Synthesis,cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC₅₀ of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.     

Synthesis and preliminary cytotoxic evaluation of substituted indoles as potential anticancer agents

A variety of indole derivatives were designed,synthesized and preliminarily evaluated for their in vitro cytotoxic activity in the A431 and H460 cell lines.All the compounds examined conferred unusual potency in a tumor cell cytotoxicity assay.The findings showed the indole derivatives would be a promising candidate for the development of new anticancer agents.     

Investigation of novel compounds via in silico approaches of EGFR inhibitors as anticancer agents

Before the experimental studies of a compound to be synthesized from in vitro to in vivo, it is possible to save both time and money with in silico approaches only with Computer Aided Drug Design (CADD) methods. In other words, compounds that can be new drug candidates can be suggested by drug design using computational drug discovery strategies. In this study, all molecules in the ChEMBL Database were virtual screened based on drugs with inhibitory properties on the Epidermal Growth Factor Receptor (EGFR), one of the receptor tyrosine kinases, which is effective in cancer cells. During this High-Throughput Screening (HTS), the number of compounds was minimized according to the parameters of the reference drugs, physicochemical properties such as logP, M.W., HBA, HDB, RosLip. As a result of in silico approaches and molecular docking analysis, ten compounds with the highest docking scores were determined and a model compound that could be a new drug candidate was proposed.     

Structure-based design,synthesis of novel inhibitors of Mycobacterium tuberculosis FabH as potential anti-tuberculosis agents

Mycobacterium tuberculosis FabH,an essential enzyme in mycolic acids biosynthetic pathway,is an attractive target for novel anti-tuberculosis agents.Structure-based design,synthesis of novel inhibitors of mtFabH was reported in this paper.A novel scaffold structure was designed,and 12 candidate compounds that displayed favorable binding with the active site were identified and synthesized.     

2-巯基苯并咪唑衍生物的设计、合成及抗肿瘤活性研究

为了从苯并咪唑类衍生物中寻找新的活性化合物,以溴乙酸作为起始原料,设计合成了17个2-巯基苯并咪唑衍生物4a～4q。采用噻唑蓝(MTT)法测试了目标化合物对人宫颈癌细胞(He La)、人乳腺癌细胞(MCF-7)、人肝癌细胞(HepG2)、人非小细胞肺癌细胞(A549)的增殖抑制活性。结果显示,大部分化合物具有较好的抗肿瘤活性,其中,((1H-苯并[d]咪唑-2-基)硫基)-1-(4-二苯甲基哌嗪-1-基)乙烷-1-酮(4l)对HepG2细胞的抑制活性最好,IC_(50)值为12. 62±0. 78μmol/L,接近于对照药品吉非替尼(9. 72±0. 38μmol/L)。此外,利用分子对接方法对目标化合物的构效关系进行了讨论。     

Combination of pharmacophore modeling and 3D-QSAR analysis of potential glyoxalase-I inhibitors as anticancer agents

Glyoxalase system is an ubiquitous system in human cells which has been examined thoroughly for its role in different diseases. It comprises two enzymes; Glyoxalase I (Glo-I) and Glyoxalase II (Glo-II) which perform detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic bystanders. In silico computer Aided Drug Design approaches were used and ninety two diverse pharmacophore models were generated from eighteen Glyoxalase I crystallographic complexes. Subsequent QSAR modeling followed by ROC evaluation identified a single pharmacophore model which was able to predict the expected Glyoxalase I inhibition. Screening of the National Cancer Institute (NCI) database using the optimal pharmacophore Hypo(3VW9) identified several promising hits. Thirty eight hits were successfully predicted then ordered and evaluated in vitro. Seven hits out of the thirty eight tested compounds showed more than 50% inhibition with low micromolar IC₅₀.     

