scholarly journals Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3128
Author(s):  
Aldar A. Munkuev ◽  
Evgenii S. Mozhaitsev ◽  
Arina A. Chepanova ◽  
Evgeniy V. Suslov ◽  
Dina V. Korchagina ◽  
...  
Keyword(s):  
Cell Lines ◽  
Colon Adenocarcinoma ◽  
Anticancer Therapy ◽  
Topoisomerase 1 ◽  
Promising Target ◽  
Ic50 Values ◽  
Hct 116 ◽  
Citronellic Acid ◽  
Sensitizing Effect ◽  
Further Development

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.

scholarly journals A New Pentafluorothio-Substituted Curcuminoid with Superior Antitumor Activity

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 947
Author(s):  
Benedikt Linder ◽  
Leonhard H. F. Köhler ◽  
Lisa Reisbeck ◽  
Dominic Menger ◽  
Dharmalingam Subramaniam ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Cell ◽  
Cell Lines ◽  
Human Tumor ◽  
Colon Adenocarcinoma ◽  
Tumor Cell Lines ◽  
Noticeable Increase ◽  
Ic50 Values ◽  
Executioner Caspases ◽  
G1 Cells

A new and readily available pentafluorothiophenyl-substituted N-methyl-piperidone curcuminoid 1a was prepared and investigated for its anti-proliferative, pro-apoptotic and cancer stem cell-differentiating activities against a panel of human tumor cell lines derived from various tumor entities. The compound 1a was highly anti-proliferative and reached IC50 values in the nanomolar concentration range. 1a was superior to the known anti-tumorally active curcuminoid EF24 (2) and its known N-ethyl-piperidone analog 1b in all tested tumor cell lines. Furthermore, 1a induced a noticeable increase of intracellular reactive oxygen species in HT-29 colon adenocarcinoma cells, which possibly leads to a distinct increase in sub-G1 cells, as assessed by cell cycle analysis. A considerable activation of the executioner-caspases 3 and 7 as well as nuclei fragmentation, cell rounding, and membrane protrusions suggest the triggering of an apoptotic mechanism. Yet another effect was the re-organization of the actin cytoskeleton shown by the formation of stress fibers and actin aggregation. 1a also caused cell death in the adherently cultured glioblastoma cell lines U251 and Mz54. We furthermore observed that 1a strongly suppressed the stem cell properties of glioma stem-like cell lines including one primary line, highlighting the potential therapeutic relevance of this new compound.

scholarly journals Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-d]pyrimidin-4(5H)-one Scaffold

2021 ◽  
Vol 14 (3) ◽  
pp. 265
Author(s):  
Ana Dolšak ◽  
Tomaž Bratkovič ◽  
Larisa Mlinarič ◽  
Eva Ogorevc ◽  
Urban Švajger ◽  
...  
Keyword(s):  
Systematic Investigation ◽  
The Novel ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Dioxygenase ◽  
Promising Target ◽  
Synthetic Procedure ◽  
Ic50 Values ◽  
Novel Scaffold ◽  
Further Development ◽  
Micromolar Range

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC50 values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.

scholarly journals Four New ent-Kaurane Diterpene Glycosides from Isodon henryi

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2736 ◽  
Author(s):  
Liu ◽  
Zhang ◽  
Wu ◽  
Chen ◽  
Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Spectroscopic Methods ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Aerial Parts ◽  
Ic50 Values ◽  
Hct 116 ◽  
Relationship Of ◽  
First Time

To obtain diterpene glycosides from an aqueous extract of the aerial parts of Isodon henryi and further investigate their cytotoxicities, in this study, a total of seven compounds were isolated, including six ent-kaurane diterpene glycosides (1–6) and one diterpene aglycon (7). Among the seven ent-kaurane diterpenes obtained, four were novel compounds, including ent-7,20-epoxy- kaur-16-en-1α,6β,7β,15β-tetrahydroxyl-11-O-β-d-glucopyranoside (1), ent-7,20-epoxy-kaur-16-en- 6β,7β,14β,15β-tetrahydroxyl-1-O-β-d-glucopyranoside (2), ent-7,20-epoxy-kaur-16-en-6β,7β,15β- trihydroxyl-1-O-β-d-glucopyranoside (3), and ent-7,20-epoxy-kaur-16-en-7β,11β,14α,15β-tetrahydr- oxyl-6-O-β-d-glucopyranoside (4), and three were isolated from this plant for the first time (5–7). Their structures were elucidated by utilizing spectroscopic methods and electronic circular dichroism analyses. Furthermore, the cytotoxicities of all seven compounds were investigated in four human cancer cell lines, including A2780, BGC-823, HCT-116, and HepG2. The IC50 values of these diterpenes ranged from 0.18 to 2.44 mM in the tested cell lines. In addition, the structure–cytotoxicity relationship of diterpene glycosides was also evaluated to study the effect of glycosylation on the cytotoxicity of diterpene compounds.

