Synthesis and Pharmacological Evaluation of 4‐Aryloxyquinazoline Derivatives as Potential Cytotoxic Agents

In the present study, novel 4‐aryloxyquinazoline derivatives were synthesized and screened for in vitro cytotoxicity on human cancer cell lines at 10 μM. Some of the synthesized compounds displayed moderate to significant and selective cytotoxic activity against various leukemia, melanoma, ovarian, breast, and colon cancer cell lines. (E)‐3‐(3,4‐Dimethoxyphenyl)‐1‐(4‐(quinazolin‐4‐yloxy)phenyl)prop‐2‐en‐1‐one ( 9b ) was the most potent compound among all with an average growth inhibition of 70% against leukemia cancer cell lines. The compound also produced strong inhibition (75%) of colon cancer cell lines with 42.58% lethality of HCT‐116 cell line.     

Design,synthesis, and anticancer evaluation of acetamide and hydrazine analogues of pyrimidine

A library of acetamide and hydrazine analogues were generated on the pyrimidine ring through a multistep reaction starting from 5-nitro-pyrimidine-4,6-diol and pyrimidine-4,6-diol, respectively. The synthesized analogues were screened for in vitro cytotoxic activity against various human cancer cell lines like HCT-1 and HT-15 (colon), MCF-7(breast), PC-3 (prostrate), SF268 (CNS) using MTT method. From the bioassay results, it was observed that even though many of the synthesized derivatives exhibited a good potency against various screened cancer cell lines, compound 14a from the acetamide series was found to show potent anticancer activity on all the tested cancer cell lines with IC₅₀ value of 0.36μM on CNS cell line and 1.6μM on HT-21 cell line, and compound 19xxi from hydrazine series of pyrimidine showed potent activity against three tested cancer cell lines with IC₅₀ value of 0.76μM on HT-29 cell line, 2.6μM on HCT-15, and 3.2μM on MCF-7 cell line.     

Synthesis and Biological Evaluation of Novel 5,7-Diphenylimidazo[1,2-a]pyridine Derivatives

A series of novel 5,7-diphenylimidazo[1,2-a]pyridine derivatives was designed and synthesized. The in vitro cytotoxic activities of all the target compounds against human colorectal cancer（HT-29）, human lung can- cer（H460）, human gastric cancer（MKN45） and human breast cancer（MDA-MB-231） cell lines were evaluated. The pharmacological results indicated that most of the target compounds showed moderate to excellent activities against the tested cell lines. The most promising compound 4h（0.20, 0.006, 0.08, 0.021 μmol/L） was 2.6, 5.1, 3.6 and 21.9 times more active than EPC2407（0.52, 0.031, 0.29, 0.46 μmol/L） against HT-29, H460, MKN45 and MDA-MB-231 cell lines, respectively.     

The Preparation, Characterization and Biological Activity of Palladium(II) and Platinum(II) Complexes of Tridentate NNS Ligands Derived from S-methyl- and S-benzyldithiocarbazates and the X-ray Crystal Structure of the [Pd(mpasme)Cl] Complex

