Asperphenamate全合成新方法及体外抗乳腺癌活性评价

目的探索活性天然产物asperphenamate全合成的新方法，并对其体外抗人乳腺癌作用进行评价。方法以L-苯丙氨酸为起始原料，经过7步反应得到光学活性的目标产物，其结构经红外光谱、CD光谱、核磁共振氨谱、ESI-MS及旋光度确证。采用MTT法，对雌激素受体肿瘤细胞T47D和MDA-MB231进行体外抗乳腺癌活性测试。结果与结论以总收率34％合成了asperphenamate。体外抗乳腺癌活性测试表明asperphenamate对两种肿瘤细胞株没有抑制活性。     

含双环哌啶结构 HIV-1 抑制剂的设计合成及生物活性研究

目的 设计合成一系列具有新型结构特征的双环哌啶类 C-C 族趋化因子受体5(CCR5) 抑制剂并测定其抗 HIV-1 活性。方法 以HIV-1 辅助受体 CCR5 抑制剂 Vicriviroc 的结构为模板,通过改变左侧哌嗪结构、取代基位置等方法设计并合成一系列新化合物。并利用 MS 及 ¹H-NMR 谱对这些化合物进行了结构表征。结果与结论 合成了 15 个新结构化合物,活性测试结果表明,该系列化合物具有较强的抗 HIV-1 R5 病毒株的活性 (IC₅₀ = 1.20 ～ 66.24 µmol·L^-1 )。 当 R¹ 为芳基结构且两个氮原子满足标准的丙二胺结构时,化合物的活性更好。     

L-异谷氨酰胺类氨肽酶N抑制剂的合成及初步活性

目的 设计并合成一系列新型L-异谷氨酰胺类衍生物,并测定其对氨肽酶N (APN)的抑制活性。方法 以L-谷氨酸为基本骨架,与3,4-二氯苯甲酸形成酰氯发生酰化、环合反应得到关键中间体环状酸酐,再经氨解反应合成目标化合物。采用体外抑酶试验测定化合物抑制氨肽酶N的活性。 结果与结论 合成了15个未见报道的L-异谷氨酰胺衍生物,其结构经过¹H-NMR、MS、和IR的确证。其中化合物I₄、I₆显示出较好的抑制氨肽酶N活性(IC₅₀=20~40 μmol.L^-1),有进一步研究的价值。     

8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物的设计、合成及抗真菌活性研究

目的 设计、合成一系列 8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物,测定其体外抗真菌活性。方法 以邻氟苯胺为起始原料,经与丙烯酸加成、在多聚磷酸（PPA）中环合制得中间体8-氟-2,3-二氢喹啉-4(1H)-酮;该中间体与各种 N⁴-取代的氨基脲缩合得到目标化合物。采用二倍浓度稀释法测试各目标化合物的体外抗真菌活性,实验选用 8 种临床上常用的致病真菌为测试菌株,以氟康唑、伊曲康唑为阳性对照药。结果与结论 16 个 8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物均未见文献报道,其结构经¹H-NMR、MS 谱确证;活性测试结果表明,合成的多个目标化合物对测试真菌表现出较好的体外抑菌活性,尤其是对红色毛藓菌的活性均好于阳性对照药。     

L-蛋氨酸类似物 L-2-氨基-４-叠氮基丁酸的合成

目的 优化L-2-氨基-４-叠氮基丁酸的合成工艺。方法 以L-蛋氨酸为起始原料经硫甲基化、水解一锅法合成L-2-氨基-4-羟基丁酸（2）,2在浓盐酸中环合得到重要中间体α-氨基-γ-丁内酯盐酸盐（3）,3 经溴代开环、成酯、叠氮化、水解4步反应制得目标产物。结果与结论 以L-蛋氨酸为起始原料,经 6 步反应合成目标产物,其结构经¹H-NMR 和 IR 谱确证。该合成方法原料易得、条件温和、操作简单、易于中试放大。     

