Targeting hepatocellular carcinoma: Synthesis of new pyrazole-based derivatives,biological evaluation,DNA binding,and molecular modeling studies

A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1H-pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8, the pyrazolopyrimidine 3, and the pyrazolylaminothiazolone 17 were the most active with IC₅₀ values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds.     

Deep Structural Analysis of RPAP3 and PIH1D1, Two Components of the HSP90 Co-chaperone R2TP Complex

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Optimization of (Phenylmethylidene)‐hydantoins as Prostate Cancer Migration Inhibitors: SAR‐Directed Design,Synthesis, and Pharmacophore Modeling

Prostate cancer is one of the most common cancer forms among males of Western countries. Natural products proved to be an unparalleled source of molecular diversity. The 4‐(hydroxyphenylmethylidene)hydantoin (PMH; 1 ), (5Z)‐5‐(4‐hydroxybenzylidene)imidazolidine‐2,4‐dione, was isolated from the Red Sea sponge Hemimycale arabica, and recently showed junctional complexes stabilization, anti‐invasive, and antimetastatic activities in vitro and in vivo. The related synthetic analogue, (5Z)‐5‐[4‐(ethylsulfanyl)benzylidene]imidazolidine‐2,4‐dione ( 2 ), showed several‐fold‐improved in vivo antimetastatic properties against the highly invasive prostate cancer. To further optimize the activity of PMHs, various ligand‐based strategies were used including the extension of the structure, structural simplification, linker extension, and computer‐assisted CoMFA (Comparative Molecular Field Analysis) results. These strategies yielded thirty 2nd‐generation PMHs, designed based on the 1st‐generation PMHs, such as 1 and 2 . Wound‐healing assay was selected to evaluate the in vitro anti‐migratory potential of these new PMHs against the PC‐3 cell line. Several active PMHs, including 10, 13, 24, 29 , with nearly twelvefold enhancement of activity vs. 2 , were identified. Active compounds were then used to build a pharmacophore model using the SYBYL's DIStance COmparison technique (DISCOtech). Active PMHs were also screened for fragment‐based drug likeness using the OSIRIS program, and an overall drug score was also calculated. Interestingly, the overall drug scores of 24 and 29 along with their anti‐migratory activity were significantly greater than those of 1 and 2 . In conclusion, PMHs can be the appropriate scaffolds for the urgently needed drug candidates for the control of androgen independent prostate cancer.     

Synthesis,Pharmacological Study and Modeling of 7-Methoxyindazole and Related Substituted Indazoles as Neuronal Nitric Oxide Synthase Inhibitors

The synthesis, pharmacological evaluation and modelisation of 7-methoxyindazole (7-MI) and related alkoxy-indazoles as novel inhibitors of neuronal nitric oxide synthase are presented. 7-MI remains the most active compound of this series in an in vitro enzymatic assay of neuronal nitric oxide synthase activity. Modeling studies of the interaction of 7-substituted indazole derivatives complexed with nNOS and the relationship with their respective biological activities suggest that a bulky substitution on position-7 is responsible for a steric hindrance effect which does not allow these compounds to interact with nNOS in the same way as 7-NI and 7-MI.     

血清HE4、VEGF、MCP-1及CCL20与乳腺癌患者保乳术后局部复发的关系研究

摘要 目的：探讨血清人附睾蛋白4（HE4）、血管内皮生长因子（VEGF）、单核细胞趋化因子-1（MCP-1）及CC趋化因子配体20（CCL20）与乳腺癌患者保乳术后局部复发的关系。方法：选择2015年7月~2018年7月期间本院收治的乳腺癌患者312例作为研究对象,均符合保乳术手术指征,成功实施乳腺癌保乳术,所有患者均随访3年。检测两组血清HE4、VEGF、MCP-1、CCL20水平情况,单因素及多因素Logistic回归分析影响术后局部复发的因素。使用受试者工作特征（ROC）曲线分析HE4、VEGF、MCP-1、CCL20水平单独及联合检测对保乳术后局部复发的预测价值。结果：随访过程中失访6例,剩余的306例患者根据随访结果,分为局部复发组27例、无局部复发组279例,局部复发率为8.82%。局部复发组的血清HE4、VEGF、MCP-1、CCL20水平均高于无局部复发组（P<0.05）。单因素分析结果显示,乳腺癌患者保乳术后局部复发与年龄、淋巴结转移、切缘状态、人表皮生长因子受体2（Her-2）、细胞增殖相关抗原（Ki-67）、术后规范化疗、术后足程放疗有关（P<0.05）。多因素Logistic回归分析结果显示术后规范化疗、年龄偏高、术后足程放疗是保乳术后局部复发的保护因素,HE4、VEGF、MCP-1、CCL20水平偏高,切缘状态、Her-2、Ki-67阳性以及淋巴结转移是保乳术后局部复发的危险因素（P<0.05）。HE4、VEGF、MCP-1、CCL20联合应用预测乳腺癌患者保乳术后局部复发的效能高于单一指标应用。结论：乳腺癌保乳术后局部复发患者体内HE4、VEGF、MCP-1、CCL20水平高表达,四指标联合检测可辅助预测保乳术后局部复发。且乳腺癌患者保乳术后复发还受到切缘状态、Her-2、Ki-67等多种因素的影响。     

New benzimidazothiazole derivatives as anti-inflammatory,antitumor active agents: Synthesis,in-vitro and in-vivo screening and molecular modeling studies