New complexes of general formula, [M(NNS)Cl] (M = Pd^II, Pt^II; NNS = anionic forms of the 6-methyl-2-formylpyridine Schiff bases of S-methyl- and S-benzyldithiocarbazates) have been prepared and characterized by a variety of physico-chemical techniques. Based on conductance and spectral evidence, a square-planar structure is assigned to these complexes. The crystal and molecular structure of the [Pd(mpasme)Cl] complex (mpasme=anionic form of the 6-methyl-2-formylpyridine Schiff base of S-methyldithiocarbazate) has been determined by X-ray diffraction. The complex has a distorted square-planar geometry with the ligand coordinated to the palladium(II) ion via the pyridine nitrogen atom, the azomethine nitrogen atom and the thiolate sulfur atom; the fourth coordination position around the palladium(II) ion is occupied by the chloride ligand. The distortion from a regular square-planar geometry is ascribed to the restricted bite angle of the ligand. Both the Schiff bases exhibit strong cytotoxicity against the human ovarian cancer (Caov-3) cell lines, the S-methyl derivative being two times more active than the S-benzyl derivative. The [Pt(mpasme)Cl] complex is moderately active but the palladium(II) complex is weakly active against this cancer. None of the complexes of Hmpsbz are active against Caov-3. The Schiff base, Hmpasme exhibits moderate activity against the bacteria, MRSA, P. aeruginosa and S. typhimurium but is inactive against B. subtilis. Coordination of the ligand with palladium(II) substantially reduces its activity. The Schiff base, Hmpasbz and its palladium(II) and platinum(II) complexes are inactive against these bacteria. The Schiff bases and their palladium(II) and platinum (II) complexes are inactive against the pathogenic fungi, C. albican, Aspergillus ochraceous and Saccharomyces cerevisiae.     

Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumor activity

The reaction of cyanoacetyl hydrazine (1) with 3-acetylpyridine (2) gave the hydrazide-hydrazone derivative 3. The latter compound undergoes a series of heterocyclization reactions to give new heterocyclic compounds. The antitumor evaluation of the newly synthesized products against three cancer cell lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) was performed. Most of the synthesized compounds showed high inhibitory effects.     

Bimetallic Iron–Palladium Catalyst System as a Lewis-Acid for the Synthesis of Novel Pharmacophores Based Indole Scaffold as Anticancer Agents

The Friedel–Crafts reaction between substituted indoles as nucleophiles with chalcones-based benzofuran and benzothiophene scaffolds was carried out by employing a highly efficient bimetallic iron–palladium catalyst system. This catalytic approach produced the desired bis-heteroaryl products with low catalyst loading, a simple procedure, and with acceptable yield. All synthesized indole scaffolds 3a–3s were initially evaluated for their cytotoxic effect against human fibroblast BJ cell lines and appeared to be non-cytotoxic. All non-cytotoxic compounds 3a–3s were then evaluated for their anticancer activities against cervical cancer HeLa, prostate cancer PC3, and breast cancer MCF-7 cell lines, in comparison to standard drug doxorubicin, with IC₅₀ values 1.9 ± 0.4 µM, 0.9 ± 0.14 µM and 0.79 ± 0.05 µM, respectively, and appeared to be moderate to weak anticancer agents. Fluoro-substituted chalcone moiety-containing compounds, 3b appeared to be the most active member of the series against cervical HeLa (IC₅₀ = 8.2 ± 0.2 µM) and breast MCF-7 cancer cell line (IC₅₀ = 12.3 ± 0.04 µM), whereas 6-fluroindol-4-bromophenyl chalcone-containing compound 3e (IC₅₀ = 7.8 ± 0.4 µM) appeared to be more active against PC3 prostate cancer cell line.     

Synthesis,characterization and biological activities of 3-methylbenzyl 2-(6-methyl pyridin-2-ylmethylene)hydrazine carbodithioate and its transition metal complexes

A tridentate nitrogen-sulfur Schiff base, 3-methylbenzyl 2-(6-methylpyridin-2-ylmethylene)hydrazine carbodithioate (6mpyS3M), was synthesized by condensation of 6-methylpyridine-2-aldehyde with S-3-methylbenzyldithiocarbazate. It crystallized in space group P 2₁/n. It displayed intermolecular N–H···N hydrogen bonding between the α-nitrogen and the pyridyl nitrogen. The thione sulfur is in a trans position with respect to the 6-methylpyridine fragment across the C–N bond but adopts a cis position with the 3-methylbenzyl fragment through the C–S bond. Octahedral complexes containing two 6mpyS3M ligands were prepared with Cu(II), Ni(II), Zn(II) and Cd(II). 6mpyS3M and its metal complexes were assayed against selected microbes and two breast cancer cell lines. 6mpyS3M was strongly active against both cancer cell lines. Its metal complexes showed high selectivity with Cu(II), Ni(II) and Zn(II) complexes strongly active against only one of the cancer cell lines, whereas the Cd(II) complex was strongly active only against the other. Only Cu(II) and Cd(II) complexes were active against some of the bacteria.     