Synthesis and biological evaluation of nitric oxide-releasing sixalkoxyl biphenyl derivatives as anticancer agents

A series of novel nitric oxide-donating sixalkoxyl biphenyl derivatives （14a-1） were synthesized by coupling furoxan with alkoxyl biphenyl skeleton using amino acids as the spacers, and their cytotoxicity against HepG2 cells in vitro were evaluated by MTT method. It was found that 14c, 14d, 14f, 14i, 14j and 14k showed more potent cytotoxic activities than control 5-fluorouracil. NO release assay of target compounds indicated that the maximum amount of NO released by most active compounds 14c and 14j was about 6 × 10^-2 μmol/L, whereas 14a and 14h with very weak activity only released NO of 1 × 10^-2 μmol/L.     

New benzothiazole/benzoxazole-pyrazole hybrids with potential as COX inhibitors: design,synthesis and anticancer activity evaluation

Ten new hybrids were designed and synthesized, their chemical structures were confirmed through spectral and elemental analysis. The new hybrids were screened against lung, breast and liver cancer cell lines (A549, MCF7 and Hep3B), in addition to normal fibroblast cells. Compound 13a was the most active and selective one on the lung cancer cell line (A549), its IC₅₀ and S.I. values were 2.4 µM and 83.2, respectively. Compound 14b was active on MCF7 with the best selectivity towards this cell line. The new derivatives were screened for their inhibitory activity against COX enzymes, the obtained results revealed that compound 13a and 14b were more active inhibitors for COX-2 than celecoxib. This finding encourages us to consider COX-2 inhibitory activity as a proposed mechanism for their anticancer activity.     

Synthesis and cytotoxicity screening of derivatives of the simplified ecteinascidin pentacyclic skeleton as anticancer agents

A series of new ecteinascidin pentacyclic-derived compounds bearing aryl carboxylic amide side chains at C-22 have been designed and synthesized. The cytotoxicity evaluation confirmed their potent antitumor activity by use of eight different cell lines. Studies on the structure-activity relationship of them showed that the chemical structure of C-22 pendants have great effects on the tumor-killing activity. Notably, Compounds 6, 7 and 8 with benzo[b]thiophene-2-carboxamide pendants exhibited excellent broad-spectrum antitumor activity with the low IC₅₀ values of 10^?7?M.     

Design, synthesis, and screen of cathepsin K inhibitors

We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e,9d,9p,9j and 9k (IC₅₀≤0.005μmol/L) were equal to or greater than that of the lead compound 9a.Less hydrophobic compounds showed weaker potency,which can be explained by the hydrophobic nature of the cathepsin K binding pockets.     

Design,synthesis and biological evaluation of new rhodacyanine analogues as potential antitumor agents

In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring（5a-5h）,the isoquinolinium ring（6a-6c） and the quinolinium ring（7a-7e） linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line（H460） by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC₅₀ values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC₅₀ = 0.006μmol/L) was 216.7 times more active than MKT-077(IC₅₀ = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.     

Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

Synthesis,anticancer activity and docking studies of pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) inhibitors

A search for anticancer agents has prompted the design and synthesis of new chalcone, pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) kinase inhibitors. These derivatives’ binding affinities were predicted by AutoDock, which showed that chalcone, pyrazoline and pyrimidine derivatives as EGFR-kinase inhibitors have good binding energies, ranging from ?10.91 to ?7.32 kcal/mol. These compounds were synthesized and characterized using elemental analysis (CHN analysis) and spectroscopic techniques (FTIR and NMR). Among the pyrazoline derivatives, 4Aiii has revealed a superior in vitro activity, inhibiting the EGFR kinase even at a low concentration of 0.19 μM compared to the pyrimidine derivative, 5Bii. In contrast, the cytotoxic effect of these derivatives was studied against hormonal and non-hormonal breast cancer cell lines. Most of the pyrazoline derivatives were able to express their cytotoxic effect efficiently against hormonal breast cancer but only one pyrimidine derivative managed to express its activity against hormonal breast cancer.     

