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Reagents: (a) s-BuLi, TMEDA, THF, then CH3I; (b) (COCl)2, DMF, CH2Cl2, then PhOH, DMAP, Et3N, 52% for two steps; (c) BBr3, CH2Cl2; (d) Boc2O, DMAP, CH2Cl2, 75% for two steps; (e) D ring precursor 11, LDA, TMEDA, THF, then enone 12, 35%; (f) aq. HF, TFA, CH3CN; (g) H2, 10% Pd/C, dioxane-CH3OH, 41% for two steps; (h) HNO3, H2SO4; (i) H2, 10% Pd/C, CH3OH, 81% for two steps; (j) RR′NCH2C(O)Cl (HCl salt), DMF, or BrCH2C(O)Br, Na2CO3, CH3CN-DMPU, then RR′NH.

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Compd.MIC, μg·mL-1
SA101SA161SA158EF159SP160EC107EC155AB110BC108KP153
29213tet(M)tet(K)tet(M)tet(M)25922tet(A)1960613047tet(A)
170.062 50.251.00.1250.015 60.251620.58
180.250.50410.062 5116248
191244116> 322> 32> 32
200.1250.250.50.062 50.015 60.58114
210.1250.250.062 50.1250.015 60.2520.512
2224224> 32> 328> 32> 32
234> 32> 32> 322> 328> 32> 32> 32
240.015 60.1250.250.031 20.016 580.125818
250.1250.250.50.1250.016 582814
260.015 60.015 60.015 60.016 50.016 510.031 280.1250.5
270.510.50.50.016 540.1253244
2848881> 328> 32> 32> 32
290.250.50.50.250.015 61160.2588
300.250.510.250.015 62320.125332
318> 32> 32164> 32> 32> 32> 32> 32
32221620.54> 323216> 32
3312120.1254160.51616
340.510.50.50.06120.0644
350.250.50.250.50.125240.1253232
2Tetracycline0.125643232321> 6411> 64
6Tigacycline0.062 50.1250.1250.015 60.015 60.12510.50.251
), ArticleFig(id=1210518255672881822, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210518240091041849, language=CN, label=Table 1, caption=

In vitro antibacterial activity of fluorocycline analogues

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Compd.MIC, μg·mL-1
SA101SA161SA158EF159SP160EC107EC155AB110BC108KP153
29213tet(M)tet(K)tet(M)tet(M)25922tet(A)1960613047tet(A)
170.062 50.251.00.1250.015 60.251620.58
180.250.50410.062 5116248
191244116> 322> 32> 32
200.1250.250.50.062 50.015 60.58114
210.1250.250.062 50.1250.015 60.2520.512
2224224> 32> 328> 32> 32
234> 32> 32> 322> 328> 32> 32> 32
240.015 60.1250.250.031 20.016 580.125818
250.1250.250.50.1250.016 582814
260.015 60.015 60.015 60.016 50.016 510.031 280.1250.5
270.510.50.50.016 540.1253244
2848881> 328> 32> 32> 32
290.250.50.50.250.015 61160.2588
300.250.510.250.015 62320.125332
318> 32> 32164> 32> 32> 32> 32> 32
32221620.54> 323216> 32
3312120.1254160.51616
340.510.50.50.06120.0644
350.250.50.250.50.125240.1253232
2Tetracycline0.125643232321> 6411> 64
6Tigacycline0.062 50.1250.1250.015 60.015 60.12510.50.251
