Design and Synthesis of New Substituted Pyrazolopyridines with Potent Antiproliferative Activity

2020 ◽  
Vol 16 (2) ◽  
pp. 176-191
Author(s):  
Vassiliki Giannouli ◽  
Nikolaos Lougiakis ◽  
Ioannis K. Kostakis ◽  
Nicole Pouli ◽  
Panagiotis Marakos ◽  
...  
Keyword(s):  
Cell Lines ◽  
Antiproliferative Activity ◽  
Ring Closure ◽  
Design And Synthesis ◽  
Anticancer Properties ◽  
Cellular Processes ◽  
Highly Active ◽  
Sar Studies ◽  
Ic50 Values ◽  
New Compounds

Background: Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer properties. Objective: Based on previously discovered substituted pyrazolopyridines with promising antiproliferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive compounds. Methods: The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antiproliferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed. Results: Eight compounds displayed IC50 values in the low μM range, allowing the extraction of interesting SAR’s. Two of the most potent compounds against all cell lines share a common pattern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged. Conclusion: Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87-4.3 µM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.

scholarly journals New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 447
Author(s):  
Christos Vassileiou ◽  
Stefania Kalantzi ◽  
Eleanna Vachlioti ◽  
Constantinos M. Athanassopoulos ◽  
Christos Koutsakis ◽  
...  
Keyword(s):  
Cell Lines ◽  
Antiproliferative Activity ◽  
Normal Breast ◽  
Head Group ◽  
Highly Active ◽  
Ic50 Values ◽  
Breast Cells ◽  
The One ◽  
Polyamine Toxins ◽  
Mcf 7

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC50 values of 2.63–2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC50 values of 3.15–12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC50 values of 0.09–3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells.

Microwave-assisted Synthesis of Polymethoxychalcone Mannich Bases and Their Antiproliferative Activity

2019 ◽  
Vol 16 (2) ◽  
pp. 117-121 ◽  
Author(s):  
Peipei Han ◽  
Wenhua Zhou ◽  
Mingxia Chen ◽  
Qiuan Wang
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Mannich Base ◽  
Cancer Cell Lines ◽  
Secondary Amines ◽  
Conventional Heating ◽  
Microwave Assisted ◽  
Ic50 Values ◽  
Antiproliferative Activities

A series of eight polymethoxychalcone Mannich base derivatives 2a-2h was synthesized via the microwave-assisted Mannich reaction of natural product 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) with various secondary amines and formaldehyde. Compared to conventional heating method (80°C), the microwave-assisted method (700W, 65°C) is efficient with short reaction time (0.5-1 h) and good yields (74-88%). The antiproliferative activities of eight Mannich base derivatives were evaluated in vitro on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3) by CCK-8 assay. The results showed that all of the Mannich base derivatives exhibited potential antiproliferative activities on tested cancer cell lines with the IC50 values of 9.13-48.51 µM. Some active compounds exhibited more activity as compared to positive control cis-Platin. Among them, compound 2b revealed to have the strongest antiproliferative activity against all the three cancer cell lines with IC50 values ranging from 9.13 to 11.24 µM.

Pyrrolizines as Potential Anticancer Agents: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction

2019 ◽  
Vol 18 (15) ◽  
pp. 2124-2130
Author(s):  
Amany Belal
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Caspase 3 ◽  
Assay Method ◽  
Breast Adenocarcinoma ◽  
Compound I ◽  
Design Synthesis ◽  
Ic50 Values ◽  
New Compounds

Background: For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Methods: Structures of the new compounds were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method. Result: Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC50 values were less than 5 µM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC50 values were less than 10 µM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC50 values less than 10 µM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds). Conclusion: The obtained results encourage considering these three compounds as novel anticancer prototypes.

scholarly journals Antibacterial and Cytotoxic Phenolic Polyketides from Two Marine-Derived Fungal Strains of Aspergillus unguis

2022 ◽  
Vol 15 (1) ◽  
pp. 74
Author(s):  
Cao Van Anh ◽  
Joo-Hee Kwon ◽  
Jong Soon Kang ◽  
Hwa-Sun Lee ◽  
Chang-Su Heo ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Detailed Analysis ◽  
Cell Lines ◽  
Spectroscopic Data ◽  
Bacterial Activity ◽  
Tumor Cell Lines ◽  
Fungal Strains ◽  
Aspergillus Unguis ◽  
Ic50 Values ◽  
New Compounds

A chemical investigation on the EtOAc extracts from two marine-derived fungal strains of Aspergillus unguis resulted in the isolation of three previously undescribed phenolic polyketides including unguidepside C (1), aspersidone B (3), and agonodepside C (12), and their 14 known congeners. The structures of the new compounds were determined based on detailed analysis and comparison of their spectroscopic data with literature values, as well as Snatzke’s method. The new compounds (1, 3, and 12) displayed a significant anti-Gram-positive bacterial activity, with MIC values ranging from 5.3 to 22.1 µM. Additionally, the isolated compounds (1–11 and 13–16) were evaluated for their cytotoxicity against a panel of tumor cell lines. Most of them (except for 9) displayed cytotoxicity against all the tested cell lines, with IC50 values ranging from 2.5 to 46.9 µM.

