纺锤体驱动蛋白抑制剂的设计、合成与生物活性研究

纺锤体驱动蛋白(kinesin spindle protein, KSP/Eg5)作为潜在的肿瘤治疗靶点, 使发现KSP抑制剂成为热点. 设计并合成了4-氧基-β-四氢咔啉衍生物作为新型的KSP抑制剂, 并测定了其对KSP的抑制活性, 均优于阳性对照物. 其中化合物9c抑制KSP的IC50＝0.065 μmol•L－1, 优于阳性对照物Monastro l100多倍. 生物活性研究表明为抗肿瘤药物提供了新结构类型的候选化合物.     

Preliminary investigation of cytotoxic potential of 2-quinolone derivatives using in vitro and in vivo (solid tumor and liquid tumor) models of cancer

2-Quinolone analogs are powerful inhibitors of farnesyl transferase, and are a novel class of anticancer drugs. The present study focused on continual efforts to elucidate the anticancer activity of synthesized 2-quinolone derivatives without N-methyl or 3-aryl substitution. Three derivatives namely JST, JST2 and JST13 were synthesized in our lab and screened for in vitro and in vivo anticancer activities. Significant cytotoxicity was observed in MCF-7 cells treated with JST2 and JST13. Both the derivatives’ treatment showed damage to the DNA. In vivo studies for JST2 and JST13 were performed at two doses 100 and 200 mg/kg using Ehrlich ascites carcinoma (liquid) and Dalton lymphoma ascites (solid) models. Both derivatives showed a significant reduction in the tumor progression by increasing the mean life span and by improving the haematological profile and antioxidant status of the liver in a liquid tumor model. More prominent effect was observed in a solid tumor model by reduction in solid tumor weight and tumor volume.     

3D-QSAR Study on a Series of Indolo[1,2-b]quinazoline Derivatives with Anticancer Activity and their Molecular Design

Indolo[1,2-b]quinazoline derivatives have recently been reported as a type of compound with potential anticancer activity. On the basis of our the published two-dimensional quantitative structure-activity relationship (2D-QSAR) of these compounds, a further study on the three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the method of comparative molecular field analysis (CoMFA). A reasonable, receivable, and an effective 3D-QSAR model has been established, in which the correlation coefficient (r²) and cross-validation coefficient (q²) values are 0.986 and 0.695, respectively, the statistical squared deviation ratio (F) is 114.6, and the standard deviation (SD) is 0.084. The results suggest that the electrostatic effect of substituent R₁ and steric effect of substituent R₂ play a very important role in the improvement of the anticancer activity of these compounds. In this article, some significant conclusions, which are in good agreement with the conclusions obtained using 2D-QSAR, were drawn as follows. (1) The electrostatic effect in the substituent R₁ part plays a major role, and it is very important to make the first atom of R₁ carrying more positive charges in order to improve the anticancer activity of the compounds. (2) The steric effect plays a major role in the substituent R₂ part, and the volume of R₂ should be moderate. Based on the above conclusions, three new molecules of Indolo[1,2-b]quinazoline derivatives with higher anticancer activity have been theoretically designed and are waiting for support from experiment. The QSAR results can offer a theoretical reference for the pharmaceutical synthesis.     

Design,Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC₅₀ values of 1.38, 5.34, and 5.21 µM, respectively. The structure–activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.     

Natural Product Rottlerin Derivatives Targeting Quorum Sensing

Rottlerin is a natural product consisting of chalcone and flavonoid scaffolds, both of which have previously shown quorum sensing (QS) inhibition in various bacteria. Therefore, the unique rottlerin scaffold highlights great potential in inhibiting the QS system of Pseudomonas aeruginosa. Rottlerin analogues were synthesised by modifications at its chalcone- and methylene-bridged acetophenone moieties. The synthesis of analogues was achieved using an established five-step synthetic strategy for chalcone derivatives and utilising the Mannich reaction at C6 of the chromene to construct morpholine analogues. Several pyranochromene chalcone derivatives were also generated using aldol conditions. All the synthetic rottlerin derivatives were screened for QS inhibition and growth inhibition against the related LasR QS system. The pyranochromene chalcone structures displayed high QS inhibitory activity with the most potent compounds, 8b and 8d, achieving QS inhibition of 49.4% and 40.6% and no effect on bacterial growth inhibition at 31 µM, respectively. Both compounds also displayed moderate biofilm inhibitory activity and reduced the production of pyocyanin.     

