Synthesis and Biological Evaluation of 7‐Azaisoindigo Derivatives

A series of novel 7‐azaisoindigo derivatives 3–14 were designed, synthesized, and structurally characterized by IR, ¹H‐NMR, ¹³C‐NMR, mass spectra, and elemental analyses. Their antiproliferative activities were evaluated in a hormone‐independent prostate cancer cell line DU145. Among them, compounds 8 , 9 , 14 showed the highest activities. Our study also showed that compounds 7 , 11 , 12 exhibited higher inhibitory activities on CDK2/cyclin A than that of the positive control meisoindigo. Western blot analysis on DU145 cells treated with compounds 7 and 9 demonstrated that 7‐azaisoindigo derivatives could decrease the level of CDK2 activity (phosphorylation) and the expression of cyclin D1, and increase the expression of endogenous cyclin‐dependent inhibitor p27.     

New pyrimidinone and fused pyrimidinone derivatives as potential anticancer chemotherapeutics

A series of novel substituted pyrimidinones and fused pyrimidinones (compounds 3 – 18 ) were synthesized starting with oxiranylmethanone 2 . The in vitro cytotoxicity against a human breast adenocarcinoma (MCF‐7) cell line was investigated and most of the tested compounds showed potent cytotoxic activity against the MCF‐7 cell line comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF‐7 cells with increasing doses (2, 5, 10, and 20 µg/mL) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF‐7 cells. In general, derivatives 11 and 16 revealed the highest anticancer activity among the tested compounds.     

茚并异喹啉酮类拓扑异构酶1抑制剂的研究进展

拓扑异构酶1（Top1）在调控DNA的拓扑形态中起关键作用,是抗肿瘤药物研发的重要靶点。喜树碱是强效的Top1抑制剂,但具有较多缺陷,在众多寻找成药性更好的非喜树碱类Top1抑制剂的研究中,Cushman小组发展的茚并异喹啉酮类新型化合物是其中的典型代表。目前该领域的研究,已经发现了数十个活性优良的先导化合物,并先后有3个进入临床研究阶段。本文综述了茚并异喹啉酮类新药发展历程及其研究策略。     

Synthesis and Quantum Chemical Studies of New 4‐aminoquinazoline Derivatives as Aurora A/B Kinase Inhibitors

Nine novel 4‐aminoquinazoline derivatives were designed and synthesized. Biochemical and cellular analyses demonstrated that most of the derivatives exhibited a strong activity to inhibit Aurora A and B kinases and to suppress the proliferation of a panel of human tumor cell lines (U937, K562, A549, LoVo, and HT29). Quantum chemical studies were also carried out to determine the structural features of these compounds engaged in the inhibition of Aurora kinases.     

Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells

New 4‐arylazo‐3,5‐diamino‐1H‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC₅₀ 3.0 µM) and 8f (IC₅₀ 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC₅₀ 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b , via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC₅₀ 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.     

哌啶酮类法尼基转移酶抑制药的微波幅射合成与抗肿瘤活性

目的合成设计哌啶酮类法尼基转移酶抑制药，并对其抗肿瘤活性进行初步评价。方法以取代苯甲醛为起始原料，经Perkin反应和Michael加成，最后在微波辐射条件下环合得到目标化合物，并用MTT法测试它们抑制人Hela细胞和ANC-1细胞的IC50值。结果采用微波辐射技术合成哌啶酮类化合物，反应时间为20～45 min，产率为36.0%～67.1%。经1H-NMR、ESI-MS及IR对化合物的结构确证，总共合成11个新化合物。初步抗肿瘤活性测试结果显示11个目标化合物均有抑瘤活性，其中8个化合物IC50值低于氟尿嘧啶。结论哌啶酮类法尼基转移酶抑制药的合成路线可靠，具有显著抗肿瘤活性。     

Synthesis and Biological Evaluation of Some Pyrazoline Derivatives Bearing a Dithiocarbamate Moiety as New Cholinesterase Inhibitors

In the present study, new pyrazoline derivatives were synthesized via the reaction of 1‐(chloroacetyl)‐3‐(2‐furyl)‐5‐aryl‐2‐pyrazolines with sodium salts of N,N‐disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17 , when compared with eserine. Compounds effective on AChE carry the 2‐dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2‐dimethylaminoethyl and 3,4‐methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration.     

