了初步药代动力学研究（8种进行体内和体外，2种体外），结果表明7种候选药物的生物利用度，血药浓度等达到要求，并进一步对候选药物进行了制剂学进行了研究。研究结果提升了我国海洋小分子药物创新能力，为进一步海洋创新药物研究提供了研究基础，7种候选药物有望发展成新药。

关键词：海洋生物 候选药物 制备 药效学 安全性 药代动力学 成药性

Abstract：In this project，ten drug candidates derived from marine organisms are selected for drugability evaluation.Firstly，large scale manufacture of each compound was processed.The compounds were prepared by column chromatography and total synthesis.The standard methods using HPLC analysis for quality control were established.Dolabrane-type diterpene tagalsin C （TC） was found to have cytotoxicities to a panel of human malignant cell lines by inducing apoptotic cell death and to inhibit tumor growth in vivo in five mouse tumour models without obvious toxicity to the animals.TC induced apoptosis，resulted in the blocking DNA synthesis and inducing DNA fragments caused by the activation of caspase pathway to down-regulate PARP.The macrolactone bryostatin 19 exhibited promising inhibition against acute leukemia and hepatoma either in vitro or in vivo.It is associated with the proapoptotic protein PUMA and the anti-apoptotic protein Bcl-XL.Alkaloid HDN-1 could inhibit the growth of leukemia cell line HL-60，and induces the HL-60 cell differentiation to mature cells，while it inhibited the tumor growth of human hepatic cancers and mice lewis lung carcinoma，especially on HL-60 cells with and without ATRA by targeting to the C terminal of HSP90.Norditerpenoid（wbg）showed significant activity against both non-small-cell lung cancer and small-cell lung cancer.Ophiobolin analogue HDZ-137 can reverse the multidrug resistance of adrimycin on breast cancer at low dose through inhibition on expression of genes related with drug resistance.Alkaloid WHJ-64 is a selective CDK4 inhibitor to inhibit pancreatic carcinoma in vivo.Benzoic macrolactone GSW-1 showed antidiabetic effects and lowering the blood glucose level in db/db mice through ameliorating the expression of obesity-related pro-inflammatory cytokines.The analgesic effects of peptides Eb1.6 and analgesitide in vitro and in vivo were tested and were confirmed，while their acting mechanisms were investigated.The thrombolytic effects of an alkaloid FGFC1 revealed it to be a promising candidate for drugability.All candidates were evaluated for their safeties including acute toxicity and genotoxicity，indicating that all candidates are lower toxic within the effective does.In addition，the pharmacokinetic experiments in vitro and in vivo were investigated，which provided additional data to support the drugability of the candidates.

Key Words：Marine organisms；Drug candidates；Manufacture；Pharmacological effects；Safety；Pharmacokinetic；Drugability

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