Synthesis and Biological Evaluation of Amino Chalcone Derivatives as Antiproliferative Agents

Chalcone is a common scaffold found in many biologically active compounds. The chalcone scaffold was also frequently utilized to design novel anticancer agents with potent biological efficacy. Aiming to continue the research of effective chalcone derivatives to treat cancers with potent anticancer activity, fourteen amino chalcone derivatives were designed and synthesized. The antiproliferative activity of amino chalcone derivatives was studied in vitro and 5-Fu as a control group. Some of the compounds showed moderate to good activity against three human cancer cells (MGC-803, HCT-116 and MCF-7 cells) and compound 13e displayed the best antiproliferative activity against MGC-803 cells, HCT-116 cells and MCF-7 cells with IC₅₀ values of 1.52 μM (MGC-803), 1.83 μM (HCT-116) and 2.54 μM (MCF-7), respectively which was more potent than the positive control (5-Fu). Further mechanism studies were explored. The results of cell colony formatting assay suggested compound 10e inhibited the colony formation of MGC-803 cells. DAPI fluorescent staining and flow cytometry assay showed compound 13e induced MGC-803 cells apoptosis. Western blotting experiment indicated compound 13e induced cell apoptosis via the extrinsic/intrinsic apoptosis pathway in MGC-803 cells. Therefore, compound 13e might be a valuable lead compound as antiproliferative agents and amino chalcone derivatives worth further effort to improve amino chalcone derivatives’ potency.     

Polycyclic aromatic hydrocarbon-bridged coumarin derivatives for organic light-emitting devices

Three biscoumarin dyes bridged by polycyclic aromatic bridges (anthracen, pyrene and dibenzo[g,p]chrysene) were prepared as the emissive materials for the application of organic light-emitting devices. The relationship between their structures, photophysical properties, electrochemical properties and performances of organic light-emitting devices are described. The multilayered doped devices with a configuration of ITO/NPB (20 nm)/TBADN: biscoumarin compound (x wt%, 30 nm)/TPBi (30 nm)/Liq (2 nm)/Al (100 nm) have been successfully fabricated by vacuum-deposition method. All the devices showed green emission with high electroluminescent efficiencies. Especially, the device based on the compound containing pyrene as a bridge group at 7% doping concentration showed the best performance with a maximum brightness of 10552 cd/m², maximum luminous efficiency of 5.39 cd/A and maximum external quantum efficiency (EQE) of 2.35%.     

A porous hydrogel scaffold mimicking the extracellular matrix with swim bladder derived collagen for renal tissue regeneration

As a worldwide public health issue, chronic kidney disease still lacks of effective therapeutic approaches due to the challenges in conventional organ transplantation and dialysis. Renal tissue engineering offers an advantageous therapeutic or regenerative option over typical donor organ. However, despite the great progress of decellularized extracellular matrix based scaffold for the renal regeneration, several safety concerns and complex composition still remain to be addressed. Herein, the extracellular matrix-mimicking hydrogel scaffolds were developed through covalent and physical cross-linking between swim bladder-derived natural collagen (COL) and anti-fibrosis chondroitin sulfate (CS) derivatives. The biomimetic hydrogels showed proper mechanical property, excellent thermal stability and high biocompatibility both in vitro and in vivo, by altering the mass ratio of COL and CS. When implanted in partially nephrectomized rat model, the 1COL/2CS scaffold enable it recruit more native kidney cells, reduce the tubular damage, and even induce the regeneration of renal tubular-like tissue and restore renal metabolic function more effectively comparing with the pure 2COL and 2CS scaffold. These results suggest that the biomimetic scaffold is a promising functional platform for treating renal diseases.     

Synthesis,Antiprotozoal Activity,and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.     

Tetrabutylammonium bromide (TBAB): a neutral and efficient catalyst for the synthesis of biscoumarin and 3,4-dihydropyrano[c]chromene derivatives in water and solvent-free conditions

A simple, efficient and ecofriendly procedure has been developed using tetrabutylammonium bromide as catalyst for the synthesis of biscoumarin and dihydropyrano[c]chromene derivatives in water and solvent-free neat conditions. The present methodology offers several advantages such as excellent yields, short reaction time and environmentally benign milder reaction conditions.     

Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes

A novel series of proflavine ureas, derivatives 11a–11i, were synthesized on the basis of molecular modeling design studies. The structure of the novel ureas was obtained from the pharmacological model, the parameters of which were determined from studies of the structure-activity relationship of previously prepared proflavine ureas bearing n-alkyl chains. The lipophilicity (LogP) and the changes in the standard entropy (ΔS°) of the urea models, the input parameters of the pharmacological model, were determined using quantum mechanics and cheminformatics. The anticancer activity of the synthesized derivatives was evaluated against NCI-60 human cancer cell lines. The urea derivatives azepyl 11b, phenyl 11c and phenylethyl 11f displayed the highest levels of anticancer activity, although the results were only a slight improvement over the hexyl urea, derivative 11j, which was reported in a previous publication. Several of the novel urea derivatives displayed GI₅₀ values against the HCT-116 cancer cell line, which suggest the cytostatic effect of the compounds azepyl 11b–0.44 μM, phenyl 11c–0.23 μM, phenylethyl 11f–0.35 μM and hexyl 11j–0.36 μM. In contrast, the novel urea derivatives 11b, 11c and 11f exhibited levels of cytotoxicity three orders of magnitude lower than that of hexyl urea 11j or amsacrine.     

