新型HIV-NNRTIs先导物二芳基苯胺类的结构优化和类药性评价
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摘要
由人类免疫缺陷病毒(HIV)感染引起的获得性免疫缺陷综合征(艾滋病,AIDS),目前仍是医学界难以攻克的疾病之一。现有的抗艾滋病药物虽然能够有效地延缓病情的进程,但也存在易产生耐药性、服药量大和价格昂贵等问题。因此,寻找能克服现有药物问题的新结构、新作用靶标的抗艾滋病新药是目前艾滋病研究的热点之一。
非竞争性的非核苷类逆转录酶抑制剂(Non-nucleoside reverse transcriptase inhibitors, NNRTIs)是高效逆转录疗法(HAART)的重要组成部分。目前已经上市的该类药物有5个(nevirapine, delavirdine, efavirine, etravirine, rilpivirine)。尽管它们都作用于HIV-1的逆转录酶的疏水性口袋(NNIBP),但从药物的化学结构可知NNRTIs具有结构多样性。其中etravirin(eTMC125, 2008)和rilpivirine (TMC278, 2011)为新一代非核苷类逆转录酶抑制剂,均属于二芳基嘧啶类化合物(DAPYs)。它们对野生型和多种耐药性病毒株(如K103N, Y181C, K103N/Y181C等)均具有相当强的抑制活性(nM)。而于2011年5月20日FDA最新批准上市的Rilpivirine (TMC278)的抗HIV-1活性和抗耐药性能均比TMC125更好,更长效。
本研究课题的最终目标是要发现具有新骨架结构、对野生型和多种HIV耐药性病毒株均有强抑制活性的新一代HIV-NNRTI类新药。我们在前期工作中,基于已有的NNRTIs类生物信息和药物结构,通过采用生物电子等排体替换的研究策略已发现了一类新骨架结构的新一代NNRTI类新先导物:二芳烃取代苯胺类化合物(Darylanalines,DAANs)。DAANs类新先导物对野生型和多种耐药性病毒株均显示出了与TMC125相当的强抑制活性(nM)。DAANs类新先导物是用一个带有取代基的苯环代替了DAPY类化合物结构的中间嘧啶环,从而形成了含有三个取代苯环的新骨架结构,但同时保持了与DAPYs化合物类似的分子柔性和分子形态。前期分子模拟结果表明:新先导物与DAPY类化合物在药物作用靶点RT的活性口袋(NNIBP)中的作用方式非常类似,与RT结合时呈现了与DAPY类化合物相同的“U”形构象。分子对接结果还发现,DAANs先导物中间苯环特定位有氨基取代时,该氨基可作为氢键供体和氢键受体分别与靶标表面关键氨基酸K101的主链羰基和侧链氨基形成两根氢键,从而为新先导物的高活性提供了理论上的支持。前期构效关系表明DAANs先导物结构中的对氰苯基(A环)、中间苯环(B环)、邻对位三取代苯(C环)和AB环间的氨链是分子活性的必需结构要素和基团;提示B环氨基的间位取代基和C环对位的取代基都与分子活性相关,有进一步修饰的化学空间。
本论文研究是前期工作的继续,着重于对已发现的DAANs类新先导物做进一步的结构优化,以期继续提高该类分子对HIV野生型和多种耐药性病毒株的抑制活性,同时改善分子的理化性质,使之更具有类药性。本论文的结构修饰点着重于在B环引入不同的极性基团和C环对位取代基的变化。前者意在改善分子的水溶性并产生与靶点间的新作用点,后者基于同类候选药TMC278的氰乙烯基结构,试图引入较长的线性基团进入NNIBP的强疏水的“狭长”的空腔中,与其表面的氨基酸残基以及保守氨基酸W229产生π-π作用,有利于抑制耐药性病毒的复制。本论文完成了20个新目标化合物的设计和合成,所有结构均经1HNMR和MS得以确证,纯度经HPLC检测均在95%以上,从而保证了其活性结果的可靠性。20个DAANs类新目标化合物在细胞试验(TZM-bl cell line)中对野生型HIV病毒(NL4-3)的复制均显示出强或明显抑制活性。其中新化合物41、43和49的EC50值分别是0.53 nM、0.87 nM和0.39 nM,活性强于同试验中的阳性对照药TMC12(51.5 nM),与TMC278的活性相当(EC50值是0.52 nM)。还有11个新目标化合物的EC50值在1-10 nM之间,3个化合物的EC50值在0.01-0.1μM之间和3个新化合物的EC50值>0.1μM。继而,对5个高活性新化合物进行了RT变异病毒株(K101E、E138K)的抑制活性试验,结果表明化合物43和49的活性(EC50 4–9 nM)仍可与TMC278 (EC50 ~5 nM)相当。本论文的新结果不仅证实了先期构效关系的可靠性,而且表明了现有优化策略的可行性。
为了解该类活性化合物的结构与药用性质关系,我们在pH 7.0和pH 7.4条件下测定了新化合物的水溶解度,结果发现高活性的43和49在两个pH条件下的溶解度都要好于TMC278。水溶性获得改善的活性化合物将有利于体内吸收。部分新化合物进行了人肝微粒体试验以考察它们的药代稳定性。结果表明该类化合物的细小结构变化会导致半衰期的明显差别(32-365 min)。上述活性最好的新化合物41、43和49在该试验中的半衰期分别为69.3 min、80.58 min和48.13 min,表明其代谢稳定性可能要略差于TMC278(90 min)。
总而言之,本论文设计合成了20个新活性化合物,发现了新DAAN类化合物43和49对HIV野生型和耐药性病毒株的抑制活性均可与国际上活性最强的同类候选药TMC278相媲美,并有改善了的水溶解性。新研究结果还揭示了新的结构与活性的关系、结构与药用性质的关系,推动了新一代NNRTI类新药的研究进程,为进一步的深入研究奠定了良好的基础。更多的类药性评价研究尚在进行中。
The human immunodeficiency virus (HIV) caused AIDS (Acquired Immune Deficiency Syndrome), which is an incurable disease. Although current anti-HIV drugs can inhibit HIV replication efficiently and prolong patients’life, the rapid appearance of drug resistance, high cost, and huge quantity greatly limited their clinical use. Therefore, it is necessary and urgent to find new drug with new structure scaffolds and new mechanism of action to overcome the problems of current anti-HIV drugs.