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全合成研发的依拉环素
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郭宗儒
药学学报 | 新药发现与研究实例简析 2022,57(12): 3695-3698
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药学学报 | 新药发现与研究实例简析 2022, 57(12): 3695-3698
全合成研发的依拉环素
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郭宗儒
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  • 中国医学科学院、北京协和医学院药物研究所, 北京 100050
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出版时间: 2022-12-12 doi: 10.16438/j.0513-4870.2018-1134
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郭宗儒. 全合成研发的依拉环素. 药学学报, 2022 , 57 (12) : 3695 -3698 . DOI: 10.16438/j.0513-4870.2018-1134
. Acta Pharmaceutica Sinica, 2022 , 57 (12) : 3695 -3698 . DOI: 10.16438/j.0513-4870.2018-1134
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新药创制是复杂的智力活动, 涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹, 而构建化学结构是最重要的环节, 因为它涵盖了药效、药代、安全性和生物药剂学等性质。本栏目以药物化学视角, 对有代表性的药物的成功构建, 加以剖析和解读。
作用于细菌核糖体30s亚基阻断蛋白合成的四环素类药物已有70年的历史, 后来逐渐被其他抗感染药物取代, 原因之一是四环素类鲜有新的优化分子问世。2005年经结构修饰上市的替加环素疗效有一定的提升, 但2018年问世的依拉环素标志着研究路径和方法的重大突破—以人工全合成设计和构建四环结构, 在关键的D环上预构了难以用修饰方法获得的基团, 打开了研制新型四环素的途径, 并且实现了工业化生产。实现全合成方略是天然药物研究的必由之路。此外, 在评价化合物的活性上针对了多种耐药菌发生的基因变异, 将研发的起点建立在对抗临床上多重耐药的病原菌, 也是本品研究特色。(编者按)
1 研发背景
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四环素类抗生素已有70多年的历史, 曾在治疗革兰阳性和阴性菌感染性疾病方面发挥重要作用, 但几十年的应用生成了耐药菌, 早期发现的天然四环素类药物, 如金霉素(1, chlorotetraxycline)、四环素(2, tetracycline)、土霉素(3, oxytetracycline) 和多西环素(4, doxycycline) 等现已较少临床应用。
后来研制的米诺环素(5, minocycline, 1971上市) 和替加环素(6, tigacycline, 2005年上市) 是天然产物半合成的四环素, 其特征是在环的7位或7和9位引入基团, 因而提高了对耐药菌的抑制性。修饰的化学反应的局限性限制了结构变换的广泛探索, 人工合成构建四环结构有可能提供优化的新四环素, 依拉环素是个范例。
2 作用机制
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四环素类药物的作用机制是阻断细菌蛋白质合成, 经与细菌核糖体30S亚基在A位点发生特异性结合, 阻止了氨基酸酰化的tRNA与核糖体受体A位点的结合。结构中C10~C12位酚基、酮基和烯醇基与靶标中多个氨基酸残基发生氢键结合, 并与镁离子形成配合结合, 编织成网络状结合, 对抗菌活性产生重要影响。C10~C12位上氧原子电荷密度越高, 与上述的结合能力越强, 抗菌活性也越强, 体现了分子中“南部”结构配置非常重要。四环素还可抑制70S和80S核糖体功能, 因此表现为广谱抗生素。
3 耐药性的产生
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长期应用四环素类药物使细菌产生四环素抗性基因(tetracycline resistance genes, TRGs), 基因变异至少涉及两个方面, 一是细菌产生外排基因(efflux genes), 将四环素泵出胞外以减少细胞内的药物浓度, 例如外排基因tet(A)~tet(D) 和tet(K)~tet(L) 广泛存在于革兰阳性和阴性菌体中; 另一是细菌产生核糖体保护基因(ribosome protection genes), 核糖体保护蛋白改变了核糖体构象, 从而解除或逃逸了四环素对蛋白合成的抑制作用, 例如tet(O)~tet(O) 等保护基因常见于金葡菌和链球菌等革兰阳性菌耐药株中。研究新的四环素药物目标是对上述产生耐药基因的病原体有抑制作用并优于现有四环素类的广谱四环素新药。
4 分子设计依据
