μM For MCF-7 Research Articles

Synthesis and in vitro anticancer evaluation of 8b-hydroxy-1-(6-substitutedbenzo[d]thiazol-2-yl)-3-(3-substitutedphenyl)-1,8b-dihydroindeno[1,2-c]pyrazol-4(3aH)-ones

A series of 1,8b-dihydroindeno[1,2-c]pyrazol-4(3aH)-ones has been efficiently synthesized on reaction of 2-(3-substitutedbenzoyl)-(1H)-indene-1,3(2H)-diones 1 and 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles 2 in presence of dry ethanol under reflux conditions in good yields. The structures of all the synthesized derivatives were elucidated by using different physical and spectral techniques (FTIR, 1H NMR, 13C NMR, 2D NMR and HRMS). The synthesized hydroxypyrazolones were assayed for their anticancer activity against two human cancer cell lines (i) lung carcinoma (A549) and (ii) breast carcinoma (MCF7) using MTT assay. Among all the tested compounds, 3d and 3k with IC50 values in the range of 30.68 ± 0.57 µM to 34.87 ± 0.76 µM exhibited moderate inhibitory ability against both the tested cancer cell lines in comparison to the standard drug Doxorubicin (0.95 ± 0.10 µM for A549 and 1.09 ± 0.11 µM for MCF7). The moderately active compounds of the series i.e.3d and 3k were further tested against normal human embryonic kidney cell line (HEK 293T) to examine their toxicity against normal cell lines. Selectivity Index (S.I.) of the most active compounds 3d and 3k was calculated for both the cancer cell lines which revealed that these derivatives i.e. 3d (S.I = 2.82 for A549 and 2.90 for MCF7) and 3k (S.I = 2.78 for A549 and 2.95 for MCF7) are safer anticancer agents.

Design, Synthesis and Molecular Docking of Novel Quinazolinone Hydrazide Derivatives as EGFR Inhibitors.

A series of novel quinazolinone hydrazide derivatives were designed and synthesized as EGFR inhibitors. The results indicated that most of the aimed compounds had potential anti-tumor cell proliferation and EGFR inhibitory activities. In the comprehensive analysis of all the tested compounds, the target compound 9c showed the best anti-tumor cell proliferation activity, (IC50 =1.31 μM for MCF-7, IC50 =1.89 μM for HepG2, IC50 =2.10 μM for SGC), and IC50 =0.59 μM for the EGFR inhibitory activity. Docking results showed that compound 9c could ideally insert the active site and interact with the critical amino acid residues (Val702, Lys721, Met769, Asp831) in the active site.

Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells.

Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl group from lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notable HDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid and hematologic cancers. The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, a novel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents. We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy, halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for their cytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biological assays. SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 μM in various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety), 2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutions on phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 μM in MCF-7 (breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primary human hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogs were further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHA molecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulated the expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the Chick Chorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHA analogs. From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ring improves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novel SAHA analogs could be potential therapeutic agents in treating breast cancer.

Gold(I)-Catalyzed Synthesis of 4H-Benzo[d][1,3]oxazines and Biological Evaluation of Activity in Breast Cancer Cells.

The first gold(I)-catalyzed cycloisomerization procedure applied to the synthesis of substituted 4H-benzo[d][1,3]oxazines has been developed starting from N-(2-alkynyl)aryl benzamides. The chemoselective oxygen cyclization via the 6-exo-dig pathway yielded the observed heterocycles in modest to good chemical yields under very mild reaction conditions. The obtained oxazines were assayed on the breast cancer (BC)-derived cell lines MCF-7 and HCC1954 with differential biological activity. The newly synthesized 4H-benzo[d][1,3]oxazine compounds showed several degrees of cell proliferation inhibition with a remarkable effect for those compounds having a substituted aryl at C-2 of the molecules. The 4H-benzo[d][1,3]oxazines showed an IC50 ranking from 3.1 to 95 μM in MCF-7 and HCC1954 cells. These compounds represent potential drug candidates for BC treatment. However, additional assays are needed to elucidate their complete effect over the cellular and molecular hallmarks of cancer.

New Chitosan Polymer Scaffold Schiff Bases as Potential Cytotoxic Activity: Synthesis, Molecular Docking, and Physiochemical Characterization.