NNRTIs (Non-nucleoside Reverse Transcriptase Inhibitors) non-competitively binding to an allosteric hydrophobic pocket adjacent to the substrate binding site of RT enzyme and result conformation alternation of RT, thus inhibiting the enzymatic function of RT. NNRTIs are indispensable component of highly active anti-retroviral therapy (HAART). So far, five NNRTI drugs (nevirapine, delavirdine, efavirine, etravirine, rilpivirine) have been approved for treating HIV-1 infection. Although the structures of the five drugs are diversity, they all bind to the same binging pocket of HIV-1 RT. As next-generation NNRTIs, new drugs Etravirine (TMC125, 2008) and rilpivirine (TMC278, 2011) showed very highly potency against wild-type and many drug resistant viral strains, such as K103N, Y181C and K103N/Y181C. Both TMC125 and TMC278 belong to diaryprimidine (DAPY) family compounds, and TMC278 is more potent than TMC125 against both wild and resistant HIV viral strains.
In our previous studies, we have discovered a novel class of diarylanilines (DAANs) as new next-generation NNRTIs based on known biological information and NNRTI drug structures. As new leads, DAANs with a new structural scaffold that consist of three substituted phenyl moieties exhibited high potency against both wild-type and drug-resistant HIV viral strains. Previous SAR studies indicated that the presence of an ortho-amino group on the middle phenyl ring (B-ring) is very important for enhancing anti-HIV activity of DAANs. Molecular modeling results demonstrated that the amino group can serve as H-bond donor and acceptor to provide two hydrogen bonds with the main chain carbonyl group of key amino acid K101 and the side chain amino of K101 respectively. Additionally, the p-cyanophenyl (A-ring) and the linker NH between A-ring and B-ring are also necessary and essential structural moieties for anti-HIV activity.
As a continue study, we currently structural optimization of new leads focused on the further improvement of molecular potency against HIV wild-type and drug-resistant viral strains and drug-like properties. We introduced different polar groups on the middle phenyl-ring (B-ring) and changed the para-substitutes on the tri-substituted phenyl-ring (C-ring). The former aimed at to improve molecular water-soluble and probably provide additional interaction points and the latter for introducing a suitable hydroohobic linear groups to interact with the high conserved amino acid residues W229 in the deep and narrow hydrophobic tunnel to enhance anti-HIV potency. Herein, we reported the design, synthesis and bioorganical evaluation of 20 new DAANs compounds. Their all structures were identified by 1HNMR and MS and all purities reached above 95% by HPLC, thus ensuring biodata reliable. Twenty new DAAN compounds were first tested against wild-type HIV viral strain (NL4-3) in the TZM-bl cell line and all exhibited obvious or significant high potency with an EC50 value range of <1-100 nM. Among them, new compounds 41, 43 and 49 exhibited extremely hign potencies with very low EC50 values of 0.53 nM、0.87 nM and 0.39 nM, respectively, which are more potent than TMC125 (1.5 nM) and comparable with TMC278 (0.52 nM), a very promising candidat in clinical trial III, in the same assays. Additionally, other 11 new compounds were also very potent with a low EC50 value range of 1-10 nM and rest 6 compounds showed EC50 values of less than 0.1μM. Next, some active compounds were evaluated against K101E and E138K mutated virus strains. The most potent compounds 43 and 49 still showed high potency with EC50 values of 4-9 nM comparable to TMC278 (~5 nM) in the same assay. These very promising results confirmed our previous SAR and supported current structural optimization strategy.
Furthermore, water solubility of all new target compounds in pH 7.0 and 7.4 respectively, were evaluated, indicating that 43 and 49 are more soluble than TMC278 in above two conditions. Following, human liver microsome assay were performed to evaluate the metabolic stability of 10 new active compounds. However, quite different half-life values (32 -365 min) were observed, thus indicating that minor structural change might greatly affect molecular metabolic stability. The half-life time of high potent compounds 41, 43 and 49 are less than TMC278 (90 min) in the same assay.
In summary, 20 of new active DAAN compounds were designed and synthesized successfully. New compounds 43 and 49 exhibited extremely high potency against both wild-type and mutanted HIV viral strains and improved water-solubility, which are comparable to or better than TMC278 in the same assays. Current promising results will greatly encourage us to further improve drug-like properties of active DAANs aimed at to determine new NNRTI drug candidate(s). More assays are underway.
