抗艾滋病药物 79. 新型二金刚烷酰-2',2'-二甲基二氢吡喃并色酮 (DCP) 类似物作为有效抗 HIV 药物的设计、合成、分子建模和构效关系。
Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.
机构信息
Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
出版信息
Bioorg Med Chem. 2010 Sep 15;18(18):6678-89. doi: 10.1016/j.bmc.2010.07.065. Epub 2010 Aug 2.
Abstract
In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates.
摘要
在一项持续的研究中，合成了 23 个 3'R,4'R-二-O-(-)-莰烷酰基-2',2'-二甲基二氢吡喃并[2,3-f]色酮 (DCP) 衍生物（5-27），并对其抗 HIV 活性进行了筛选，针对非耐药 NL4-3 株和多种逆转录酶（RT）抑制剂耐药（RTMDR-1）株，以 2-EDCP（4）和 2-MDCP（35）为对照。新的 DCP 类似物 5、9、14 和 22 对 HIVNL4-3 表现出很强的抗 HIV 活性，EC50 和治疗指数（TI）值分别为 0.036 μM 至 0.14 μM 和 110 至 420。化合物 5 和 9 对 RTMDR-1 也表现出良好的活性（EC50 为 0.049 和 0.054 μM；TI 分别为 310 和 200），比先导化合物 4 和 35 强两倍（EC50 为 0.11 和 0.19 μM；TI 分别为 60 和 58）。水溶性评估表明，5 和 22 的水溶性比 4 高 5-10 倍。首次对该化合物类型进行了定量构效关系（QSAR）建模研究，这些模型应该有助于设计未来的抗 HIV DCP 类似物和潜在的临床候选药物。
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本文引用的文献
1
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Tetrahedron Lett. 2010 Aug 18;51(33):4382-4386. doi: 10.1016/j.tetlet.2010.06.058.
2
Global epidemiology of HIV.全球艾滋病病毒流行病学。
Curr Opin HIV AIDS. 2009 Jul;4(4):240-6. doi: 10.1097/COH.0b013e32832c06db.
3
Review. Drug resistance of human immunodeficiency virus and overcoming it by natural products.综述：人类免疫缺陷病毒的耐药性及天然产物对其的克服
In Vivo. 2009 Jan-Feb;23(1):1-6.
4
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Chem Rev. 1948 Oct;43(2):271-317. doi: 10.1021/cr60135a004.
5
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Bioorg Med Chem Lett. 2008 Feb 15;18(4):1484-9. doi: 10.1016/j.bmcl.2007.12.055. Epub 2007 Dec 25.
6
Making a difference on excited-state chemistry by controlling free space within a nanocapsule: photochemistry of 1-(4-alkylphenyl)-3-phenylpropan-2-ones.
Org Lett. 2007 Aug 30;9(18):3575-8. doi: 10.1021/ol0713990. Epub 2007 Aug 1.
7
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J Med Chem. 2007 Jul 12;50(14):3163-6. doi: 10.1021/jm070383c. Epub 2007 Jun 7.
8
Domino reactions of 1,3-bis-silyl enol ethers with benzopyrylium triflates: efficient synthesis of fluorescent 6H-benzo[c]chromen-6-ones, dibenzo[c,d]chromen-6-ones, and 2,3-dihydro-1H-4,6-dioxachrysen-5-ones.1,3-双硅烯醇醚与三氟甲磺酸苯并吡喃鎓盐的多米诺反应：高效合成荧光6H-苯并[c]色烯-6-酮、二苯并[c,d]色烯-6-酮和2,3-二氢-1H-4,6-二氧杂并四苯-5-酮。
Chemistry. 2006 Jan 23;12(4):1221-36. doi: 10.1002/chem.200501024.
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