In this work, we synthesize the sulfonated Schiff bases of the chitosan derivatives 2a-2j without the use of a catalyst in two moderately straightforward steps with good yield within a short reaction time. The morphology and chemical structure of chitosan derivatives were investigated using FT-IR, NMR (1H—13C), XRD, and SEM. Furthermore, our chitosan derivatives were tested for their anticancer activity against the MCF-7 cancer cell line, and doxorubicin was used as a standard. In addition, the normal cell lines of the breast cancer cell MCF-10A, and of the lung cell MRC-5 were tested. Compound 2 h, with a GI50 value of 0.02 µM for MCF-7, is highly active compared with the standard doxorubicin and other compounds. The synthesized compounds 2a-2j exhibit low cytotoxicity, with IC50 > 100 μg/ml, against normal cell lines MCF-10A, MRC-5. We also provide the results of an in-silico study involving the Methoxsalen protein (1Z11). Compound 2h exhibits a higher binding affinity for 1Z11 protein (−5.9 kcal/mol) and a lower binding affinity for Doxorubicin (−5.3 kcal/mol) than certain other compounds. As a result of the aforementioned findings, the use of compound 2h has an anticancer drug will be researched in the future.

Cetylpyridinium chloride inhibits human breast tumor cells growth in a no-selective way.

Analyze the antitumor capacity of cetylpyridinium chloride (CPC) on human breast tumor cells, and the possible action mechanism. The human breast tumor cells MCF-7 and no-tumor breast cells MCF-10A were exposed to CPC under various condition (concentration and duration). Cell viability was measured with MTT assay, the LIVE/DEAD assay, and fluorescence microscopy. Membrane permeability after CPC exposure was evaluated by Calcein AM assay, mitochondrial morphology with a MitoView staining, and genotoxicity with the comet assay and fluorescence microscopy. CPC was cytotoxic to both MCF-7 and MCF-10A as of a 24-h exposure to 0.1 µM. Cytotoxicity was dose-dependent and reached 91% for MCF-7 and 78% for MCF-10A after a 24-h exposure to 100 µM CPC, which outperformed the positive control doxorubicin in effectiveness and selectivity. The LD50 of CPC on was 6 µM for MCF-7 and 8 µM for MCF-10A, yielding a selectivity index of 1.41. A time response analysis revealed 64% dead cells after only 5 min of exposure to 100 µM CPC. With respect to the action mechanisms, the comet assay did not reveal genome fragmentation. On the other hand, membrane damage was dose-dependent and may also affect mitochondrial morphology. Cetylpyridinium chloride inhibits MCF-7 cell growing in a non-selective way as of 5 min of exposure. The action mechanism of CPC on tumor cells involves cell membrane damage without change neither mitochondrial morphology nor genotoxicity.

Novel 3-fluoro-4-morpholinoaniline derivatives: Synthesis and assessment of anti-cancer activity in breast cancer cells

Heterocyclic morpholine compounds are well-known for their anti-cancer activity. In this study, novel morpholine and its sulfonamide derivatives were designed and synthesized as potential anti-tumor agents. The new compounds were obtained from amine derivatives via nucleophilic addition reactions, providing the desired products in 70 to 90% yield. The docking analysis was performed for all thirty-one compounds. Out of them, we represent the docking poses for compounds NAM-5 and NAM-7 as representatives. After docking analysis, compounds NAM-5 and NAM- 7 were tested for in vitro antitumor activity against breast cancer cell lines (MCF-7 and MDA-MB-231) and healthy mouse embryonic fibroblast cell line (3T3L-1). Amongst these, sulfonamide group-containing compound NAM-5 showed significant anti-proliferative activity with IC50 of 1.811 µM and 2.143 µM for MCF-7 and MDA-MB-231 cells, respectively. On the other hand, NAM-7 showed good anti-proliferative activity against MCF-7 (IC50 1.883 µM) but slightly lower activity against MDA-MB-231 cells (IC50 4.688 µM). The activity of both the compound was also tested on 3T3L-1 Cell line which showed activity similar to clinically approved anti-cancer drug doxorubicin (DOX). The cell death analysis by flow-cytometry confirmed apoptosis mediated cell death in 3T3L-1, MCF-7 and MDA-MB-231 cells when treated with the NAM-5 and NAM-7, respectively. The results demonstrated that the synthesized sulfonamide derivatives have significant potential as anti-cancer agents and have a substantial importance in cancer therapeutics with favourable safety profile. Structural analysis of docked poses of sulfonamide derivatives attempts to shed light on the structural basis of sulfonamide derivatives based anti-cancer effect.