非竞争性的非核苷类逆转录酶抑制剂(Non-nucleoside reverse transcriptase inhibitors, NNRTIs)是高效逆转录疗法(HAART)的重要组成部分。目前已经上市的该类药物有5个(nevirapine, delavirdine, efavirine, etravirine, rilpivirine)。尽管它们都作用于HIV-1的逆转录酶的疏水性口袋(NNIBP),但从药物的化学结构可知NNRTIs具有结构多样性。其中etravirin(eTMC125, 2008)和rilpivirine (TMC278, 2011)为新一代非核苷类逆转录酶抑制剂,均属于二芳基嘧啶类化合物(DAPYs)。它们对野生型和多种耐药性病毒株(如K103N, Y181C, K103N/Y181C等)均具有相当强的抑制活性(nM)。而于2011年5月20日FDA最新批准上市的Rilpivirine (TMC278)的抗HIV-1活性和抗耐药性能均比TMC125更好,更长效。
本研究课题的最终目标是要发现具有新骨架结构、对野生型和多种HIV耐药性病毒株均有强抑制活性的新一代HIV-NNRTI类新药。我们在前期工作中,基于已有的NNRTIs类生物信息和药物结构,通过采用生物电子等排体替换的研究策略已发现了一类新骨架结构的新一代NNRTI类新先导物:二芳烃取代苯胺类化合物(Darylanalines,DAANs)。DAANs类新先导物对野生型和多种耐药性病毒株均显示出了与TMC125相当的强抑制活性(nM)。DAANs类新先导物是用一个带有取代基的苯环代替了DAPY类化合物结构的中间嘧啶环,从而形成了含有三个取代苯环的新骨架结构,但同时保持了与DAPYs化合物类似的分子柔性和分子形态。前期分子模拟结果表明:新先导物与DAPY类化合物在药物作用靶点RT的活性口袋(NNIBP)中的作用方式非常类似,与RT结合时呈现了与DAPY类化合物相同的“U”形构象。分子对接结果还发现,DAANs先导物中间苯环特定位有氨基取代时,该氨基可作为氢键供体和氢键受体分别与靶标表面关键氨基酸K101的主链羰基和侧链氨基形成两根氢键,从而为新先导物的高活性提供了理论上的支持。前期构效关系表明DAANs先导物结构中的对氰苯基(A环)、中间苯环(B环)、邻对位三取代苯(C环)和AB环间的氨链是分子活性的必需结构要素和基团;提示B环氨基的间位取代基和C环对位的取代基都与分子活性相关,有进一步修饰的化学空间。
本论文研究是前期工作的继续,着重于对已发现的DAANs类新先导物做进一步的结构优化,以期继续提高该类分子对HIV野生型和多种耐药性病毒株的抑制活性,同时改善分子的理化性质,使之更具有类药性。本论文的结构修饰点着重于在B环引入不同的极性基团和C环对位取代基的变化。前者意在改善分子的水溶性并产生与靶点间的新作用点,后者基于同类候选药TMC278的氰乙烯基结构,试图引入较长的线性基团进入NNIBP的强疏水的“狭长”的空腔中,与其表面的氨基酸残基以及保守氨基酸W229产生π-π作用,有利于抑制耐药性病毒的复制。本论文完成了20个新目标化合物的设计和合成,所有结构均经1HNMR和MS得以确证,纯度经HPLC检测均在95%以上,从而保证了其活性结果的可靠性。20个DAANs类新目标化合物在细胞试验(TZM-bl cell line)中对野生型HIV病毒(NL4-3)的复制均显示出强或明显抑制活性。其中新化合物41、43和49的EC50值分别是0.53 nM、0.87 nM和0.39 nM,活性强于同试验中的阳性对照药TMC12(51.5 nM),与TMC278的活性相当(EC50值是0.52 nM)。还有11个新目标化合物的EC50值在1-10 nM之间,3个化合物的EC50值在0.01-0.1μM之间和3个新化合物的EC50值>0.1μM。继而,对5个高活性新化合物进行了RT变异病毒株(K101E、E138K)的抑制活性试验,结果表明化合物43和49的活性(EC50 4–9 nM)仍可与TMC278 (EC50 ~5 nM)相当。本论文的新结果不仅证实了先期构效关系的可靠性,而且表明了现有优化策略的可行性。
为了解该类活性化合物的结构与药用性质关系,我们在pH 7.0和pH 7.4条件下测定了新化合物的水溶解度,结果发现高活性的43和49在两个pH条件下的溶解度都要好于TMC278。水溶性获得改善的活性化合物将有利于体内吸收。部分新化合物进行了人肝微粒体试验以考察它们的药代稳定性。结果表明该类化合物的细小结构变化会导致半衰期的明显差别(32-365 min)。上述活性最好的新化合物41、43和49在该试验中的半衰期分别为69.3 min、80.58 min和48.13 min,表明其代谢稳定性可能要略差于TMC278(90 min)。
总而言之,本论文设计合成了20个新活性化合物,发现了新DAAN类化合物43和49对HIV野生型和耐药性病毒株的抑制活性均可与国际上活性最强的同类候选药TMC278相媲美,并有改善了的水溶解性。新研究结果还揭示了新的结构与活性的关系、结构与药用性质的关系,推动了新一代NNRTI类新药的研究进程,为进一步的深入研究奠定了良好的基础。更多的类药性评价研究尚在进行中。
The human immunodeficiency virus (HIV) caused AIDS (Acquired Immune Deficiency Syndrome), which is an incurable disease. Although current anti-HIV drugs can inhibit HIV replication efficiently and prolong patients’life, the rapid appearance of drug resistance, high cost, and huge quantity greatly limited their clinical use. Therefore, it is necessary and urgent to find new drug with new structure scaffolds and new mechanism of action to overcome the problems of current anti-HIV drugs.