Platinum and Palladium‐triazole Complexes as Highly Potential Antitumor Agents

The palladium complexes [(dppe)Pd(L)₂PdCl₂], [(dppe)Pd(L)₂PtCl₂], [(dppp)Pd(L)₂PdCl₂], [(dppm) Pd(L)₂NiCl₂], and [(dppm)Pd(L)₂SnCl₄] 15–19 were prepared. The antiproliferative activity of the newly synthesized complexes as well as their previously prepared analogues 3–14 and 20–26 were screened against a large panel of human cancer cell lines derived from haematological CD4⁺ human T‐cells containing an integrated HTLV‐1 genome (MT‐4). The complex 12a , b exhibited remarkable antiproliferative activity against MT‐4, CD4⁺ human acute T‐lymphoblastic leukemia (CCRF‐CEM), human splenic B‐lymphoblastoid cells (WIL‐2NS), human acute B‐lymphoblastic leukemia (CCRF‐SB), skin melanoma (SK‐MEL‐28), and prostate carcinoma (DU145) cell lines (CC₅₀ = 0.5 μM, 0.4 ± 0.05 μM, 0.6 ± 0.05 μM, 0.4 ± 0.1 μM, and 0.8 ± 0.2 μM, respectively), meanwhile, 9a , b , 14a , b , and 23 showed significant activity against the CCRF‐SB cell lines (CC₅₀ = 0.6 ± 0.06 μM, 0.7 ± 0.05 μM, 0.6 ± 0.05 μM, and 0.8 ± 0.15 μM, respectively). Further, 19 exhibited activity against the CCRF‐CEM cell line (CC₅₀ = 0.4 ± 0.05 μM).     

青蒿素芳香醚类衍生物的合成

设计合成了十个新的青蒿素芳香醚类衍生物，进行了抗疟与抗肿瘤活属恬的药理筛选，结果显示这些衍生物除有抗疟活性外还具有明显的抗肿瘤活性。     

Synthesis and Evaluation of Salicylanilide Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC₅₀ values of 10.4 ± 2.25 and 15.4 ± 2.33 nm , respectively, which were comparable to the positive control of gefitinib (IC₅₀ = 12.1 ± 2.21 nm ). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC₅₀ values of 0.42 ± 0.43 μm and 0.57 ± 0.43 μm , which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ▵G_b = −25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well.     

Synthesis and Biological Evaluation of 2,4,6-Trihydroxychalcone Derivatives as Novel Protein Tyrosine Phosphatase 1B Inhibitors

A series of 2,4,6‐trihydroxychalcone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC₅₀ values in the micromolar range. Compound 4a had the greatest in vitro inhibition activity against PTP1B (IC₅₀ = 0.27 ± 0.01 μm ) and the best selectivity (6.9‐fold) for PTP1B relative to T‐cell protein tyrosine phosphatases. The compounds identified herein provide a foundation on which to design specific inhibitors of PTP1B and other PTPs.     

Structure‐based Design,Synthesis, and Biological Evaluation of Isatin Derivatives as Potential Glycosyltransferase Inhibitors

Peptidoglycan glycosyltransferase (PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure‐based virtual screening of about 3 000 000 commercially available compounds against the crystal structure of the glycosyltransferase (GT) domain of the Staphylococcus aureus penicillin‐binding protein 2 (S. aureus PBP2) resulted in identification of an isatin derivative, 2‐(3‐(2‐carbamimidoylhydrazono)‐2‐oxoindolin‐1‐yl)‐N‐(m‐tolyl)acetamide ( 4 ) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4 , in particular 2‐(3‐(2‐carbamimidoylhydrazono)‐2‐oxoindolin‐1‐yl)‐N‐(3‐nitrophenyl)acetamide ( 4l ), against Gram‐positive Bacillus subtilis and S. aureus with MIC values of 24 and 48 μg/mL, respectively. Saturation transfer difference (STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S. aureus PBP2. Competitive STD‐NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S. aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.     

Synthesis and Evaluation of Flavanones as Anticancer Agents

A few flavanones were synthesised by cyclisation of corresponding 3-(heteroaryl)-1(2-hydroxyphenyl) prop-2-en-1-one with sodium acetate in alcohol–water and evaluated for activity. Synthesised compounds were assayed for their in vitro anticancer activity against three human cancer cell lines, mammary adenocarcinoma (MCF7), human colon adenocarcinoma (HT29) and human kidney adenocarcinoma (A498) using sulforhodamine B dye. Results indicated that most of the compounds exhibited significant in vitro anticancer potential. Among them, compound having furan ring showed most potent activity against all the tested cell lines.     

Synthesis and 3D‐QSAR Analysis of 2‐Chloroquinoline Derivatives as H37RV MTB Inhibitors

Frequency of tuberculosis is progressively increasing worldwide. New emerging strains of bacilli that are emerging are resistant to the currently available drugs which make this issue more alarming. In this regard, a series of substituted quinolinyl chalcones, quinolinyl pyrimidines, and pyridines were synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H₃₇RV. To establish the role of the 2‐chloroquinoline nucleus as a pharmacophoric group and study its influence on the antimycobacterial activity, a 3D‐QSAR study based on CoMFA and CoMSIA was undertaken on this set of 2‐chloroquinoline derivatives. Statistically significant models that are able to well correlate the antimycobacterial activity with the chemical structures of the 2‐chloroquinolines have been developed. The contour maps resulting from the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction‐field contour maps also showed a high level of internal consistency. The information obtained from the field 3‐D contour maps may be fruitfully utilized in the design of more potent 2‐chloroquinoline‐based analogs as potential antitubercular candidates.