2-苯基-5-吡啶基-1,3,4-噁二唑类化合物的合成及黄嘌呤氧化酶抑制活性

目的 设计合成2-苯基-5-吡啶基-1,3,4-噁二唑类化合物,并对其黄嘌呤氧化酶抑制活性进行初步评价。方法 以对羟基苯甲酸甲酯为原料,经烃化、肼解、环合等反应合成目标化合物。以非布司他为阳性对照药,采用牛源的黄嘌呤氧化酶对目标化合物的抑制活性进行评价。结果 共合成了15 个未见文献报道的目标化合物,结构经核磁共振氢谱、飞行时间质谱和红外光谱确证。目标化合物均表现出一定的黄嘌呤氧化酶抑制活性,其中化合物 4m（IC₅₀=1.04 µmol·L^-1）活性最好,但低于阳性对照药非布司他（IC₅₀=0.024 µmol·L^-1）。结论 2-苯基-5-吡啶基-1,3,4-噁二唑类化合物作为新型黄嘌呤氧化酶抑制剂,其构效关系值得进一步研究。     

3-苯甲酰基-2H-1-苯并吡喃-2-酮衍生物的设计、合成及抗肿瘤活性

目的 设计合成3-苯甲酰基-2H-1-苯并吡喃-2-酮衍生物,并评价其抗肿瘤活性。方法 以取代苯乙酮为原料,首先与碳酸二乙酯经Claisen缩合得到相应的取代β-酮酸酯,再与取代水杨醛经Knoevenagel缩合,同时环合得到目标化合物。采用人急性早幼粒白血病细胞HL-60及人乳腺癌细胞T47D对部分目标化合物的抗肿瘤活性进行初步评价。结果 合成了18个目标化合物,其中13个未见文献报道,目标化合物的结构经核磁共振氢谱和红外光谱确证。化合物III₁₅对人乳腺癌细胞T47D的抑制活性较强,IC₅₀值为38 μmol.L^-1;化合物III₁、III₂、III₁₅对人急性早幼粒白血病细胞HL-60的抑制活性较好,IC₅₀值分别为37、36、16 μmol.L^-1。结论 3-苯甲酰基-2H-1-苯并吡喃-2-酮衍生物作为新型肿瘤抑制剂,其构效关系值得进一步研究。     

含磷毒剂体外药效学评价方法建立

目的 含磷毒剂主要是通过抑制乙酰胆碱酯酶(AChE)发生毒害作用,本文旨在建立一种在体外快速测定AChE 活性的方法,为有机磷毒剂中毒及解救时AChE活性检测奠定基础。方法 以动物全血红细胞作为AChE的来源,利用硫代乙酰胆碱与巯基显色剂DTNB反应形成黄色化合物的原理,用分光光度法在412 nm处比色定量测定AChE活性。首先利用还原型谷胱甘肽能提供巯基,其显色效应相当于硫代胆碱,故用谷胱甘肽进行DTNB法测定AChE活性标准曲线的绘制;其次进行了DTNB法测定全血样品AChE活性的方法学研究,主要包括对全血进行20, 40和60等不同倍数的稀释后测定AChE活性、使用兔、豚鼠、比格犬及猴等不同动物全血红细胞作为AChE的来源进行AChE活性的测定,同时对不同批次全血样品及同一批次血样不同时间的AChE活性进行测定,验证DTNB法测定AChE活性的方法的可行性;最后选择兔全血红细胞作为AChE的来源,对有机磷毒剂如沙林及梭曼进行了体外药效学评价,梭曼终浓度为6.25 nmol·L^-1～0.4 μmol·L^-1,沙林终浓度为6.25 nmol·L^-1～4 μmol·L^-1,以不同浓度沙林及梭曼的负对数对兔子全血AChE抑制百分率的对数作图,求出沙林及梭曼抑制动物全血AChE的量效曲线,计算得到其IC₅₀值和IC₉₀值。结果 以吸光度值（标准管吸光度值-零管吸光度值）为纵坐标,AChE活性为横坐标作图,即得谷胱甘肽标准曲线,标准曲线方程为Y=0.0029＋0.1218X,r＝0.9999,结果表明,该检测方法在AChE活性为0～10.8 mmol·L^-1的范围内保持线性。选取兔全血40倍稀释后作为AChE的来源进行实验,通过对不同动物批内及批间AChE活性进行测定并统计得出,批内差异为0.44%～0.67%,批间差异为1.03%～2.27%。表明该方法批内及批间差异较小,均不超过10%,可以进行有机磷类化合物的体外药效学评价。不同浓度沙林及梭曼对兔全血AChE活性抑制的量效关系表明其作用强度的顺序为：梭曼＞沙林,该实验结果与文献报道相符合。梭曼对兔全血AChE量效曲线图表明,其量效曲线方程为：Y= 372.69-45.53X,R=-0.9930;梭曼对兔全血AChE活性抑制的IC₅₀值和IC₉₀分别为83 nmol·L^-1和0.62 μmol·L^-1。沙林对兔全血AChE量效曲线图表明,其量效曲线方程为：Y= 284.45-3905X,R=-0.9679;沙林对兔全血AChE活性抑制的IC₅₀值和IC₉₀分别为1.2 μmol·L^-1和15 μmol·L^-1。结论 该方法能够快速测定不同动物全血红细胞AChE的活性,实验结果可靠,重现性好,可用于多种有机磷毒剂体外药效学评价。由于红细胞中AChE全部存在于细胞膜表面,因此,本测定方法不需将红细胞溶解就能够直接测定AChE活性,能够减少制备酶原的过程,适于快速完成体外AChE活性的分析测定。     