NNRTIs (Non-nucleoside Reverse Transcriptase Inhibitors) non-competitively binding to an allosteric hydrophobic pocket adjacent to the substrate binding site of RT enzyme and result conformation alternation of RT, thus inhibiting the enzymatic function of RT. NNRTIs are indispensable component of highly active anti-retroviral therapy (HAART). So far, five NNRTI drugs (nevirapine, delavirdine, efavirine, etravirine, rilpivirine) have been approved for treating HIV-1 infection. Although the structures of the five drugs are diversity, they all bind to the same binging pocket of HIV-1 RT. As next-generation NNRTIs, new drugs Etravirine (TMC125, 2008) and rilpivirine (TMC278, 2011) showed very highly potency against wild-type and many drug resistant viral strains, such as K103N, Y181C and K103N/Y181C. Both TMC125 and TMC278 belong to diaryprimidine (DAPY) family compounds, and TMC278 is more potent than TMC125 against both wild and resistant HIV viral strains.
In our previous studies, we have discovered a novel class of diarylanilines (DAANs) as new next-generation NNRTIs based on known biological information and NNRTI drug structures. As new leads, DAANs with a new structural scaffold that consist of three substituted phenyl moieties exhibited high potency against both wild-type and drug-resistant HIV viral strains. Previous SAR studies indicated that the presence of an ortho-amino group on the middle phenyl ring (B-ring) is very important for enhancing anti-HIV activity of DAANs. Molecular modeling results demonstrated that the amino group can serve as H-bond donor and acceptor to provide two hydrogen bonds with the main chain carbonyl group of key amino acid K101 and the side chain amino of K101 respectively. Additionally, the p-cyanophenyl (A-ring) and the linker NH between A-ring and B-ring are also necessary and essential structural moieties for anti-HIV activity.
As a continue study, we currently structural optimization of new leads focused on the further improvement of molecular potency against HIV wild-type and drug-resistant viral strains and drug-like properties. We introduced different polar groups on the middle phenyl-ring (B-ring) and changed the para-substitutes on the tri-substituted phenyl-ring (C-ring). The former aimed at to improve molecular water-soluble and probably provide additional interaction points and the latter for introducing a suitable hydroohobic linear groups to interact with the high conserved amino acid residues W229 in the deep and narrow hydrophobic tunnel to enhance anti-HIV potency. Herein, we reported the design, synthesis and bioorganical evaluation of 20 new DAANs compounds. Their all structures were identified by 1HNMR and MS and all purities reached above 95% by HPLC, thus ensuring biodata reliable. Twenty new DAAN compounds were first tested against wild-type HIV viral strain (NL4-3) in the TZM-bl cell line and all exhibited obvious or significant high potency with an EC50 value range of <1-100 nM. Among them, new compounds 41, 43 and 49 exhibited extremely hign potencies with very low EC50 values of 0.53 nM、0.87 nM and 0.39 nM, respectively, which are more potent than TMC125 (1.5 nM) and comparable with TMC278 (0.52 nM), a very promising candidat in clinical trial III, in the same assays. Additionally, other 11 new compounds were also very potent with a low EC50 value range of 1-10 nM and rest 6 compounds showed EC50 values of less than 0.1μM. Next, some active compounds were evaluated against K101E and E138K mutated virus strains. The most potent compounds 43 and 49 still showed high potency with EC50 values of 4-9 nM comparable to TMC278 (~5 nM) in the same assay. These very promising results confirmed our previous SAR and supported current structural optimization strategy.
Furthermore, water solubility of all new target compounds in pH 7.0 and 7.4 respectively, were evaluated, indicating that 43 and 49 are more soluble than TMC278 in above two conditions. Following, human liver microsome assay were performed to evaluate the metabolic stability of 10 new active compounds. However, quite different half-life values (32 -365 min) were observed, thus indicating that minor structural change might greatly affect molecular metabolic stability. The half-life time of high potent compounds 41, 43 and 49 are less than TMC278 (90 min) in the same assay.
In summary, 20 of new active DAAN compounds were designed and synthesized successfully. New compounds 43 and 49 exhibited extremely high potency against both wild-type and mutanted HIV viral strains and improved water-solubility, which are comparable to or better than TMC278 in the same assays. Current promising results will greatly encourage us to further improve drug-like properties of active DAANs aimed at to determine new NNRTI drug candidate(s). More assays are underway.
引文
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[17] D’Aqulia RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection: a randomized, double-blind, placebocontrolled trial. Ann Intern Med, 1997, 124: 1019-1030.
[18] Johnson S, Chan J, Bennett CL. Hepatotoxicity after prophylaxis with a nevirapine-containing antiretroviral regimen. Ann Intern Med, 2002, 137: 146-147.
[19] Cattelan AM, Trevenzoli M, Sasset L, et al. Toxic epidermal necrolysis induced by nevirapine therapy: descrip of teo case and review of the literature. J Infect, 2001, 43: 246-249.
[20] Boone, L. R. Next-geneeration HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Opin. Investig. Drugs., 2006, 7, 2: 128-135.
