scholarly journals Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3496 ◽  
Author(s):  
Irina V. Il’ina ◽  
Nadezhda S. Dyrkheeva ◽  
Alexandra L. Zakharenko ◽  
Alexander Yu. Sidorenko ◽  
Nikolay S. Li-Zhulanov ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Gene Knockout ◽  
Biological Investigation ◽  
Cytotoxic Effects ◽  
Design Synthesis ◽  
Structural Types ◽  
Promising Target ◽  
Ic50 Value ◽  
Cytotoxic Compounds ◽  
Hek293ft Cell

Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 −/− cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs

2021 ◽  
Vol 86 (3) ◽  
pp. 2499-2521
Author(s):  
K. C. Nicolaou ◽  
Santhosh Reddy Rekula ◽  
S. Mothish Kumar ◽  
Ananda Rao Podilapu ◽  
Ryan P. Matuszak ◽  
...  
Keyword(s):  
Biological Investigation ◽  
Structural Motifs ◽  
Design Synthesis

Review: Highly Selective Compounds for the Antibody-Directed Enzyme Prodrug Therapy of Cancer

2003 ◽  
Vol 56 (9) ◽  
pp. 841 ◽  
Author(s):  
Lutz F. Tietze ◽  
Tim Feuerstein
Keyword(s):  
Monoclonal Antibody ◽  
Malignant Cells ◽  
High Potency ◽  
Selective Treatment ◽  
Enzyme Prodrug Therapy ◽  
Ic50 Value ◽  
Tumour Associated Antigens ◽  
Cytotoxic Compounds

Antibody-directed enzyme prodrug therapy (ADEPT) is a recent development for a selective treatment of cancer, based on site-directed formation at the surface of malignant cells of cytotoxic compounds from non-toxic prodrugs with a conjugate of an appropriate enzyme and a monoclonal antibody which binds to tumour-associated antigens. New potent prodrugs of analogues of the antibiotic CC-1065 have been developed. These show a remarkable selectivity with a Q(IC50) value of up to more than 3000. Moreover, the formed drug has a high potency with an IC50 of 30 pM.

Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents

2021 ◽  
Vol 21 ◽  
Author(s):  
Paulo Fernando da Silva Santos-Júnior ◽  
Martine Schmitt ◽  
João Xavier de Araújo-Júnior ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Combined Therapy ◽  
Experimental Studies ◽  
New Drugs ◽  
Host Cells ◽  
Sar Studies ◽  
Promising Target ◽  
Ic50 Value ◽  
Leishmania Spp ◽  
Etiological Agents ◽  
Antiparasitic Agents

: Trypanosomatidae family belongs to the Kinetoplastida order, which consists of obligatory parasites that affect plants and all classes of vertebrates, especially humans and insects. Among the heteroxenic parasites, Leishmania spp., Trypanosoma cruzi, and T. brucei are protozoa of most significant interest for medicinal chemistry, being etiological agents of Leishmaniasis, Chagas, and Sleep Sickness diseases, respectively. Currently, inefficient pharmacotherapy, especially in chronic phases and low selectivity towards parasite/host cells, justifies the need to discover new drugs to treat them effectively. Among other targets, the sterol 14α-demethylase (CYP51), an enzyme responsible for ergosterol's biosynthesis in Trypanosomatidae parasites, has received more attention in the development of new bioactive compounds. In this context, antifungal ravuconazole proved to be the most promising drug among this class against T. cruzi, being used in combined therapy with Bnz in clinic trials. Non-antifungal inhibitors, such as VFV and VNF, have shown promising results against T. cruzi and T.brucei, respectively, being tested in Bnz-combined therapies. Among the experimental studies involving azoles, compound (15) was found to be the most promising derivative, displaying an IC50 value of 0.002 µM against amastigotes from T. cruzi, in addition to being non-toxic and highly selective towards TcCYP51 (< 25 nM). Interestingly, imidazole analog (16) was active against infectious forms of these three parasites, demonstrating Ki values of 0.17, 0.02, and 0.36 nM for CYP51 from T. cruzi, T. brucei, and L. infantum. Finally, this review will address promising inhibitors targeting sterol 14α-demethylase (CYP51) from Trypanosomatidae parasites, highlighting SAR studies, interactions with this target, and recent contributions and advances in the field, as well.