苯甲酰胺类组蛋白去乙酰化酶抑制剂的合成及 抗肿瘤细胞增殖活性

目的 针对组蛋白去乙酰化酶（HDAC）的结构特点,设计合成一系列化合物并进行体外抗肿瘤活性评价,为进一步优化设计提供指导。方法 以 2-羟基-4-硝基苯甲醛为原料,经环合、还原、与芳醛衍生物反应、水解后,在N,N-碳酰二咪唑存在下经缩合反应合成目标化合物。结果与结论 共合成了11个新苯甲酰胺类衍生物,化合物的结构经质谱、核磁共振氢谱确证;体外抗肿瘤活性评价结果表明,其中 4 个化合物（4b、4c、4d、4h）对肿瘤细胞具有显著的增殖抑制活性,化合物4h的活性最好,它对 HL60、MCF-7、A549 肿瘤细胞的 IC₅₀值分别为2.81、＞50、4.79 μmol·L^-1。     

4,6-双苯基-2-氨基-3-氰基吡啶类化合物的合成及其 抗肿瘤活性研究

目的 设计合成一系列4,6-双苯基-2-氨基-3-氰基吡啶类化合物,并对其体外抗肿瘤活性进行初步评价。方法 以取代苯甲醛、取代苯乙酮、丙二腈和醋酸铵为原料,经一步反应制得目标化合物。采用MTT法,以 MX-58151 为阳性对照药,以 A549、HT-29 和 SMMC-7721为测试细胞株对目标化合物进行体外抗肿瘤活性评价。 结果与结论 合成了13 个未见报道的4,6-双苯基-2-氨基-3-氰基吡啶类化合物, 其结构经¹H-NMR、MS 和 IR 谱确证。体外活性测试结果显示,多数化合物能够在较低的浓度下抑制肿瘤细胞增殖。其中,2-氨基-6-（4-氟苯基）-4-（2,3,4-三甲氧基苯基）-3-氰基吡啶 具有显著的抗肿瘤细胞增殖活性,IC₅₀值达纳摩尔级水平,明显优于阳性对照药MX-58151。     