[21] Bader, J.P., Mcmahon, J. B., Schultz, R. J., Narayanan, V. L., et al. Proc. Natal. Acad. Sci. U.S.A. 1991, 88: 6740
[22] Borkow G, Arion D, Wainberg MA, et al. The thiocarboxanilide non-nucleoside inhibitor UC781 restores antiviral activity of 3’-azido-3’2-deoxythymidine(AZT) against AZT-resistant human immunodeficiency virus type. Antimicrob Agents Chemother, 1999, 43: 259-263.
[23]周婷,新型HIV非核苷类逆转录酶抑制剂(NNRTIs)--取代苯并咪唑衍生物的设计合成及活性评价,中国人民解放军军事医学科学院硕士论文,2005.
[24]朱骏杰,曹江营,刘新泳,新一代非核苷类HIV-1逆转录酶抑制剂研究进展,中国新药杂志,2009,3: 206-212.
[25] Gagnon A, Bonneau PR, et al. Thiotetrazole alkynylacetanilides as potent and bioavailable non-nucleoside inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptase. Bioorg. Med. Chem. Lett., 2007, 17, 16: 4437-4441.
[26] Marie-Pirerre de Béthune, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development and use in the treatment of HIV-1 infection: areview of the last 20 years (1989-2009), Antiviral Research, 2010, 85, 1: 75-90.
[27] Dhavl G. Prajapati, R. Ramajayam, et al. The search for potent, small molecule NNRTIs: A review, Bioorg. Med. Chem., 2009,17: 5744-5762.
[28] Ruiz-Caro J., Basavapathruni A., Jorgensena W. L., Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase, Bioorg. Med. Chem. Lett., 2006, 16: 668.
[1] Ding J, Das K, Hsiou Y, Sarafianos SG, Clark AD, et al. Structureand functional implications of the polymerase activesite region in a complex of HIV-1 RT with a doublestranded DNA template-primer and an antibodyFab fragment at 2.8 Aresolution. J Mol Biol, 1998, 284, 1095-1111.
[2]朱骏杰,曹江营,刘新泳,新一代非核苷类HIV-1逆转录酶抑制剂研究进展,中国新药杂志,2009,3: 206-212.
[3] Barreca ML, Rao A,Deluca L, et al. Computational strategies in discovering novel non-nucleoside inhibitors of HIV-1 RT. J Med Chem, 2005, 48, 9: 3433-3437
[4]陈先红,谢蓝.抗耐药性HIV非核苷类逆转录酶抑制剂研究进展.中国药学化学杂志, 2006, 16, 3: 182-287.
[5] Xingtao Tian, Bingjie Qin, Lan xie, et al. Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorganic & Medicinal Chemistry Letters, 2009, 19: 5482-5485.
[6] Xingtao Tian, Bingjie Qin, Lan xie, et al. Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors, J Med Chem, 2010, 53: 8287-8297.
[ 1 ] Gorvin JH. The synthesis of Di- and Tri-arylamines through Halogen Displacement by Base-activated Arylamines: Comparison with the Ullmann Condensation. J Che Soc Perkin Trans 1, 1988, 1331-1335.
[2]张进琪,精细有机合成,南京大学出版社,1990,1:114.
[3] Lawrence E. Fisher, Joan M. Caroon, Jahangir, S. Russell Stabler, Scott Lundberg, Joseph M. Muchowski, O-Methylarenehydroxamates as ortho-lithiation directing groups. Titanium (III)-mediated conversion of O-methyl hydroxamates to primary amides, J. Org. Chem., 1993, 58, 3643-3647
[4] Nakyen Choy, K. C. Russell, Julio C. Alvarez, Alexa Fider, Synthesis and redox properties of novel alkynyl flavins, Tetrahedron Letters, 2000, 41: 1515-1518.
[5]秦炳杰,新型抗耐药性HIV-NNRTIs先导物的设计与发现。博士学位论文,2009,军事医学科学院.
[6] Xingtao Tian, Bingjie Qin, Lan xie, et al. Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors, J. Med .Chem., 2010, 53: 8287-8297.
[7] Mordant G, Schmitt B, Pasquier E, et al. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. European Journal of Medicinal Chemistry ,2007, 42: 567-579.
[8] Mariappan Periasamy, et al. Methods of anhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis. Journal of Organometallic Chemistry, 2000, 609: 137-151.
[9]田兴涛,二芳基吡啶类新型HIV-1NNRTIs的设计、合成及生物活性评价。博士学位论文,2009,军事医学科学院。
[1]田兴涛,二芳基吡啶类新型HIV-1NNRTIs的设计、合成及生物评价,2009,军事医学科学院博士论文.
[2]展鹏,刘新泳,新型HIV-1非核苷类逆转录酶抑制剂放入结合模式特征与抗耐药性抑制剂设计研究进展,中国药物化学杂志,2009,19,3:228-235.
[3] Anti-HIV assay (TZM-bl). Anti-HIV-1 activity is measured as reductions in Luc reporter gene expression after a single round of virus infection in TZM-bl cells. HIV-1 at 200 TCID50 and various dilutions of test samples (eight dilutions, 4-fold stepwise) are mixed in a total volume of 150μL growth medium in 96-well black solid plates (Corning-Costar). Freshly trypsinized cells (10,000 cells in 100μL of growth medium) are added to each well. One set of eight control wells receive cells plus virus (virus control), and another set of eight wells receive cells only (background control). After a 48 h incubation, culture medium is removed from each well and 100μL of Bright Glo reagent is added to the cells. After a 2 min incubation at room temperature, the luciferase activity in the assay wells are measured using a Victor 2 luminometer. The 50% inhibitory dose (EC50) is defined as the sample concentration that caused a 50% reduction in Relative Luminescence Units (RLU) compared to virus control wells after subtraction of background RLU. Statistical analysis. A CallcuSyn software (Biosoft, Cambridge, UK) is used for dose effect analysis to derive IC50.