Evaluation of drug candidature: In silico ADMET,binding interactions with CDK7 and normal cell line studies of potentially anti-breast cancer enamidines

We have recently explored novel class of potentially anti-breast cancer active enamidines in which four molecules 4a-c and 4h showed higher anticancer activity compared to standard drug doxorubicin. As a part of extension of this work, we have further evaluated in silico cheminformatic studies on bioactivity prediction of synthesized series of enamidines using mole information. The normal cell line study of four lead compounds 4a-c and 4h against African green monkey kidney vero strain further revealed that the compounds complemented good selectivity in inhibition of cancer cells. The in silico bioactivity and molecular docking studies also revealed that the compounds have significant interactions with the drug targets. The results reveal that enamidine moieties are vital for anti-breast cancer activity as they possess excellent drug-like characteristics, being potentially good inhibitors of cyclin dependent kinases7 (CDK7).     

Molecular design,synthesis and biological activities of amidines as new ketol-acid reductoisomerase inhibitors

Diamidine （A） was identified in our in vitro bio-assay as a possible inhibitor of ketol-acid reductoisomerase （KARI） from the ACD database search based on the known three-dimensional crystal structure of KARI. An investigation on interaction of A on KARI active sites, led to the design and synthesis of 15 novel monoamidines. Some of those showed better biological activity than A on rice KARI （in vitro） and in greenhouse herbicidal tests （in vivo）. The structure-biological activity relationship was investigated, which provides valuable information to further study of potential KARI inhibitors.     

Design,synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents

In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.     

Synthesis and biological evaluation of novel coumarin-chalcone derivatives containing urea moiety as potential anticancer agents

The increasing interest on new drug discovery is constantly up to date as drugs do not increase survival adequately against increasing cancer cases worldwide. Based on the reported anticancer activity of coumarin, chalcone and urea derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted chalcone-urea moieties 5a-k. Through a structure-based molecular hybridization approach, a series of novel coumarin-chalcone derivatives containing urea moiety was synthesized and screened for their in vitro antiproliferative activities against the cancer cell lines (H4IIE and HepG2). In addition, the synthesized compounds were tested on a cell line that was not cancerous (CHO) and the damage, it could give to normal cells was determined. Among the synthesized compounds, 5k exhibited better inhibition of H4IIE compared to Sorafenib. 5j also showed better inhibition against HepG2 than Sorafenib. In particular, 5k induced H4IIE apoptosis, arrested cell cycle at the S phase. Therefore, 5k and 5j may be potent antitumor agents, representing a promising lead for further optimization.     

Dihydropyrazole and dihydropyrrole structures based design of Kif15 inhibitors as novel therapeutic agents for cancer

Mitotic Kinesin motors, Eg5 and Kif15, have recently emerged as good targets for cancer as they play an inevitable role during mitosis. But, most of the Eg5 inhibitors were found ineffective when the cancer cells develop resistance to them by escalating the expression of Kif15 as alternative to Eg5. Therefore, the drugs that target Kif15 became necessary to be used either as a single or in combination with Eg5 inhibitors. The present study used 39 dihydropyrazole and 13 dihydropyrrole derivatives that were having in vitro inhibitory potential against kinesin motors to develop a common pharmacophore hypothesis AHRR and atom-based QSAR model. The model was used for virtual screening of ZINC database and the resultant hits were docked against Kif15. The four drug candidates with high docking score were examined for their activity and pharmacokinetic behaviour. Based on the results these drugs could be considered as lead candidates in further drug development for cancer.     

Design, synthesis and primary activity of thiomorpholine derivatives as DPP-IV inhibitors

Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV（DPP-IV） inhibitors, with natural and non-natural L-amino acids as the starting materials.Their structures were characterized by ¹H NMR,¹³C NMR and HR-MS.The target compounds were screened for the DPP-IV inhibition,and the preliminary SAR result was obtained.Particularly, compounds 4c,4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test （OGTT）.The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.