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives

Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.     

Design,Synthesis and Anticancer Activity of Novel 6-（Aminophenyl）-2,4-bismorpholino-1,3,5-triazine Derivatives Bearing Arylmethylene Hydrazine Moiety

In an attempt to develop potent and selective anticancer agents,we designed and synthesized a series of novel bis（morpholino-1,3,5-triazine） derivatives beating aylmethylene hydrazine moiety and evaluated their cytotoxicity,in vitro,against H460（non-small-cell lung cancer）,HT-29（human colorectal cancer） and MDA-MB-231（human breast cancer） cell lines.The pharmacological results indicate that all the compounds exhibit enhanced cytotoxicity than BMCL-200908069-1,and six target compounds（7e,7h,7j,9a,9b,9c） were superior to PAC-1 against all the tested cancer cell lines.The most active compound 7j,with IC50（inhibitory concentration 50％）values of 0.75,0.34 and 0.60 μ mol/L against HT-29,H460 and MDA-MB-231 cancer cell lines,was 39-,28-,and 60-fold more potent than BMCL-200908069-1 （29.24,9.52 and 36.21 μmol/L）,respectively.     

N(4)-tolyl-2-benzoylpyridine-derived thiosemicarbazones and their palladium(II) and platinum(II) complexes: Cytotoxicity against human solid tumor cells

Complexes [Pt(2Bz4oT)Cl], [Pt(2Bz4mT)Cl], and [Pt(2Bz4pT)Cl] were prepared with N(4)-ortho-(H2Bz4oT), N(4)-meta-(H2Bz4mT), and N(4)-para-(H2Bz4pT) tolyl-2-benzoylpyridine-derived thiosemicarbazones. The thiosemicarbazones exhibited moderate anti-proliferative activity against HepG2 (hepatoma) and UACC-62 (melanoma) cancer cell lines, but showed high anti-proliferative effect against A431 (epithelial carcinoma) cancer cell lines. Upon coordination to platinum(II) the anti-proliferative activity decreases in all cases. The cytotoxicity of the previously prepared palladium(II) analogues [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] was also investigated. As in the case of the platinum(II) complexes, coordination to palladium(II) did not lead to activity improvement. Investigations on the mechanism of cytotoxic action against A431 cells revealed that [Pd(2Bz4oT)Cl] induced DNA fragmentation and apoptosis while H2Bz4oT did not present this effect. The high anti-proliferative effect of the thiosemicarbazones and [Pd(2Bz4oT)Cl] against A431 cells, together with the pro-apoptotic effect of [Pd(2Bz4oT)Cl] suggests that these compounds have potential as chemotherapeutic drug candidates.     

Synthesis and in vitro antitumor activity of 1,3,4-oxadiazole derivatives based on benzisoselenazolone

A series of novel 1,3,4-oxadiazole derivatives based on benzisoselenazolone has been prepared and tested for antiproliferative activity in vitro against the cells of human cancer cell lines: SSMC-7721 (human liver cancer cell), MCF-7 (human breast cancer cell) and A549 (human lung cancer cell). All the compounds obtained exhibited antiproliferative activity and showed selective cytotoxicity against different cancer cells. Compounds 7d and 7i showed significant antiproliferative activities against MCF-7 cells, with IC50 values of 1.07 and 1.76?μM respectively. Compound 7d were found to be the most potent compound against SSMC-7721 cells, with IC50 values 4.46?μM.     