Molecular Docking, Antioxidant, Anticancer and Antileishmanial Effects of Newly Synthesized Quinoline Derivatives

2020 ◽  
Vol 20 (13) ◽  
pp. 1516-1529 ◽  
Author(s):  
Zoonish Malghani ◽  
Arif-Ullah Khan ◽  
Muhammad Faheem ◽  
Muhammad Z. Danish ◽  
Humaira Nadeem ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Adverse Effects ◽  
Cell Lines ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Quinoline Derivatives ◽  
Brine Shrimp Lethality Assay ◽  
Anti Cancer ◽  
Ic50 Values ◽  
Hct 116

Background: Due to the pressing need and adverse effects associated with the available anti-cancer agents, an attempt was made to develop the new anti-cancer agents with better activity and lesser adverse effects. Objective: Synthetic approaches based on chemical modification of quinoline derivatives have been undertaken with the aim of improving anti-cancer agents’ safety profile. Methods: In the present study, quinoline derivatives 6-hydroxy-2-(4-methoxyphenyl) quinoline-4-carboxylic acid (M1) and 2-(4-chlorophenyl)-6-hydroxyquinoline-4-carboxylic acid (M3) were synthesized by the reaction of aldehyde and pyruvic acid. The complete reaction was indicated by thin-layer chromatography. Newly synthesized M1and M3were tested for in silico and in vitro studies. Results: M1 and M3 were docked against selected targets. Both the test compounds showed good affinity against all targets except the p300\CBP-associated factor target as there was no H-bond formed by M1. IC50 values of M1 and M3 against 1, 1-diphenyl-picrylhydrazyl free radical scavenging activity were 562 and 136.56ng/mL, respectively. In brine shrimp lethality assay, M1 and M3 showed IC50 value of 81.98 and 139.2ng/mL, respectively. IC50 values recorded for M1 and M3 in tumor inhibition activity were 129 and 219μg/mL, respectively. M1 and M3 exhibited concentration-dependent anti-cancer effects against human cell lines of hepatocellular carcinoma (HepG2) and colon cancer (HCT-116). Against HepG2 cells, M1 and M3 exhibited IC50 of 88.6 and 43.62μg/mL, respectively. M1 and M3 utilized against HCT-116 cell lines possessed IC50 values of 62.5 and 15.3μg/mL. M1 and M3 also showed an anti-leishmanial effect with IC50 values of 336.64 and 530.142μg/mL, respectively. Conclusion: From the results of pharmacological studies, we conclude that the newly synthesized compound showed enhanced anti-oxidant, anti-cancer and anti-leishmanial profile with good yield.

scholarly journals New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 973
Author(s):  
Nadezhda S. Dyrkheeva ◽  
Aleksandr S. Filimonov ◽  
Olga A. Luzina ◽  
Alexandra L. Zakharenko ◽  
Ekaterina S. Ilina ◽  
...  
Keyword(s):  
Cell Lines ◽  
Anticancer Agents ◽  
Biological Activities ◽  
Usnic Acid ◽  
Topoisomerase 1 ◽  
Binding Domains ◽  
Promising Therapeutic Target ◽  
Wide Range ◽  
Ic50 Values ◽  
Low Cytotoxicity

Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3′ end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23–0.40 μM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 ≥ 60 μM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan’s cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This “protective” effect from topotecan on non-cancerous cells requires further investigation.

scholarly journals Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

2020 ◽  
Vol 02 (03) ◽  
pp. e143-e149
Author(s):  
Qingwei Zhang ◽  
Guili Xu ◽  
Ya Bao ◽  
Minru Jiao ◽  
Jianqi Li
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Antitumor Drugs ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Antiproliferative Activities

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

scholarly journals Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

2020 ◽  
Vol 02 (02) ◽  
pp. e117-e123
Author(s):  
Qingwei Zhang ◽  
Guili Xu ◽  
Ya Bao ◽  
Minru Jiao ◽  
Jianqi Li
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Antitumor Drugs ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Antiproliferative Activities

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

scholarly journals Design, Synthesis, Antibacterial, Antifungal and Anticancer Evaluations of Novel β-Pinene Quaternary Ammonium Salts

2021 ◽  
Vol 22 (20) ◽  
pp. 11299
Author(s):  
Li Zhang ◽  
Xue-Zhen Feng ◽  
Zhuan-Quan Xiao ◽  
Guo-Rong Fan ◽  
Shang-Xing Chen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Anticancer Agents ◽  
Quaternary Ammonium ◽  
Biological Activities ◽  
Cell Membrane Permeability ◽  
Vitro Assay ◽  
Ic50 Values ◽  
Hct 116 ◽  
Mcf 7