Abstract P074: STAT3 pathway in palbociclib resistance in breast cancer cell lines and the role of inhibitors such as tocilizumab and silymarin

Abstract Introduction Resistance to cyclin inhibitors such as palbociclib is a challenge in the treatment of hormone-dependent metastatic breast cancer. Likewise, triple negative tumors are resistant to these inhibitors. The role of the present research is to identify the role that the transcription factor STAT3 (antiapoptotic transcription factor) and the inhibitors of the STAT3 pathway, such as tocilizumab (interleukin 6 receptor inhibitor) and silymarin (extract of milk thistle containing silibinin, a STAT3 inhibitor), could have in this situation. Methods Breast cancer cell lines MCF-7 (positive for estrogen receptors) and MDA-MB-231 (triple negative) were cultured in DMEM + 10% FBS for 72 hours with different concentrations of palbociclib, tocilizumab and silymarin in order to obtain cell growth inhibition values ​​(IC50) in each compound and combinations of palbociclib with tocilizumab or silymarin. In these cases, the combination indexes (CI < 1 (synergy) and CI > 1 (antagonism)) were calculated using CompuSyn software. Likewise, an RNA extraction was carried out from the untreated cell lines to determine the basal expression levels of STAT3 by RT-qPCR. Results The IC50 of palbociclib in MCF-7 was 3.14 µM and in MDA-MB-231, 29.69 µM. The results of RT-qPCR for the basal expression of STAT3 revealed its absence of expression in MCF-7 and the presence of expression in MDA-MB-231, which could be related to the greater resistance to palbociclib of this last cell line. Tocilizumab did not present cytotoxicity per se and silymarin did not reach IC50 value in the cell lines studied (both compounds in doses up to 100 µM). Regarding the combinations of silymarin (50 µM and 75 µM) and palbociclib (0.1 µM and 1 µM), a synergistic effect (CI < 1) was detected in all the combinations studied in MCF-7 and in most of the same in MDA-MB-231 (except 75 µM silymarin and 0.1 µM palbociclib). However, in the case of the combination of tocilizumab (10 µM and 50 µM) and palbociclib (0.1 µM, 1 µM and 5 µM in MCF-7, and 5 µM, 10 µM and 25 µM in MDA-MB-231) synergy was only obtained in half of the combinations studied in both cell lines. Conclusion STAT3 factor could be related to resistance to cyclins in hormone-dependent breast cancer and to the lower sensitivity to these drugs observed in triple-negative breast cancer. The synergistic combination of palbociclib with silymarin, a STAT3 inhibitor, in both the hormone-sensitive and triple negative cell lines indicates that silymarin could help to enhance the effect of palbociclib in breast cancer and, even, help to reverse the resistance to this drug both in the hormone dependent and triple negative, although further studies would be needed to confirm this fact. Citation Format: Kevin Doello, Cristina Mesas, Víctor Amecua, Marco Fuel, Laura Cabeza, Raúl Ortiz. STAT3 pathway in palbociclib resistance in breast cancer cell lines and the role of inhibitors such as tocilizumab and silymarin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P074.

Syntheses, structures, and anticancer activities of a series of trinuclear Cu(II) complexes with N-methylanthraniloyl(4-phenylthiosemicarbazide)