Synthesis,characterization, and anticancer activity of some azole‐heterocyclic complexes with gold(III), palladium(II), nickel(II), and copper(II) metal ions

Four new complexes of Au(III), Pd(II), Ni(II), and Cu(II) ions were synthesized, derived from a novel heterocyclic ligand (L) that has both triazole and tetrazole rings. The ligand synthesis was through successive steps to achieve both heterocyclic rings. The synthesized compounds were characterized using conventional techniques like infrared, ultra violet—visible and proton/carbon nuclear magnetic resonance spectroscopy, metal and thermal analyses, and molar conductivity. All complexes were suggested to have square planar geometry, gold, nickel, and palladium complexes were salts while copper neutral complexes have the chemical formulas; [AuL₂]Cl.2H₂O, [PdL₂]Cl₂.2H₂O, [NiL₂]Cl₂.2H₂O, and [CuL₂]. The cytotoxic effect was studied on breast cancer cell line (MCF‐7 cell line) at different concentrations by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay method, for the ligand (L) and complexes. The results showed that gold(III) and nickel(II) complexes have the highest cytotoxicity among all compounds against cancer cell lines.     

Design,Synthesis, and Anticancer Activity of 3H–benzo[f]chromen‐3‐one Derivatives

A series of substituted aminomethylbenzocoumarin derivatives 8a–i have been synthesized, characterized, and structure of compound 8g was confirmed by X‐ray single crystal analysis. All the synthesized compounds were tested for their anticancer activity against cancer cell lines A549 (lung carcinoma cell line), MCF7 (breast cancer cell line), and A375 (melanoma cell line). Compounds 8a , 8f , and 8h showed excellent growth inhibitory activity against all three cell lines, respectively. Compounds 8a and 8f were also found to be quite promising at very low concentration as an anticancer agent against MCF7 and A549 cell lines. Compounds 8g and 8i showed excellent antimitotic activity with IC₅₀ 0.32 and19.98 nM for A549 cell line.     

Synthesis and X-ray structure of platinum(II), palladium(II) and copper(II) complexes with pyridine–pyrazole ligands: Influence of ligands’ structure on cytotoxic activity

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-phosphonic acid dimethyl ester (2a) has been used to obtain a series of platinum(II), palladium(II) and copper(II) complexes (3a–7a) as potential anticancer compounds. The molecular structures of the platinum(II) and copper(II) complexes 3a and 6a have been determined by X-ray crystallography. The cytotoxicity of the phosphonic ligand 2a and its carboxylic analog 2b as well as their complexes has been evaluated on leukemia and melanoma cell lines. Copper(II) complexes were found to be more efficient in the induction of melanoma cell death than the platinum(II) or palladium(II) complexes. Cytotoxic effectiveness of compound 7b against melanoma WM-115 cells was two times better than that of cisplatin. The reaction of compound 5b with 9-methylguanine has been studied.     

Isolation of a new triterpene derivative and in vitro and in vivo anticancer activity of ethanolic extract from root bark of Zizyphus nummularia Aubrev

The various parts of Zizyphus nummularia has been used traditionally in several disease conditions. However, its anticancer activity and mechanism of action remain to be elucidated. Considering this, the objective of this study was to isolate, identify and screen for possible anticancer activity in vitro and in vivo of the ethanolic extract (EE) and isolated identified compound (IC) from Z. nummularia root bark. The in vitro activity against human breast cancer, leukaemia, ovarian cancer, colon adenocarcinoma and human kidney carcinoma cell lines was determined. The in vivo activity in female Swiss albino mice against Ehrlich ascites carcinoma (EAC) was determined. The isolated compound is a new triterpene derivative. EE/IC showed cytotoxicity against different cell lines. The administration of EE/IC decreased tumour parameters such as tumour volume, viable tumour cell count and increased body weight, haematological parameters and life span in comparison to the EAC control mice.     