β-pinene is a monoterpene isolated from turpentine oil and numerous other plants’ essential oils, which has a broad spectrum of biological activities. In the current work, six novel β-pinene quaternary ammonium (β-PQA) salts were synthesized and evaluated in vitro for their antifungal, antibacterial and anticancer activities. The in vitro assay results revealed that compounds 4a and 4b presented remarkable antimicrobial activity against the tested fungi and bacteria. In particular, compound 4a showed excellent activities against F. oxysporum f.sp. niveum, P. nicotianae var.nicotianae, R. solani, D. pinea and Fusicoccumaesculi, with EC50 values of 4.50, 10.92, 9.45, 10.82 and 6.34 μg/mL, respectively. Moreover, compound 4a showed the best antibacterial action against E. coli, P. aeruginosa, S. aureus and B. subtilis, with MIC at 2.5, 0.625, 1.25 and 1.25 μg/mL, respectively. The anticancer activity results demonstrated that compounds 4a, 4b, 4c and 4f exhibited remarkable activity against HCT-116 and MCF-7 cell lines, with IC50 values ranged from 1.10 to 25.54 μM. Notably, the compound 4c displayed the strongest cytotoxicity against HCT-116 and MCF-7 cell lines, with the IC50 values of 1.10 and 2.46 μM, respectively. Furthermore, preliminary antimicrobial mechanistic studies revealed that compound 4a might cause mycelium abnormalities of microbial, cell membrane permeability changes and inhibition of the activity of ATP. Altogether, these findings open interesting perspectives to the application of β-PQA salts as a novel leading structure for the development of effective antimicrobial and anticancer agents.

scholarly journals Synthesis and Characterization of New Series of 1,3-5-Triazine Hydrazone Derivatives with Promising Antiproliferative Activity

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2708 ◽  
Author(s):  
Hessa H. Al Rasheed ◽  
Azizah M. Malebari ◽  
Kholood A. Dahlous ◽  
Ayman El-Faham
Keyword(s):  
Cell Lines ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Human Cancer Cell Lines ◽  
Triazine Derivatives ◽  
Ic50 Values ◽  
Hct 116 ◽  
Benzaldehyde Derivatives ◽  
Mcf 7

A new series of s-triazine hydrazone derivatives was prepared based on the reaction of 6-hydrazino-2,4-disubstituted-s-triazine with p-substituted benzaldehyde derivatives using a straightforward synthetic pathway. The antiproliferative activity of all synthesized compounds was evaluated against two human cancer cell lines; breast cancer MCF-7 and colon carcinoma HCT-116 using MTT assay. Among all, 11 compounds have shown strong to moderate antiproliferative activity with IC50 values in the range 1.01–18.20 µM in MCF-7 and 0.97–19.51 µM in HCT-116. The best results were obtained with 4,4’-(6-(2-(pyridin-2-ylmethylene)hydrazinyl)-1,3,5-triazine-2,4-diyl) dimorpholine 11 (IC50 = 1.0 µM and 0.98 µM in MCF-7 and HCT-116 cell lines, respectively). The substituents on the s-triazine core as well as the substituent at the benzylidene moiety have a great effect on the antiproliferative activity. Whereas compounds containing dimorpholino-s-triazine derivatives 8a–e showed more potent antiproliferative in MCF-7 compared to their analogs 7a–f (compounds containing two-piperidine rings), compounds containing one piperidine and one morpholine ring 9a–f showed better IC50 values in the range 10.4–22.2 µM. On the other hand, compounds containing two-piperidine rings 7a–f showed more potent antiproliferative in HCT-116 (IC50 values in the range 8.8–19.5 µM) than their analogs 8a–e and 9a–f.

scholarly journals Tumoricidal Potential of Novel Amino-1,10-phenanthroline Derived Imine Ligands: Chemical Preparation, Structure, and Biological Investigations

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2865
Author(s):  
Kollur Shiva Prasad ◽  
Renjith Raveendran Pillai ◽  
Chandan Shivamallu ◽  
Shashanka K. Prasad ◽  
Anisha S. Jain ◽  
...  
Keyword(s):  
Dft Calculations ◽  
Cell Lines ◽  
Density Functional ◽  
Computational Analysis ◽  
Md Simulations ◽  
Distribution Functions ◽  
Ic50 Values ◽  
Hct 116 ◽  
Mcf 7

Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well as immortalized human keratinocytes. The observations indicated that both the molecules possesses dose-dependent selective cytotoxicity of cancer cells with no detrimental effect on the normal cell lines. Furthermore, the detailed computational analysis of newly synthetized ligands (PIB and PTM) has been conducted in order to identify their most important parts from the perspective of local reactivity. The IC50 values of PIB treatment on MCF-7, HeLa, HCT-116 and PC-3 were 15.10, 16.25, 17.88, 17.55 and 23.86 micromoles, respectively. Meanwhile, the IC50 values of PTM on MCF-7, HeLa, HCT-116, PC-3 and HaCat were observed to be 14.82, 15.03, 17.88, 17.28 and 21.22 micromoles, respectively. For computational analysis, we have employed the combination of Density Functional Theory (DFT) calculations and MD simulations. DFT calculations provided us with information about structure and reactivity descriptors based on the electron distribution. Surfaces of molecular electrostatic potential (MEP) and averaged local ionization energy (ALIE) indicated the sites within studied molecules that are most reactive. These results indicated the importance of nitrogen atoms and OH group. Additionally, the values of bond dissociation for hydrogen abstraction showed that both molecules, especially the PTM, are stable toward the influence of autoxidation mechanism. On the other side, MD simulations gave us an insight how ligands interact with water molecules. Namely, the radial distribution functions (RDF) indicated that the hydrogen atom of the OH group in the case of the PIB has the most pronounced interactions with water.

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