NO供体型维甲酸类化合物的合成及其对肿瘤细胞增殖的抑制作用

目的设计合成NO供体型维甲酸类化合物，以期获得对乳腺癌肿瘤细胞的增殖有较好抑制作用的化合物。方法将N-（4-羟基苯基）维甲酰胺（4-HPR）与NO供体呋咱氮-氧化物缩合，合成具有NO释放和诱导乳腺癌细胞凋亡作用的NO供体型维甲酸类化合物；测试目标物体外对乳腺癌肿瘤细胞的增殖抑制作用。结果与结论合成了7个新化合物，其结构经IR、MS和^1H-NMR确证。目标物均具有不同程度的抑制肿瘤细胞增殖作用，其中化合物5a、5b、5f、5g对肿瘤细胞的增殖抑制作用较强，值得进-步研究。     

Antitumor agents. 254. Synthesis and biological evaluation of novel neo-tanshinlactone analogues as potent anti-breast cancer agents

In our previous study, neo-tanshinlactone (1) showed potent and selective anti-breast cancer activity. To explore the SAR of 1, nine analogues (15-18, 24-28) were designed and synthesized. Together with 1 and tamoxifen (TAM), all newly synthesized compounds and some intermediates were evaluated for in vitro anticancer activity against several human tumor cell lines. Compounds without a ring D did not show promising activity, while compounds with a methylated furan ring D showed better activity than those with unsubstituted furan or hydroxy-dihydrofuran rings. Among all newly synthesized compounds, compound 15 with an ethyl group at the 4-position showed the best activity and selectivity with ED50 values of 0.45 and 0.18 microg/mL against MCF-7 and ZR-75-1 (ER+) and 13.5 and 10.0 microg/mL against MDA MB-231 and HS 587-1 (ER-), respectively. Furthermore, 15 also showed potent activity against SK-BR-3 (ER-, HER2+) with an ED50 value of 0.10 microg/mL. Our preliminary SAR studies showed that a methylated furan ring D and the C-4 substituent in ring A are critical for anti-breast cancer activity. Further development of 1 and 15 as anti-breast cancer drug candidates is warranted.     

2-甲基-3-取代苯基吡咯并吡嗪酮类化合物的合成及抗癌活性研究

目的 寻找具有抗癌活性的新吡咯并吡嗪酮类化合物。方法 以吡咯、对氨基苯乙酮为原料,经Friedel-Crafts酰化、醇解、亲核取代、环合及醇解反应制得母体化合物2-甲基-3-对氨基苯基吡咯并[1,2-a]吡嗪-1(2H)-酮,再通过酰基化/磺酰基化和烷基化反应引入酰基和烷基即制得系列吡咯并吡嗪酮类化合物。结果 合成了8个未见文献报道的吡咯并吡嗪酮类化合物,其结构经¹H-NMR、MS和IR谱确证。结论 8个目标化合物的体外抗乳腺癌细胞、肝癌细胞和肺癌细胞的活性试验结果显示,化合物4、5 具有明显的抗癌活性。     

Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents

A series of new isatin-thiazoline 3a–h and isatin-benzimidazole 4a–h derivatives were synthesized via condensation of isatin Mannich bases 2a–h with either 2-aminothiazoline or 2-aminobenzimidazole. The structures of the newly synthesized compounds were characterized by spectral data. The anti-breast cancer activity of some of the synthesized compounds was assessed in the MCF-7 human breast cancer cell line. The results showed that compounds 4b, 4d and 4g possess significant antiproliferative activity against MCF-7 cells.     

川芎嗪查尔酮类化合物的合成及其体外抗乳腺癌活性研究

目的设计、合成川芎嗪查尔酮类化合物并研究其抗乳腺癌活性。方法以盐酸川芎嗪为原料,通过酸碱中和、单氧化、重排、水解和醇羟基氧化制得重要中间体3,5,6-三甲基吡嗪-2-甲醛,再与芳乙酮发生Claisen-Schmidt羟醛缩合反应合成川芎嗪查耳酮类化合物,接着用BBr_3进行脱甲基得到了川芎嗪羟基查耳酮,并采用MTT法对目标化合物进行体外抗乳腺癌活性研究。结果合成了21个川芎嗪查尔酮类化合物,其结构均通过~1H-NMR和MS确证。生物活性结果测试表明,目标化合物对乳腺癌MCF-7和MDA-MB-231细胞均有较强抑制活,并对MDA-MB-231细胞有更强的选择抑制。其中查尔酮单元为二茂铁的衍生物9t对MCF-7和MDA-MB-231展现出了最强的抑制活性;同时,这些川芎嗪查尔酮类化合物对正常乳腺上皮细胞MCF-10A均没有毒性。结论查尔酮是一个重要的抗肿瘤药效团,能够提高川芎嗪的抗肿瘤活性,为今后发展新型、高效、低毒的具有抗肿瘤活性的川芎嗪衍生物提供了新思路。     

