郭躍偉 王斌貴 吳文惠

摘 要：該研究開展了10種海洋生物來源候選藥物的成藥性評價。主要研究任務(wù)包括候選藥物的規(guī)?；苽浼捌浼夹g(shù)，藥理藥效學(xué)評價，安全性評價和初步藥代動力學(xué)評價。在10種海洋生物來源候選藥物中，6種用于抗惡性腫瘤，2種用于鎮(zhèn)痛，1種用于抗糖尿病和1種用于溶栓。建立了10種候選藥物的規(guī)?；苽涔に?，質(zhì)量標(biāo)準(zhǔn)方法和相關(guān)的藥學(xué)研究。在抗腫瘤藥理評價中，紅樹植物角果木來源的二萜tagasin C為PAPR-1靶向抑制劑，具有膜通透性和選擇性抗腫瘤活性，對人白血病細(xì)胞，肝癌細(xì)胞等有明顯的抑制活性，而對正常細(xì)胞的毒性低。適用于治療臨床Bcl-2高表達(dá)、耐常規(guī)化療的藥物或治療復(fù)發(fā)癌癥的藥物；總合草苔蟲來源的大環(huán)內(nèi)酯bryostatin 19對人白血病和人肝癌模型有顯著的抗腫瘤作用；在治療劑量時與化療藥相比毒性小，且對免疫功能沒有影響；海洋微生物來源生物堿HDN-1為HSP90抑制劑，具有靶向抗白血病功效，誘導(dǎo)HL-60細(xì)胞分化并誘導(dǎo)的HL-60細(xì)胞分化成成熟粒細(xì)胞；微生物來源生物堿WHJ-64為CDK4選擇性抑制劑，對胰腺癌具有高效抑制作用；微生物來源的降二萜化合物wbg對非小細(xì)胞肺癌和小細(xì)胞肺癌均具有顯著抑制活性；微生物來源的變構(gòu)甾體HDZ-137與阿霉素聯(lián)用可顯著抑制對阿霉素耐藥腫瘤細(xì)胞，作用機(jī)制是抑制耐藥基因和蛋白的表達(dá)。紅樹海芒果來源的苯并大環(huán)內(nèi)酯GSW-1具有顯著鹽皮質(zhì)激素拮抗活性，可發(fā)展為對鹽皮質(zhì)激素相關(guān)重大疾病（糖尿病等）高效低毒的藥物候選物。黑星芋螺來源的寡肽Eb1.6對坐骨神經(jīng)半切鎮(zhèn)痛作用顯著，可發(fā)展為慢性疼痛鎮(zhèn)痛藥，其作用靶點(diǎn)為N-型鈣通道。而信號芋螺來源的寡肽安諾吉斯肽對多種急性和慢性疼痛模型有顯著作用，其機(jī)制與體內(nèi)乙酰膽堿遞質(zhì)系統(tǒng)和阿片系統(tǒng)有關(guān)。微生物來源混源生物堿FGFC1對急性肺血栓栓塞具有顯著溶栓作用，其作用機(jī)制為提高纖溶體系纖溶酶原活性。對10種候選藥物的安全性進(jìn)行評價，包括急性毒性和特殊毒性，結(jié)果表明，在有效劑量下，大多數(shù)候選藥物未表現(xiàn)出毒性，但個別候選藥物的安全窗較窄，有待對其給藥方式進(jìn)一步研究。對候選藥物進(jìn)行了初步藥代動力學(xué)研究（8種進(jìn)行體內(nèi)和體外，2種體外），結(jié)果表明7種候選藥物的生物利用度，血藥濃度等達(dá)到要求，并進(jìn)一步對候選藥物進(jìn)行了制劑學(xué)進(jìn)行了研究。研究結(jié)果提升了我國海洋小分子藥物創(chuàng)新能力，為進(jìn)一步海洋創(chuàng)新藥物研究提供了研究基礎(chǔ)，7種候選藥物有望發(fā)展成新藥。

關(guān)鍵詞：海洋生物 候選藥物 制備 藥效學(xué) 安全性 藥代動力學(xué) 成藥性

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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