A series of trinuclear Cu(II) complexes with N-methylanthraniloyl(4-phenylthiosemicarbazide) (H2L) have been successfully prepared and structurally determined. The organic ligand H2L readily reacts with Cu(ClO4)2 · 6 H2O and CuCl2 · 2 H2O in DMF under formation of trinuclear complexes with the compositions of [Cu3(L)2(HCOO)2] (1) and [Cu3(L)2Cl2] (2), respectively. Similar reaction with [Cu(phen)Cl2] gives rise to a trinuclear complex [Cu3(L)2(phen)]Cl2 (3a), which is alternatively prepared by a simple method including a simultaneous reaction of CuCl2 · 2 H2O with H2L, o-phenanthroline and pyridine in CH2Cl2/MeOH. The compound [Cu3(L)2(phen)](PF6)2 (3b) is isolated from a analogous reaction and subsequent workup with (n-Bu4N)(PF6). Such facile synthetic procedure is successfully applied in preparation of structurally related product [Cu3(L)2(bpy)](PF6)2 (4). In all trinuclear complexes, the deprotonated organic compound {L}2– serves as bridging ligands with (Namine, N1, S) and (O, N2) donor sets. The ligand H2L, 1 and 2 show almost no antiproliferative effects on the human MCF7 breast and HepG2 liver cancer cells. Surprisingly, 3 and 4 with IC50 values in the range of 1.37–10.24 µM for MCF7 and 1.64–8.54 µM for HepG2 exhibit significantly higher cytotoxicity than cisplatin under the same conditions.

Biologically active acylthioureas and their Ni(II) and Cu(II) Complexes: Structural, spectroscopic, anti-proliferative, nucleolytic and antimicrobial studies

The study investigated the effects of morpholine substituent and metal complexation on in vitro anticancer and antimicrobial activities of acylthioureas using two acylthiourea molecules that differ only by the presence of morpholine oxygen; N,N-diethyl-N′-(4-chlorobenzoyl)thiourea (CBDEA) and N-morpholine-N′-(4-chlorobenzoyl)thiourea (CBMOR), and their Ni(II) and Cu(II) complexes (NiCBDEA, CuCBDEA, NiCBMOR, CuCBMOR). All compounds were synthesized and characterized by physicochemical and spectroscopic studies. CBDEA, CuCBDEA, NiCBDEA, CBMOR, and NiCBMOR were structurally elucidated by single-crystal X-ray diffraction. The metal complexes were isolated as neutral four coordinate complexes of the form, ML2 (M: Ni(II), Cu(II), H.L.: CBDEA/CBMOR) in square-planar geometry. The compounds were screened for DNA binding/cleavage, antimicrobial activity, and anti-proliferative effects on human prostate cancer PC-3 and breast cancer MCF-7 cells. DNA binding interaction studies suggest that the metal complexes bind more strongly to the DNA compared to the ligands. The morpholine derivative CBMOR shows similar activity to CBDEA against PC-3 cell lines but twice as effective against MCF-3 cells at cell death and apoptotic levels. Anticancer activities were enhanced by complexation with Cu(II), as evident in CuCBMOR, which showed the optimal anticancer activity (IC50: 1.76 µM for MCF-7 and 1.97 µM for PC-3), comparable to known anticancer drug paclitaxel. The CuCBMOR apoptosis results show that the cancer cells die by apoptotic mechanisms (Apoptosis rate: 91.53 % in MCF-7 and 85.95 % in PC-3). In vitro screening of the compounds against seventeen bacteria and four yeast strains confirmed antimicrobial potency against more susceptible Gram-positive bacteria strains. The results of the study suggest that some of the compounds could be developed into novel antimicrobial and anticancer agents.

Cytotoxicity effect of honey, bee pollen, and propolis from seven stingless bees in some cancer cell lines.

Our effort to find new material for anti cancer from natural resources leads us to focus on stingless bee products such as honey, bee pollen, and propolis. The products were from seven stingless bees named Homotrigona fimbriata, Heterotrigona itama, Heterotrigona bakeri, Tetragonula sarawakensis, Tetragonula testaceitarsis, Tetragonula fuscobalteata, Tetragonula laeviceps. The stingless bee products were evaluated for their cytotoxicity effect on MCF-7, HeLa and Caco-2 cancer cell lines. This is the first time to be reported that the honey, ethanol extracts of bee pollen and propolis of H. fimbriata displayed more potent cytotoxicity than other stingless bee products. By chromatography and biological activity-guided fractionation, ethanol extract of propolis from H. fimbriata was fractionated and isolated its active compound named mangiferonic acid. Mangiferonic acid showed a cytotoxicity effect with IC50 values 96.76 µM in MCF-7, >110.04 µM in HeLa, and > 110.04 µM in Caco-2, respectively. These results exhibited the potential of ethanol extracts from propolis of H. fimbriata to be further developed for drug and experiments to verify the function are essential.