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根据已有的构效关系, 特别是解析了四环素与30S核糖体复合物的晶体结构(Bodersen DE, Clemons WM, Carter AP, et al. The structure basis for the action of the antibioticstetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell, 2000, 103: 1143-1154), 深化了作用机制的认识。四环素结构的“西北部”没有参与同核糖体的相互作用, 结构变换不会对活性有大的影响, 然而分子“西南部”与细菌核糖体A位点有广泛的氢键网络结合, 因而可优化结构以提高结合能力。D环的7位和9位结构变换成功范例是米诺环素(5) 和替加环素(6), 提高7位的极性和电负性, 可改善物化性质和与靶标结合力, 9位碱性侧链更有抑制耐药菌的作用, 因而结构的优化集中于此。
5 全合成促进结构优化
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实现天然产物的全合成不仅标志合成反应与技术的进步, 也是对复杂有机结构修饰最权威的确证, 此外, 对天然活性物质的结构优化、简化、药效团的提取与骨架迁越, 以及构效关系的解析都是促进药物研究的重要内容。在实现四环素全合成之前, 天然物改造的半合成中, 对D环的变换和基团引入只靠有限的亲电取代反应, 例如硝化或卤代, 限制了多样性变换。
Myers等研究的全合成路线可视作平台技术, 为规模制备和工业化打下基础(Sun C, Wang Q, Brubaker JD, et al. A robust platform for the synthesis of new tetracycline antibiotics. J Am Chem Soc, 2008, 130: 17913-17927)。图 1列出的路线是合成7-氟代-9-取代侧链的四环素通法。合成策略是将构成D环的含氟邻甲苯甲酸酯11在强Lewis碱的拔氢作用下, 生成碳负离子, 与预构有保护取代基的AB环化合物12经串联的Michael-Dieckmann缩合增环, 生成四环化合物13, 再于9位引入所需的侧链, 生成通式为16的目标化合物。
6 目标化合物和构效关系
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合成的目标化合物列于表 1, 都是7-氟9-含胺侧链的不同取代物。活性数据选择了代表性的10株菌株, 革兰阳性菌(前5株) 和阴性菌(后5株) 各半, 标有tet(A) 等字样的是具有抗四环素基因变异的菌株, 分别在多种阳性和阴性菌中广泛表达。
分析构效关系如下: ① 9位侧链外端的仲胺或叔胺以小体积为优选结构, 而仲胺17、20和21抑制tet(A) 和tet(K) 变异菌株随基团的加大而活性增高; ②叔胺24~28抗tet(K) 变异菌株的活性优良, 尤其突出的是四氢吡咯化合物26抑制tet(A) 高活性; ③胺碱性弱的化合物活性降低较大, 尤其对阴性菌的活性很弱, 例如18、19和28; ④ 9位是芳香胺的化合物22和23对大多数病原菌未显示活性, 提示碱性脂肪胺的必要性; ⑤侧链上叔胺环大小对活性影响显著, 26的活性最强, 而四元环(25) 和六元环(27) 对所有菌株活性都减弱到4~64倍, 推测该五元环尺寸对靶标的结合最适宜; ⑥在四氢吡咯环上引入氟原子(29和30) 对阳性菌的活性变化不大, 构型之间差异不大; 但对阴性菌活性显著降低。环上连接极性基团(31~33) 对所有菌株的活性下降, 对阴性菌尤甚。稠合环状化合物34和35保持了一定活性但不如26; ⑦化合物26对多数病原菌活性强于替加环素6 (Xiao XY, Hunt DK, Zhou JY, et al. Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem, 2012, 55: 597-605)。
7 候选物的确定和依拉环素的上市
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化合物26呈现有优势活性, 进而用转染荧光素酶报告基因的大肠杆菌测定对核糖体抑制活性, IC50为0.62 μmol·L-1, 强于四环素7倍。对多重耐药的大肠杆菌感染小鼠治疗表明, 化合物26抑菌作用强于替加环素。大鼠药代动力学实验表明, 26的口服生物利用度F = 1.7% (替加环素为1%), 半衰期t1/2 = 6.9 h (替加环素为3.9 h), 清除率CL = 0.564 L·h-1·kg-1 (替加环素为0.929 L·h-1·kg-1), 26的药代略优于替加环素。研发公司Tetraphase遂确定26为候选物, 定名为依拉环素(eravacycline), 经临床研究表明, 单一用药可治疗多重耐药菌的感染, 主要包括复杂性腹腔内感染和复杂性尿路感染。2018年美国FDA批准上市(Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs, 2016, 76: 567-588)。
2022年第57卷第12期
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doi: 10.16438/j.0513-4870.2018-1134
  • 首发时间：2025-12-24
  • 出版时间：2022-12-12
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    中国医学科学院、北京协和医学院药物研究所, 北京 100050
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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