N9位芳基取代嘌呤-8-酮类衍生物的合成及抗肿瘤活性

合成了一系列N9位芳基取代嘌呤-8-酮类衍生物, 利用核磁共振氢谱(¹H NMR)、 核磁共振碳谱(¹³C NMR)和高分辨质谱(HRMS)进行了结构确证. 采用四甲基偶氮唑盐(MTT)法测定了目标化合物的体外抗肿瘤细胞增殖活性. 结果表明, 嘌呤酮环的C2位及N9位的取代对活性有较大影响, C2位引入对位由含氮六元环取代的苯胺, N9位引入对三氟甲基苯均有利于提高抗肿瘤活性. 化合物12c对人白血病细胞(K562)、 人前列腺癌细胞(PC-3)、 人乳腺癌细胞(MDA-MB-231)及人结肠癌细胞(HCT116)的抑制效果明显优于阳性对照药R-Roscovitine.     

Design,Synthesis and Antitumor Activity of Novel Indolin-2-one Derivatives Containing 4-Thiazolidinone Moiety

A series of novel indolin-2-one derivatives containing 4-thiazolidinone moiety(7a―7r) were synthesized and evaluated for their in vitro antitumour activities against MDA-MB-231(human breast cancer), H460(human lung cancer) and HT-29(human colon cancer) cell lines by standard 3-(4,5-dimethylthiazae-2-yl)-2,5-diphenyltetrazo- lium bromide(MTT) assay. Representative compounds(7d, 7k, 7m, 7p) with higher cytotoxicity were further examined against one normal cell line(WI-38, human fetal lung fibroblasts). The preliminary investigation shows that most of the compounds display moderate to excellent potency and high selectivity against different human cancer cell lines. In particular, the most potent compound 7m shows promising cytotoxicity against MDA-MB-231, H460 and HT-29 cell lines with IC₅₀ values of 0.78, 0.056 and 0.018 μmol/L, respectively. The potency is much higher than that of Sunitinib(IC₅₀=3.46 μmol/L against MDA-MB-231, IC₅₀=2.59 μmol/L against H460, IC₅₀=1.50 μmol/L against HT-29) by 4.4, 46.3 and 83.3 fold.     

Antioxidant and cytotoxic properties of some new dipeptide-indole conjugates

In this study, 10 new indole-dipeptide conjugates were synthesized, and their anticancer activity was determined against on A2780 (ovarian cancer cell line) and MCF-7 (breast cancer cell line) cells. Among compounds, 5 and 10 showed better activity against A2780 cell lines than the standard drug docatexel at 0.1 and 1 μM concentrations, while only compound 5 showed better activity than docatexel, the MCF-7 cell line at 0.1 and 1 μM concentrations. The antioxidant potencies of the compounds were low in both the DPPH and iron reducing power methods tested when compared to standard antioxidants used in this work.     

Synthesis,computational quantum chemical study,in silico ADMET and molecular docking analysis,in vitro biological evaluation of a novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties as a potential human topoisomerase IIα inhibiting anticancer agent

Computational quantum chemical study and biological evaluation of a synthesized novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties namely BTPT [2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-6-methoxy-4-(thiophen-2-yl) pyridine] was presented in this study. The crystal structure was determined by SCXRD method. For the title compound BTPT, spectroscopic characterization like ¹H NMR, ¹³C NMR, FTIR, UV–vis were carried out theoretically by computational DFT method and compared with experimental data. Druglikeness parameters of BTPT were found through in silico pharmacological ADMET properties estimation. The molecular docking investigation was performed with human topoisomerase IIα (PDB ID:1ZXM) targeting ATP binding site. In vitro cytotoxicity activity of BTPT/doxorubicin were examined by MTT assay procedure against three human cancer cell lines A549, PC-3, MDAMB-231 with IC50 values of 0.68/0.70, 1.03/0.77 and 0.88/0.98 μM, respectively. Our title compound BTPT reveals notable cytotoxicity against breast cancer cell (MDAMB-231), moderate activity with human lung cancer cell (A-549) and less inhibition with human prostate cancer cell (PC-3) compared to familiar cancer medicine doxorubicin. From the results, BTPT could be observed as a potential candidate for novel anticancer drug development process.     

Design,Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.