Syntheses, Structures, and Bioactivity Evaluation of some Transition Metal Complexes with Aroylbis(N,N‐diethylthioureas) Derived from Natural Compounds

AbstractTwo novel benzoylthioureas derived from gallic acid, (tri‐O‐acetyl)galloyl‐N,N‐diethylthiourea HL1, and cinnamic acid, cinnamoyl‐N,N‐diethylthiourea HL2 have been successfully prepared and characterized by means of elemental analysis, IR, NMR, high‐resolution MS, and X‐ray crystallography. The organic ligands react with Ni(AcO)2 and Cu(AcO)2 in MeOH under formation of bis‐complexes with the compositions of [M(L)2] (M=Ni2+, Cu2+; L=L1, L2). Similar reactions with Co(AcO)2, however, result in Co(III) tris‐complexes [Co(L)3] (L=L1, L2) with the metal ions oxidized presumably by atmospheric dioxygen. X‐ray crystallography and spectroscopic characterization reveal a cis square‐planar coordination in the bis‐complexes and facial octahedral geometry in the tris‐complexes. In all of metal complexes, the deprotonated organic compounds ({L1}− and {L2}−) serve as (S,O)‐bidentate ligands. The ligand HL1 and its Ni(II) and Cu(II) complexes exhibit weak antiproliferative effects on the human MCF7 breast and HepG2 liver cancer cells with IC50 values in the range of 60–115 μM. Surprisingly, the tris‐complex [Co(L1)3] exhibits high cytotoxicity with IC50 values of 22.23±1.58 μM for MCF7 and 28.30±3.09 μM for HepG2 cancer cells. The activity against MCF7 cells is even more than that of cisplatin under the same conditions.

Synthesis of Resveratrol Loaded Hybrid Silica-PAMAM Dendrimer Nanoparticles With Emphases on Inducible Nitric Oxide Synthase and Cytotoxicity.

Resveratrol is a naturally occurring polyphenolic compound exhibiting therapeutic activities. However, the stability can be altered by UV light, pH and changes in temperature. Encapsulation would be an ideal strategy to improve the stability and bioavailability. Thus, trans-resveratrol (Res) was encapsulated within hybrid nanoparticles consisted with silica and G4 polyamidoamine dendrimer (PAMAM) by sol-gel method. The diameters of synthesized nanoparticles (NPs) were at a range of 212-574 nm and the encapsulation efficiency was 86 %. RAW 264.7 murine macrophage cell line induced with endotoxin/lipopolysaccharide was treated with free resveratrol and Res-loaded NPs for assessing inhibition of inducible nitric oxide synthase (iNOS), where IC50 values of free resveratrol and Res-loaded NPs were 122.68 µM and 249.74 µM. As for cytotoxicity, IC50 values of free resveratrol were found as 176.57 µM and 201.54 µM for MCF-7 and MDA-MB-231 cells, whereas 197.16 µM and 219.07 µM for Res-loaded NPs for the respective cell lines. Overall, sol-gel technique proved to be an ideal technology as can be carried out under mild conditions and Res-loaded NPs have potential to be utilized in the industry.

Anticancer activity in HeLa and MCF-7 cells via apoptopic cell death by a sterol molecule Cholesta-4,6-dien-3-ol (EK-7), from the marine ascidian Eudistoma kaverium