[4] Ting Zhou, Qian Shi, Kuo-Hsiung Lee, et al. 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., Bioorganic & Medicinal Chemistry, 2010, 18: 6678-6689.
[1]田兴涛,二芳基吡啶类新型HIV-NNRTIs的设计、合成及生物活性评价,中国人民解放军军事医学科学院博士论文,2009.
[2] Arts EJ., Wainberg MA., Advan. Virus Res., 1996, 46: 97
[3]冀蕾,非核苷类HIV-1逆转录酶抑制剂6-萘甲酰基取代HEPT及6-芳甲酰基、6-(α-氰基芳甲基)取代S-DABO类似物的设计、合成及构效关系研究,复旦大学博士论文,2006.
[4]熊远珍,非核苷类HIV-1逆转录酶抑制剂二芳基三嗪及6-萘氧基、6-(α-氰基芳甲基)取代S-DABO类似物的设计、合成及构效关系研究,复旦大学博士论文,2008.
[5]展鹏,新型芳唑(嗪)巯乙酰胺类HIV-1NNRTI的设计、合成与活性研究,山东大学博士论文,2010.
[6] Sluiscremer N, Temiz NA, Bahar I. Conformational changes in HIV-1 reverse transcriptase induced by non-nucleoside reverse transcriptase inhibitor binding. CurrHIV Res, 2004,2, 4: 323-332.
[7] Campiani, G.; Ramunno, A.; Maga, G. et al. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives. Curr. Pharm. Des., 2002, 8(8): 615-657.
[8] D’Aqulia RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection: a randomized, double-blind, placebocontrolled trial. Ann Intern Med, 1997, 124: 1019-1030.
[9] Johnson S, Chan J, Bennett CL. Hepatotoxicity after prophylaxis with a nevirapine-containing antiretroviral regimen. Ann Intern Med, 2002, 137: 146-147.
[10] Cattelan AM, Trevenzoli M, Sasset L, et al. Toxic epidermal necrolysis induced by nevirapine therapy: descrip of teo case and review of the literature. J Infect, 2001, 43: 246-249.
[11] Boone, L. R. Next-geneeration HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Opin. Investig. Drugs., 2006, 7, 2: 128-135.
[12] Pauwels R, et al. Potent and selective inhibiton of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature, 1990, 343, 2: 470-474.
[13] Baba M, et al. Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrob Agent Chemother, 1994, 38: 688-692.
[14]孟歌,非核苷类HIV-1逆转录酶抑制剂研究进展,中国医药导报, 2010, 7, 8: 9-12.
[15]孟歌,陈芬儿.HEPT类非核苷类HIV-1逆转录酶抑制剂的研究进展.中国药物化学杂志,2004, 14, 1: 57-66.
[16] Mai A, Artico M, Sbardella G, et al. Preparation and anti-HIV-1 activity of thio analogues of dichydroalkoxybenzy-loxopyrimidines. J. Med. Chem., 1995, 38, 17: 3258-3263.
[17] Mai A, Artico M, Sbardella G, et al. Dihydro (alkylthio) (naphthylmethyl) oxopyrimidines: novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series. J. Med. Chem., 1997, 40, 10: 1447-1454.
[18] Bader, J.P., Mcmahon, J. B., Schultz, R. J., Narayanan, V. L., et al. Proc. Natal. Acad. Sci. U.S.A. 1991, 88: 6740
[19] Borkow G, Wainberg MA, et al. The thiocarboxanilide non-nucleoside inhibitor UC781 restores antiviral activity of 3’-azido-3’2-deoxythymidine(AZT) against AZT-resistant human immunodeficiency virus type. Antimicrob Agents Chemother, 1999, 43: 259-263.
[20]周婷,新型HIV非核苷类逆转录酶抑制剂(NNRTIs)--取代苯并咪唑衍生物的设计合成及活性评价,中国人民解放军军事医学科学院硕士论文,2005.
[21]秦炳杰,新型抗耐药性HIV-NNRTIs先导物的设计与发现。博士学位论文,2009,军事医学科学院.
[22]朱骏杰,曹江营,刘新泳,新一代非核苷类HIV-1逆转录酶抑制剂研究进展,中国新药杂志,2009,3: 206-212. [ 23 ] Ren J, Nichols C, Bird LE, et al. Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. J. Biol. Chem., 2000, 275, 19: 14316-14320.
[24]杨劲松.抗HIV活性香豆素类化合物的研究进展.华西药学杂志,2001,16,4:285-288.
[25] Romines KR, Freeman GA, Schaller LT, et al. Structure-activity relationshipstudies of novel benzophenones leading to the discovery of a potent, next generation HIV non-nucleoside reverse transcriptase inhibitor. J. Med. Chem., 2006, 49, 2: 727-739.
[2] http://news.sohu.com/20110516/n307608314.shtml.
[3]田兴涛,二芳基吡啶类新型HIV-NNRTIs的设计、合成及生物活性评价,中国人民解放军军事医学科学院博士论文,2009.