scholarly journals Highly Substituted Benzophenone Aldehydes and Eremophilane Derivatives from the Deep-Sea Derived Fungus Phomopsis lithocarpus FS508

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 329 ◽  
Author(s):  
Jian-Lin Xu ◽  
Hong-Xin Liu ◽  
Yu-Chan Chen ◽  
Hai-Bo Tan ◽  
Heng Guo ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
A549 Cell ◽  
Marine Sediment ◽  
Deep Sea ◽  
Crystallographic Analysis ◽  
X Ray ◽  
Naturally Occurring ◽  
Ic50 Values ◽  
New Compounds

Five new benzophenone derivatives named tenellones D–H (1–5), sharing a rare naturally occurring aldehyde functionality in this family, and a new eremophilane derivative named lithocarin A (7), together with two known compounds (6 and 8), were isolated from the deep marine sediment-derived fungus Phomopsis lithocarpus FS508. All of the structures for these new compounds were fully characterized and established on the basis of extensive spectroscopic interpretation and X-ray crystallographic analysis. Compound 5 exhibited cytotoxic activity against HepG-2 and A549 cell lines with IC50 values of 16.0 and 17.6 μM, respectively.

scholarly journals Synthesis of new 3-(substituted-phenyl)-N-(2-hydroxy-2-(substituted-phenyl)ethyl)-N-methylthiophene-2-sulfonamide derivatives as antiproliferative agents

2018 ◽  
Vol 9 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Chandrakant Pawar ◽  
Dattatraya Pansare ◽  
Devanand Shinde
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
1H Nmr ◽  
13C Nmr ◽  
Antiproliferative Activity ◽  
Positive Control ◽  
Antiproliferative Agents ◽  
Ic50 Values ◽  
Mcf 7

In the present work, we report the synthesis of a series of 3-(substituted phenyl)-N-(2-hydroxy-2-(substituted-phenyl)ethyl)-N-methylthiophene-2-sulfonamide derivatives through Suzuki and Buchwald reaction. We have optimized methodology for targets from milligram to multi-gram scale. The newly synthesized compounds were characterized by 1H NMR, 19F NMR, 13C NMR, LC-MS techniques and purity was further checked by HPLC. The compounds were evaluated for their in-vitro antiproliferative activity against MCF-7, HeLa, A-549 and Du-145 cancer cell lines by CCK-8 assay. The preliminary bioassay suggests that most of the compounds show antiproliferation with different degrees and 5-fluorouracil was used as positive control. Among these compounds 2d, 2g, 2i, 4e, 4h and 4k are most active compared to the standard. All the synthesized compounds show IC50 values from 1.82-9.52 µM in different cell lines. Amongst these, compounds 2d, 2g, 2i, 4e, 4h and 4k were most potent, with IC50 values ranging from 1.82-4.28 µM in different cell lines.

scholarly journals Anti-human lung cancer activities and survey of gluthation reductase and gluthation S transferase inhibition properties with molecular modeling studies of 2′-Hydroxy-5′-methyl-3′-nitroacetophenone: A pre-clinical trial study

2021 ◽  
Author(s):  
Yawei Dou ◽  
shanshan Lv ◽  
Attalla F. El-kott ◽  
Ayman E. El-kenawy
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Human Lung ◽  
Antioxidant Properties ◽  
Human Lung Cancer ◽  
Lung Cancers ◽  
Anticancer Properties ◽  
Ic50 Values ◽  
Human Lung Carcinoma

IntroductionRecently, scientists have tried to increase organic chemistry productions for the treatment of many cancers such as lung cancers. In this regard, antioxidant molecules have a special place in the treatment of several cancers. The molecular docking method was found to calculate the biological activity of the 2′-Hydroxy-5′-methyl-3′-nitroacetophenone (2′-H-5′-M-3′-N) molecule against the enzymes studied.Material and methodsIn these calculations, the enzymes used are gluthation reductase (GR) enzyme and Glutathione S-Transferase (GT) enzyme, respectively. After the modeling calculations were completed, the ADME/T parameters were examined to calculate the future drug use properties of the 2′-H-5′-M-3′-N molecule. To survey the antioxidant properties of 2′-H-5′-M-3′-N, the DPPH test was used. Several human lung adenocarcinoma cell lines i.e., lung moderately differentiated adenocarcinoma (LC-2/ad), lung poorly differentiated adenocarcinoma (PC-14), and lung well-differentiated bronchogenic adenocarcinoma (HLC-1) cell lines were used to determine the anticancer properties of the recent molecule.ResultsCell viability of 2′-H-5′-M-3′-N was very low against PC-14, LC-2/ad, and HLC-1 cell lines without any cytotoxicity on the normal cell line. The IC50 values of 2′-H-5′-M-3′-N against LC-2/ad, PC-14, and HLC-1 cell lines were found 475, 250, and 691 µg/mL, respectively. The best anti-human lung cancer properties of 2′-H-5′-M-3′-N against the above cell lines was in the case of PC-14 cell line.ConclusionsAs mentioned, the 2′-H-5′-M-3′-N had significant antioxidant and anti-human lung cancer properties. It appears that the anti-human lung carcinoma effect of 2′-H-5′-M-3′-N is due to their antioxidant effects.