ObjectiveEudistoma kaverium, an ascidian belonging to the family Polycitoridae is previously recorded from Indian waters. The work done on this species is limited only to taxonomy and ecology. As ascidians are potential source of anticancer compounds, we have purified fractions of E. kaverium using HPLC and evaluated its anticancer activity. MethodChromatography based fractionation of the crude extract was carried out and mass spectrometry was used to identify the active molecule. Cell viability was checked using MTT assay. Flow cytometry, ROS generation, Hoechst staining and DNA fragmentation was performed to confirm the anticancer activity of the compound. ResultsA column fraction EK-7, which was identified as a sterol Cholesta-4,6-dien-3-ol using GC–MS analysis, exhibited potent cytotoxicity with IC50 value of 6.5 μM in MCF-7 and 10.2 μM against HeLa cells. Moreover, EK-7 triggered the cell cycle arrest in the sub G0/G1 stage and induced apoptosis twenty-four hours post-treatment. Hoechst staining of EK-7-treated HeLa cells portrayed apoptotic events such as changes in cell morphology, chromatin condensation, membrane swelling, and development of apoptotic bodies. The changes in light scattering by the EK-7-treated HeLa cells indicate the general characteristics of cell death as a result of apoptosis. The EK-7-treated HeLa cells show cell cycle arrest in G0/G1, G2/M and S phases and the increased amount of sub G0/G1 population indicates the increase in the apoptotic induced cell population. The isolated compound Cholesta-4,6-dien-3-ol (EK-7), based on the GC–MS analysis and library search from E. kaverium displayed potent anticancer activity which is mediated through apoptosis targeting the G0/G1 phase. ConclusionBased onthe experimental data, it shows that EK-7(Cholesta-4,6-dien-3-ol) a sterol derivative has potent anticancer activity mediated through apoptosis. If this research is continued further with preclinical and clinical trials, EK-7(Cholesta-4,6-dien-3-ol) could be possibly used as a chemotherapeutic agent in treating cancer.

Design, Synthesis and Molecular Docking of Chalcone Derivatives as Potential Anticancer Agents

AbstractTwenty derivatives of chalcones were synthesized and their anticancer activities were estimated against both breast and liver cancer besides two human normal cell lines. Out of our candidates, there were five compounds 3 b, 3 d, 3 h, 7 and 10 b that revealed a broad superlative antitumor activity against both HepG2 and MCF7 cell lines. Surprisingly, 3 h showed the most powerful anticancer activity (GI50=5.43±0.170 μM for MCF7 and GI50=1.80±0.50 μM for HepG2) and displayed the most effective inhibition activity on tubulin with IC50=4.51±0.13 μM. 3 h exerted low toxicity toward both normal human, Hs371.T and AML12, cell lines. 3 h revealed arrest of cell cycle at G2/M and induced apoptosis compared to control cells. Docking study of all newly derivatives was achieved to decide the preeminent binding mode. Generally, the outcome of the docking study showed that 3 h had better binding mode.

A novel series of benzothiazepine derivatives as tubulin polymerization inhibitors with anti-tumor potency

In this work, a series of diaryl benzo[b][1,4]thiazepine derivatives D1-D36 were synthesized and screened as tubulin polymerization inhibitors with anti-tumor potency. They were designed by introducing the seven-member ring benzothiazepine as the linker for CA-4 modification for the first time. Among them, the hit compound D8 showed potential on inhibiting the growth of several cancer cell lines (IC50 values: 1.48 μM for HeLa, 1.47 μM for MCF-7, 1.52 μM for HT29 and 1.94 μM for A549), being comparable with the positive controls Colchicine and CA-4P. The calculated IC50 value of D8 as an tubulin polymerization inhibitor was 1.20 μM. The results of the flow cytometry assay revealed that D8 could induce the mitotic catastrophe and the death of living cancer cells. D8 also indicated the anti-vascular activity. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with preliminary discussion, this work might stimulate new ideas in further modification of tubulin-related anti-cancer agents and therapeutic approaches.

Synthesis and Biological Evaluation of New 1,2,3-Triazole Derivatives of the Chrysin Flavonoid as Anticancer Agents.

Chrysin and its derivatives proved to possess potential anti-tumour activity. A new series of chrysin analogs containing 1,2,3-triazoles with different substituent groups (5a-5l) was designed, synthesized, and evaluated as potential anticancer agents. The synthesized compounds were characterized using FT-IR, 1H NMR 13C NMR spectroscopy and mass spectrometry. The anticancer activities of the synthesized compounds were studied in four cancer cell lines viz. PC3, PC3-PSMA, MCF-7 and UM-UC-3 using doxorubicin as standard. Among all the tested compounds, 5c was found as most active with IC50 value of 10.8 ± 0.04 μM in PC3 cells and 20.53 ± 0.21 μMin MCF-7 cells, respectively. Flow cytometry analyses indicated that synthesized compounds 5a, 5c, and 5h arrested MCF-7 cells at the G2/M phase in a dose-dependent manner. Chyrsin derivatives could be novel anticancer agents.