[4] Clavel F., Guetard D., Brun-Vezinet F, et al. Isolation of a New Human Retrovirus from West African patients with AIDS. Science, 1986, 233: 343-346.
[5] Perelson A. S., Neumann AU., Markowitz M., et al. HIV-1 Dynamics in Vivo: virion clearance Rate, Infected Cell Life-Span, and Viral Generation Time. Science, 1996, 271: 1582-1586.
[6] Greene WC, Debyser Z, Ikeda Y, et al. Novel targets for HIV therapy. Antiviral Research, 2008, 80: 251-265.
[7]冯筱晴,非核苷类HIV-1逆转录酶抑制剂的研究,复旦大学博士论文,2010.
[8] Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. New England Journal of Medicine, 2003, 349: 2293-2303.
[9] Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. New England Journal of Medicine, 2003, 349: 2304-2315.
[10]梁永宏,HIV-1抑制剂的研究,复旦大学博士论文,2010.
[11] Arts EJ., Wainberg MA., Advan. Virus Res. 1996, 46: 97
[12]冀蕾,非核苷类HIV-1逆转录酶抑制剂6-萘甲酰基取代HEPT及6-芳甲酰基、6-(α-氰基芳甲基)取代S-DABO类似物的设计、合成及构效关系研究,复旦大学博士论文,2006.
[13]熊远珍,非核苷类HIV-1逆转录酶抑制剂二芳基三嗪及6-萘氧基、6-(α-氰基芳甲基)取代S-DABO类似物的设计、合成及构效关系研究,复旦大学博士论文,2008.
[14]展鹏,新型芳唑(嗪)巯乙酰胺类HIV-1NNRTI的设计、合成与活性研究,山东大学博士论文,2010.
[15] Sluiscremer N, Temiz NA, Bahar I. Conformational changes in HIV-1 reverse transcriptase induced by non-nucleoside reverse transcriptase inhibitor binding. CurrHIV Res, 2004,2, 4: 323-332.
[16] Campiani, G.; Ramunno, A.; Maga, G. et al. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives. Curr. Pharm. Des., 2002, 8(8): 615-657.
[17] D’Aqulia RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection: a randomized, double-blind, placebocontrolled trial. Ann Intern Med, 1997, 124: 1019-1030.
[18] Johnson S, Chan J, Bennett CL. Hepatotoxicity after prophylaxis with a nevirapine-containing antiretroviral regimen. Ann Intern Med, 2002, 137: 146-147.
[19] Cattelan AM, Trevenzoli M, Sasset L, et al. Toxic epidermal necrolysis induced by nevirapine therapy: descrip of teo case and review of the literature. J Infect, 2001, 43: 246-249.
[20] Boone, L. R. Next-geneeration HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Opin. Investig. Drugs., 2006, 7, 2: 128-135.
[21] Bader, J.P., Mcmahon, J. B., Schultz, R. J., Narayanan, V. L., et al. Proc. Natal. Acad. Sci. U.S.A. 1991, 88: 6740
[22] Borkow G, Arion D, Wainberg MA, et al. The thiocarboxanilide non-nucleoside inhibitor UC781 restores antiviral activity of 3’-azido-3’2-deoxythymidine(AZT) against AZT-resistant human immunodeficiency virus type. Antimicrob Agents Chemother, 1999, 43: 259-263.
[23]周婷,新型HIV非核苷类逆转录酶抑制剂(NNRTIs)--取代苯并咪唑衍生物的设计合成及活性评价,中国人民解放军军事医学科学院硕士论文,2005.
[24]朱骏杰,曹江营,刘新泳,新一代非核苷类HIV-1逆转录酶抑制剂研究进展,中国新药杂志,2009,3: 206-212.
[25] Gagnon A, Bonneau PR, et al. Thiotetrazole alkynylacetanilides as potent and bioavailable non-nucleoside inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptase. Bioorg. Med. Chem. Lett., 2007, 17, 16: 4437-4441.
[26] Marie-Pirerre de Béthune, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development and use in the treatment of HIV-1 infection: areview of the last 20 years (1989-2009), Antiviral Research, 2010, 85, 1: 75-90.
[27] Dhavl G. Prajapati, R. Ramajayam, et al. The search for potent, small molecule NNRTIs: A review, Bioorg. Med. Chem., 2009,17: 5744-5762.
[28] Ruiz-Caro J., Basavapathruni A., Jorgensena W. L., Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase, Bioorg. Med. Chem. Lett., 2006, 16: 668.
[1] Ding J, Das K, Hsiou Y, Sarafianos SG, Clark AD, et al. Structureand functional implications of the polymerase activesite region in a complex of HIV-1 RT with a doublestranded DNA template-primer and an antibodyFab fragment at 2.8 Aresolution. J Mol Biol, 1998, 284, 1095-1111.
[2]朱骏杰,曹江营,刘新泳,新一代非核苷类HIV-1逆转录酶抑制剂研究进展,中国新药杂志,2009,3: 206-212.
[3] Barreca ML, Rao A,Deluca L, et al. Computational strategies in discovering novel non-nucleoside inhibitors of HIV-1 RT. J Med Chem, 2005, 48, 9: 3433-3437
[4]陈先红,谢蓝.抗耐药性HIV非核苷类逆转录酶抑制剂研究进展.中国药学化学杂志, 2006, 16, 3: 182-287.