Retinoid related molecules: new promises against lung and breast cancer

Retinoids have long interested cancer researchers due to their well-documented antiproliferative and differentiation inducing activities. However, natural compounds such as all-trans and 9-cis retinoic acid, as well as related synthetic derivatives, show only moderate anticancer activities, while at the same time inducing a broad range of undesirable activities. By taking advantage of the newly gained understanding in retinoid action and screening large numbers of novel molecules, new potent anticancer agents have been discovered that often lack typical retinoid side effects. Two of these novel types of molecules, referred to here as retinoid related molecules (RRMs), are described, one of which effectively kills non small cell lung cancer cells by apoptosis and is effective and well tolerated in vivo, while the other one belongs to a class of molecules selective for the nuclear receptor, RXR, which promises to be more effective and more tolerable than presently used compounds in anti-breast cancer adjuvant therapy. These novel molecules demonstrate the potential of novel RRMs that vastly outreaches classical retinoids.     

A comparison of pentane-1,5-diol to other diols for use in dermatology

Retinoids have long interested cancer researchers due to their well-documented antiproliferative and differentiation inducing activities. However, natural compounds such as all-trans and 9-cis retinoic acid, as well as related synthetic derivatives, show only moderate anticancer activities, while at the same time inducing a broad range of undesirable activities. By taking advantage of the newly gained understanding in retinoid action and screening large numbers of novel molecules, new potent anticancer agents have been discovered that often lack typical retinoid side effects. Two of these novel types of molecules, referred to here as retinoid related molecules (RRMs), are described, one of which effectively kills non small cell lung cancer cells by apoptosis and is effective and well tolerated in vivo, while the other one belongs to a class of molecules selective for the nuclear receptor, RXR, which promises to be more effective and more tolerable than presently used compounds in anti-breast cancer adjuvant therapy. These novel molecules demonstrate the potential of novel RRMs that vastly outreaches classical retinoids.     

Synthesis and anticancer evaluation of N-benzoyl-N'-phenyltiourea derivatives against human breast cancer cells (T47D)

New anti-breast cancer compounds have been found and may prove to have stronger activity. To predict the activities of N-benzoyl-N'-phenylthiourea (BPTU) derivatives, namely N-(3-chloro)benzoyl-N'-phenylthiourea (3-Cl-BPTU) and N-(3,4-dichloro)benzoyl-N'-phenylthiourea (3,4-2Cl-BPTU) with Sirtuin-1 receptor (PDB code: 4I5I), molecular docking was conducted at the beginning of this study. The compounds were then synthesized from benzoyl chloride derivatives and N-phenylthiourea. Molecular structure was confirmed using FTIR, ¹H NMR, ¹³C NMR and Mass Spectra, while the anticancer activity was tested in vitro against human breast cancer cells (T47D) using MTT assay. The results indicated that the anti-cancer activities of the test compounds were better than those of the hydroxyurea as the reference compound, evidenced by the Rerank Score (RS). Furthermore, cytotoxic effect of 3-Cl-BPTU (IC₅₀: 0.43 mM) and 3,4-dichloro-BPTU (IC₅₀: 0.85 mM) showed better result compared with hydroxyurea (IC₅₀: 4.58 mM). Therefore, we concluded that these compounds could possess termendous potential as the candidate for a new anticancer drug.     

Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity

ABSTRACT

Purpose: A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux.

Methods: Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice.

Results: Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis.

Conclusions: The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.