Synthesis, Anti-proliferative Activity, and Molecular Docking Study of New Series of 1,3-5-Triazine Schiff Base Derivatives.

Based on the use of s-triazine as a scaffold, we report here a new series of s-triazine Schiff base derivatives and their anti-proliferative activity against two cancer cell lines: human breast carcinoma (MCF-7), and colon cancer (HCT-116) compared with tamoxifen as a reference compound. Several derivatives exhibited growth inhibition activity in the sub-micromolar range. The results reveal that the s-triazine Schiff base derivatives showed varied activities and that the substituents on the s-triazine core have a great effect on the anti-proliferative activity. Compounds with a piperidino and benzylamino substituent on the s-triazine moiety 4b and 4c were most effective in both cell lines compared to the reference compound used. In addition, compound 4b has a para chlorine atom on the benzylidine residue, demonstrating the most potent activity with IC50 values of 3.29 and 3.64 µM in MCF-7 and HCT-116, respectively. These results indicate that in general, the nature of the substituents on the triazine core and the type of substituent on the benzilyldene ring significantly influenced the anti-proliferative activity. The results obtained from the anti-proliferative activity and the molecular docking study indicate that s-triazine-hydrazone derivatives may be an excellent scaffold for the development of new anti-cancer agents.

Prospects of Wedelolactone as a Chemotherapeutic Agent in Gynecological Cancers; Clue From its In Vitro and In Silico Investigation.

Identification and development of new drug candidates to be used singly or in combination therapy is critical in anticancer research. In recent years, accumulating evidence encouraged us to investigate the anti-proliferative effects of a small and emerging phytochemical Wedelolactone (WDL) in estrogen-dependent and independent multiple gynecological tumor models. The aim of this study was to investigate the growth inhibitory effect of WDL on estrogen- dependent and independent gynecological cell lines and to explore its inhibitory potential towards key targets through in silico study. Cytotoxicity of WDL was investigated in human breast and ovarian cancer cell lines (MCF-7 and SKOV3) through 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Epigallocatechingallate (EGCG) was used as reference natural compound while cisplatin was taken as a standard clinical agent. Both WDL and EGCG in combination with cisplatin were also evaluated for their combined growth inhibitory potential in MCF-7 cells. WDL was also evaluated in silico against key factors including braf kinases, CDPK, ERα, aromatase, topoisomerase II and dihydrofolate reductase (DHFR) playing pivotal roles in driving multiple tumors. The IC50 value of WDL was 25.77 ± 4.82 μM and 33.64 ± 1.45 μM in MCF-7 and SKOV-3 respectively. The binding energy order was as follows; WDL: DHFR >Braf kinases > CDPK; aromatase > topoisomerase II> ERα > NFkB > alkaline phosphatase; EGCG dihydrofolatereductase (DHFR) > aromatase >CDPK > topoisomerase II > braf kinases > alkaline phosphatase > CDPK > ERα > NFkB. We identified WDL as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in the oncogenic pathway including estrogen receptor ERα, as depicted through its in silico study. Based on our own research findings and from literature evidence, we conclude that further research should be encouraged to investigate different aspects of wedelolactone as an additional agent to be combined with antiestrogen/endocrine therapy.

Synthesis and Evaluation of Biological Properties of 2-Amino-thiazole-4-carboxamides: Amide Linkage Analogues of Pretubulysin.

Pretubulysin is a bio-precursor of highly toxic tetrapeptide tubulysins. Although pretubulysin has a much simpler chemical structure, it has similar anti-mitotic potency. A series of 2-amino-thiazole-4-carboxamides were designed and synthesized based on the structure of cemadotin. These are all novel compounds and their structures are characterized by 1H-NMR, 13C-NMR, and high resolution (HR)MS. The antitumor activities of these compounds were screened using the methyl thiazolyl tetrazolium colorimetric (MTT) cell viability method in MCF7 (breast cancer) and NCI-H1650 (lung cancer) cells. All the synthesized compounds 6a-n showed moderate anti-proliferation activities. Compounds 6m exhibited antitumor activity with the IC50 value of 0.47 and 1.1 µM in MCF7 and NCI-H1650 cells, respectively.