scholarly journals Pyrrole as an Important Scaffold of Anticancer Drugs: Recent Advances

2022 ◽  
Vol 25 ◽  
pp. 24-40
Author(s):  
Emilio Mateev ◽  
Maya Georgieva ◽  
Alexander Zlatkov
Keyword(s):  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Lipid Lowering ◽  
Pyrrole Derivatives ◽  
Design And Synthesis ◽  
Anticancer Properties ◽  
Highly Active ◽  
Recent Advances ◽  
Cytochrome P450 Family

With the significant increase of patients suffering from different types of cancer, it is evident that prompt measures in the development of novel and effective agents need to be taken. Pyrrole moiety has been found in various active compounds with anti-inflammatory, antiseptic, antibacterial, lipid-lowering and anticancer properties. Recent advances in the exploration of highly active and selective cytotoxic structures containing pyrrole motifs have shown promising data for future investigations. Accordingly, this review presents an overview of recent developments in the pyrrole derivatives as anticancer agents, with a main focus towards the key moieties required for the anti-tumor activities. Pyrrole molecules comprising prominent targeting capacities against microtubule polymerization, tyrosine kinases, cytochrome p450 family 1, histone deacetylase and bcl-2 proteins were reported. In addition, several mechanisms of action, such as apoptosis, cell cycle arrest, inhibiting kinases, angiogenesis, disruption of cell migration, modulation of nuclear receptor responsiveness and others were analyzed. Furthermore, in most of the discussed cases we provided synthesis schemes of the mentioned molecules. Overall, the utilization of pyrrole scaffold for the design and synthesis of novel anticancer drugs could be a promising approach for future investigations.  

scholarly journals Synthesis, Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]+ Complexes

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5735
Author(s):  
Adedamola S. Arojojoye ◽  
R. Tyler Mertens ◽  
Samuel Ofori ◽  
Sean R. Parkin ◽  
Samuel G. Awuah
Keyword(s):  
Cell Lines ◽  
Anticancer Drugs ◽  
Antiproliferative Activity ◽  
Cytotoxic Effects ◽  
X Ray ◽  
Biologically Relevant ◽  
X Ray Crystallography ◽  
Ic50 Values ◽  
Antiproliferative Activities

Herein is reported the synthesis of two Au(III) complexes bearing the (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (R,R-QuinoxP*) or (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (S,S-QuinoxP*) ligands. By reacting two stoichiometric equivalents of HAuCl4.3H2O to one equivalent of the corresponding QuinoxP* ligand, (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (1) and (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) were formed, respectively, in moderate yields. The structure of (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) was further confirmed by X-ray crystallography. The antiproliferative activities of the two compounds were evaluated in a panel of cell lines and exhibited promising results comparable to auranofin and cisplatin with IC50 values between 1.08 and 4.83 µM. It is noteworthy that in comparison to other platinum and ruthenium enantiomeric complexes, the two enantiomers (1 and 2) do not exhibit different cytotoxic effects. The compounds exhibited stability in biologically relevant media over 48 h as well as inert reactivity to excess glutathione at 37 °C. These results demonstrate that the Au(III) atom, stabilized by the QuinoxP* ligand, can provide exciting compounds for novel anticancer drugs. These complexes provide a new scaffold to further develop a robust and diverse library of chiral phosphorus Au(III) complexes.

Design and Synthesis of a New Series of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potential Colchicine Binding Site Inhibitors: Antiproliferative activity, Molecular docking, and SAR Studies

2021 ◽  
Author(s):  
Rana Tarek Diab ◽  
Zakaria Abdelsamii ◽  
Eatedal Hassan Abd-Elaal ◽  
Ahmed A. Al-Karmalawy ◽  
Nader Elmaghwry AboDya
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Antiproliferative Activity ◽  
Research Area ◽  
Pharmaceutical Companies ◽  
Anticancer Compounds ◽  
Design And Synthesis ◽  
Sar Studies ◽  
Colchicine Binding Site ◽  
Research Institutes

The development of anticancer compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs) is a promising research area for pharmaceutical companies and research institutes. A series of...

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