A new series of benzimidazothiazole derivatives has been synthesized. The structure of the products was confirmed by spectroscopic techniques such as IR, NMR and mass spectroscopy. The tested compounds were evaluated for their anti-inflammatory activity either in vitro through the COX enzyme inhibition assay, or in vivo through carrageenan paw edema technique. Results revealed that compound 25 and 29 represented the most active ones among the entire series with % inhibition 72.19, 72.07 for COX-1, and 87.46, 87.38 for COX-2, respectively. Interestingly, all synthesized compounds exhibited IC₅₀ values less than both reference drugs celecoxib and naproxen, indicating their superior potency. For compound 25, it showed about 340 and 198 times more potent than celecoxib and naproxen respectively as COX-1 inhibitor (IC₅₀ value 0.044 vs. 15.000 and 8.700 µM), and 10 and 115 times more potent than the same drugs as COX-2 inhibitor (IC₅₀ value 4.52 vs. 40.00 and 520.00 nM). The antitumor activity of the products was also evaluated and the results obtained are consistent with those obtained by the anti-inflammatory screening where compounds 25 and 29 proved to be the most active ones among the other compounds with %GI ranging from 31.5 to 62.5% and they exhibited the lowest IC₅₀ values as well. The ADMET analysis of the tested compounds was also performed in addition to the molecular modeling studies that included flexible alignment, surface and electrostatic maps in addition to the Lipinisk's rule of five.     

Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis,cell based assays,kinase profile and molecular docking study

Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a–o and 6a–g) and their corresponding free amines 5a–m and 7a–g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d–g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI₅₀ values over the tested cancer cells, and low cytotoxic effects (GI₅₀?>?10.0?µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI₅₀ and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10?µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC₅₀?=?2.25?µM), FGFR4 (IC₅₀?=?6.71?µM) and Tie2 (IC₅₀?=?6.84?µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.     

乳腺癌改良根治术患者术后复发转移的危险因素及血清CA125、COX-2、sTNFR-P55的预测价值研究

摘要 目的：探讨乳腺癌改良根治术患者术后复发转移的危险因素及血清糖类抗原125（CA125）、环加氧酶-2（COX-2）、可溶性肿瘤坏死因子受体P55（sTNFR-P55）的预测价值。方法：对2014年1月至2016年12月新疆医科大学第一附属医院收治的109例行乳腺癌改良根治术的乳腺癌患者进行前瞻性研究,所有患者术后均随访5年,其中2例失访,107例完成随访。根据5年内患者复发转移情况将其分为复发转移组（n=31）和未复发转移组（n=76）。收集患者入院时的临床病理资料,采用电化学发光法检测术前血清CA125,采用酶联免疫吸附法检测术前血清COX-2、sTNFR-P55。采用logistic回归模型分析患者术后复发转移的影响因素,绘制受试者工作特征（ROC）曲线评估血清CA125、COX-2、sTNFR-P55对术后复发转移的预测价值。结果：复发转移组肿瘤直径＞5 cm、浸润性非特殊癌、脉管癌栓、雌激素受体（ER）/孕激素受体（PR）阴性、无内分泌治疗构成比、TNM分期IIIA期、腋窝淋巴结转移数量4~9个构成比高于未复发转移组（P<0.05）。复发转移组血清CA125、COX-2、sTNFR-P55水平高于未复发转移组（P<0.05）。多因素logistic回归分析结果显示,肿瘤直径＞5 cm、浸润性非特殊癌、TNM分期IIIA期、脉管癌栓、腋窝淋巴结转移数量4~9个、CA125升高、COX-2升高、sTNFR-P55升高是乳腺癌改良根治术患者术后5年内复发转移的独立危险因素（OR=1.318、1.213、1.223、1.137、1.257、1.241、1.313、1.351,P<0.05）。血清CA125、COX-2、sTNFR-P55均可有效预测乳腺癌术后复发转移,曲线下面积（AUC）分别为0.803、0.749、0.761,三指标联合预测术后复发转移的AUC为0.915,灵敏度和特异度分别为0.94、0.83。结论：肿瘤直径、浸润性非特殊癌、TNM分期、脉管癌栓、腋窝淋巴结转移数量以及术前血清CA125、COX-2、sTNFR-P55异常升高是乳腺癌改良根治术患者术后5年内复发转移的危险因素,术前血清CA125、COX-2、sTNFR-P55联合检测可预测乳腺癌改良根治术后的复发转移风险。     

Quinazolin‐4(3H)‐one‐Based Hydroxamic Acids: Design,Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin‐4(3H)‐ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N‐hydroxy‐7‐(7‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5b ) and N‐hydroxy‐7‐(6‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5c ) (IC₅₀ values, 0.10–0.16 μm ) were found to be approximately 30‐fold more cytotoxic than SAHA (IC₅₀ values of 3.29–3.67 μm ). N‐Hydroxy‐7‐(4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5a ; IC₅₀ values of 0.21–0.38 μm ) was approximately 10‐ to 15‐fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC₅₀ values in sub‐micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c , strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.     

3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis,molecular modeling and QSAR studies

A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC₅₀ = 0.21, 0.21 and 0.23 nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10 mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R² of 0.81.     

Arylpropionic acid-derived NSAIDs: New insights on derivatization,anticancer activity and potential mechanism of action

NSAIDs displayed chemopreventive and anticancer effects against several types of cancers. Moreover, combination of NSAIDs with anticancer agents resulted in enhanced anticancer activity. These findings have attracted much attention of researchers working in this field. The 2-arylpropionic acid-derived NSAIDs represent one of the most widely used anti-inflammatory agents. Additionally, they displayed antiproliferative activities against different types of cancer cells. Large volume of research was performed to identify molecular targets responsible for this activity. However, the exact mechanism underlying the anticancer activity of profens is still unclear. In this review article, the anticancer potential, structure activity relationship and synthesis of selected profen derivatives were summarized. This review is focused also on non-COX targets which can mediate the anticancer activity of this derivatives. The data in this review highlighted profens as promising lead compounds in future research to develop potent and safe anticancer agents.