[5] Xingtao Tian, Bingjie Qin, Lan xie, et al. Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorganic & Medicinal Chemistry Letters, 2009, 19: 5482-5485.
[6] Xingtao Tian, Bingjie Qin, Lan xie, et al. Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors, J Med Chem, 2010, 53: 8287-8297.
[ 1 ] Gorvin JH. The synthesis of Di- and Tri-arylamines through Halogen Displacement by Base-activated Arylamines: Comparison with the Ullmann Condensation. J Che Soc Perkin Trans 1, 1988, 1331-1335.
[2]张进琪,精细有机合成,南京大学出版社,1990,1:114.
[3] Lawrence E. Fisher, Joan M. Caroon, Jahangir, S. Russell Stabler, Scott Lundberg, Joseph M. Muchowski, O-Methylarenehydroxamates as ortho-lithiation directing groups. Titanium (III)-mediated conversion of O-methyl hydroxamates to primary amides, J. Org. Chem., 1993, 58, 3643-3647
[4] Nakyen Choy, K. C. Russell, Julio C. Alvarez, Alexa Fider, Synthesis and redox properties of novel alkynyl flavins, Tetrahedron Letters, 2000, 41: 1515-1518.
[5]秦炳杰,新型抗耐药性HIV-NNRTIs先导物的设计与发现。博士学位论文,2009,军事医学科学院.
[6] Xingtao Tian, Bingjie Qin, Lan xie, et al. Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors, J. Med .Chem., 2010, 53: 8287-8297.
[7] Mordant G, Schmitt B, Pasquier E, et al. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. European Journal of Medicinal Chemistry ,2007, 42: 567-579.
[8] Mariappan Periasamy, et al. Methods of anhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis. Journal of Organometallic Chemistry, 2000, 609: 137-151.
[9]田兴涛,二芳基吡啶类新型HIV-1NNRTIs的设计、合成及生物活性评价。博士学位论文,2009,军事医学科学院。
[1]田兴涛,二芳基吡啶类新型HIV-1NNRTIs的设计、合成及生物评价,2009,军事医学科学院博士论文.
[2]展鹏,刘新泳,新型HIV-1非核苷类逆转录酶抑制剂放入结合模式特征与抗耐药性抑制剂设计研究进展,中国药物化学杂志,2009,19,3:228-235.
[3] Anti-HIV assay (TZM-bl). Anti-HIV-1 activity is measured as reductions in Luc reporter gene expression after a single round of virus infection in TZM-bl cells. HIV-1 at 200 TCID50 and various dilutions of test samples (eight dilutions, 4-fold stepwise) are mixed in a total volume of 150μL growth medium in 96-well black solid plates (Corning-Costar). Freshly trypsinized cells (10,000 cells in 100μL of growth medium) are added to each well. One set of eight control wells receive cells plus virus (virus control), and another set of eight wells receive cells only (background control). After a 48 h incubation, culture medium is removed from each well and 100μL of Bright Glo reagent is added to the cells. After a 2 min incubation at room temperature, the luciferase activity in the assay wells are measured using a Victor 2 luminometer. The 50% inhibitory dose (EC50) is defined as the sample concentration that caused a 50% reduction in Relative Luminescence Units (RLU) compared to virus control wells after subtraction of background RLU. Statistical analysis. A CallcuSyn software (Biosoft, Cambridge, UK) is used for dose effect analysis to derive IC50.
[4] Ting Zhou, Qian Shi, Kuo-Hsiung Lee, et al. 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., Bioorganic & Medicinal Chemistry, 2010, 18: 6678-6689.
[1]田兴涛,二芳基吡啶类新型HIV-NNRTIs的设计、合成及生物活性评价,中国人民解放军军事医学科学院博士论文,2009.
[2] Arts EJ., Wainberg MA., Advan. Virus Res., 1996, 46: 97
[3]冀蕾,非核苷类HIV-1逆转录酶抑制剂6-萘甲酰基取代HEPT及6-芳甲酰基、6-(α-氰基芳甲基)取代S-DABO类似物的设计、合成及构效关系研究,复旦大学博士论文,2006.
[4]熊远珍,非核苷类HIV-1逆转录酶抑制剂二芳基三嗪及6-萘氧基、6-(α-氰基芳甲基)取代S-DABO类似物的设计、合成及构效关系研究,复旦大学博士论文,2008.
[5]展鹏,新型芳唑(嗪)巯乙酰胺类HIV-1NNRTI的设计、合成与活性研究,山东大学博士论文,2010.
[6] Sluiscremer N, Temiz NA, Bahar I. Conformational changes in HIV-1 reverse transcriptase induced by non-nucleoside reverse transcriptase inhibitor binding. CurrHIV Res, 2004,2, 4: 323-332.
[7] Campiani, G.; Ramunno, A.; Maga, G. et al. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives. Curr. Pharm. Des., 2002, 8(8): 615-657.
[8] D’Aqulia RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection: a randomized, double-blind, placebocontrolled trial. Ann Intern Med, 1997, 124: 1019-1030.
[9] Johnson S, Chan J, Bennett CL. Hepatotoxicity after prophylaxis with a nevirapine-containing antiretroviral regimen. Ann Intern Med, 2002, 137: 146-147.
[10] Cattelan AM, Trevenzoli M, Sasset L, et al. Toxic epidermal necrolysis induced by nevirapine therapy: descrip of teo case and review of the literature. J Infect, 2001, 43: 246-249.
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