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015–2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

Novel Anti-Melanogenic Compounds, (Z)-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights

To confirm that the β-phenyl-α,β-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve (Z)-5-(substituted benzylidene)-4-thioxothiazolidin-2-one ((Z)-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound 2b (IC₅₀ = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies’ results confirmed that compounds 2b and 2f are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that 2b and 2f might potently inhibit human tyrosinase. In vitro assays of 2b and 2f were conducted using B16F10 melanoma cells. Compounds 2b and 2f significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of 2b at 10 µM and 2f at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds 2b and 2f similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.     

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents

Abstract

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13?g (IC₅₀ = 0.514?μM) and 13o (IC₅₀ = 0.275?μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC₅₀ = 0.511?μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.     

4-(1-Aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides: Synthesis,antimicrobial, anticancer evaluation and QSAR studies

A series of 4-(1-aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamide derivatives (1–20) was synthesized and evaluated for its in vitro antimicrobial and anticancer activities. Antimicrobial results indicated that compounds N-(4-(1-benzoyl-5-chloro-2-oxoindolin-3-ylideneamino) phenylsulfonyl)-4-isopropoxy benzamide (9) and N-(4-(5-chloro-1-(2-chlorobenzoyl)-2-oxoindolin-3-ylideneamino) phenylsulfonyl)-4-isopropoxybenzamide (19) were found to be the most effective ones. The anticancer results indicated that almost all the synthesized compounds were more active than the standard drug carboplatin but less active than the standard drug 5-fluorouracil (5-FU) against both the cell lines (HCT116 and RAW 264.7). 4-(1-Benzoyl-5-chloro-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (3) was found to be most potent and exhibited selectivity toward HCT 116. QSAR studies indicated that antimicrobial activity of isatin derivatives against different microbial strains was governed by lipophilic parameter, log P and topological parameters valance zero and third order molecular connectivity indices (⁰χ^v and ³χ^v).     

Synthesis and Structure–Antitumor Activity Relationship of Sulfonyl 5-Fluorouracil Derivatives

Novel sulfonyl 5-fluorouracil derivatives 2 (5-fluoro-1-(arylsulfonyl)pyrimidine-2,4(1H,3H)-diones) have been synthesized via the reaction of 5-fluorouracil with sulfonyl chloride. Their chemical structures were confirmed by means of ¹H NMR, ¹³C NMR, IR, mass spectra, and elemental analyses, and, in the case of 2a, its structure was established by single crystal X-ray diffraction. Some of the compounds were assayed for anticancer (HL-60 and BEL-7402 cells) activities. Structure–activity relationship (SAR) analysis discovered that the anticancer activity was related to the configuration, and that electron-withdrawing groups at 2-position or 4-position on the aryl group of arylsulfonyl derivatives of 5-fluorouracil could enhance the anticancer activity against the BEL-7402 cells.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Computer-aided prediction and cytotoxicity evaluation of dithiocarbamates of 9,10-anthracenedione as new anticancer agents

Anticancer activity as an associated action for a series of dithiocarbamates of 9,10-anthracenedione was predicted using the PASS computer program and analysed with PharmaExpert software. The predicted cytotoxic activity of the dithiocarbamate derivatives of 9,10-anthracenedione was evaluated in vitro on cancer cells of the human lung (A549), prostate (PC3), colon (HT29) and human breast (MCF7) using the sulforhodamine B (SRB) cell viability assay. Among these compounds, 9,10-dioxo-9,10-dihydroanthracen-1-yl pyrrolidin-1-carbodithioate and 9,10-dioxo-9,10-dihydroanthracen-2-yl pyrrolidin-1-carbodithioate were identified as the most potent anticancer agents with cytotoxic activity against the MCF-7 human breast cell line with GI₅₀ values of 1.40 μM and 1.52 μM, whereas the GI₅₀ value for the reference anticancer drug mitoxantrone was 3.93 μM. Thus, anticancer activity predicted by PASS with a probability Pa > 30% was confirmed by the experiment. Relatively small Pa values estimated by PASS indicated the novelty of the considered derivatives comparing to the compounds from the PASS training set.     

Synthesis and anticancer study of 9-aminoacridine derivatives

Acridine and its derivatives, well known as DNA intercalates lead to cell cycle arrest and apoptosis. 9-Aminoacridine derivatives were synthesized, characterized and evaluated against lung cancer (A-549) cell line and cervical cancer (HeLa) cell line by MTT assay. Compound 9 exhibited potent anticancer activity with CTC₅₀ (13.75 & 18.75 μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. In vitro short term cytotoxicity evaluation of compound 9 was carried out by Dalton’s Lymphoma Ascites (DLA) with percentage growth inhibition CTC₅₀ (337.5 μg/ml). Compound 7 also exhibited good anticancer activity with CTC₅₀ (31.25 & 36.25 μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. Further in vivo study of newly synthesized 9-aminoacridine derivative can give a ray of light in the field of anticancer drugs.