scholarly journals Antiproliferative Effects of a Series of Pyrazolines on Lung Cancer

Proceedings ◽  
2018 ◽  
Vol 2 (25) ◽  
pp. 1574
Author(s):  
Belgin Sever ◽  
Mehlika Dilek Altıntop ◽  
Elif Kaya Tilki ◽  
Miriş Dikmen ◽  
Ahmet Özdemir
Keyword(s):  
Lung Cancer ◽  
Anticancer Agents ◽  
Human Lung ◽  
Fibroblast Cell ◽  
Inhibitory Effect ◽  
Cytotoxic Effects ◽  
Human Lung Fibroblast ◽  
Antiproliferative Effects ◽  
Ic50 Value ◽  
Fibroblast Cell Lines

Lung cancer is one of the most diagnosed cancers worldwide and the development of anticancer agents for the treatment of lung cancer is an important task for researchers. For this purpose, herein pyrazoline-based compounds 1–18 were investigated for their cytotoxic effects on A549 human lung adenocarcinoma and CCD-19Lu human lung fibroblast cell lines using MTT assay. According to the results, 1-(4-methoxyphenyl)-3-(2-furanyl)-5-(4-methylphenyl)-2-pyrazoline (7) was identified as the most promising anticancer agent due to its selective inhibitory effect on A549 cell line with an IC50 value of 138.63 µg/mL when compared with cyclophosphamide (IC50 = 309.97 µg/mL).

scholarly journals Design, Synthesis and Biological Evaluation of Novel 4-Substituted Coumarin Derivatives as Antitumor Agents

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2281 ◽  
Author(s):  
Ran An ◽  
Zhuang Hou ◽  
Jian-Teng Li ◽  
Hao-Nan Yu ◽  
Yan-Hua Mou ◽  
...  
Keyword(s):  
Antitumor Agents ◽  
Cancer Cell Line ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Hypoxic Conditions ◽  
Ca Ix ◽  
Ic50 Value ◽  
Almost All ◽  
New Compounds

Herein, fifteen new compounds containing coumarin, 1,2,3-triazole and benzoyl- substituted arylamine moieties were designed, synthesized and tested in vitro for their anticancer activity. The results showed that all tested compounds had moderate antiproliferative activity against MDA-MB-231, a human breast cancer cell line, under both normoxic and hypoxic conditions. Furthermore, the 4-substituted coumarin linked with benzoyl 3,4-dimethoxyaniline through 1,2,3-triazole (compound 5e) displayed the most prominent antiproliferative activities with an IC50 value of 0.03 μM, about 5000 times stronger than 4-hydroxycoumarin (IC50 > 100 μM) and 20 times stronger than doxorubicin (IC50 = 0.60 μM). Meanwhile, almost all compounds revealed general enhancement of proliferation-inhibiting activity under hypoxia, contrasted with normoxia. A docking analysis showed that compound 5e had potential to inhibit carbonic anhydrase IX (CA IX).

scholarly journals Nimesulide Based Novel Glycolamide Esters: Their Design, Synthesis, and Pharmacological Evaluation

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Kavitha Kankanala ◽  
Vangala Ranga Reddy ◽  
Yumnam Priyadarshini Devi ◽  
Lakshmi Narasu Mangamoori ◽  
Khagga Mukkanti ◽  
...  
Keyword(s):  
Cancer Cell Line ◽  
Human Colon ◽  
Colon Cancer Cell Line ◽  
Cytotoxic Activities ◽  
Step Method ◽  
Human Colon Cancer ◽  
Cytotoxic Effects ◽  
Design Synthesis ◽  
First Time

The nimesulide based novel glycolamide esters were designed and synthesized for the first timeviaa three-step method starting from nimesulide. Structures of the synthesized compounds were confirmed by spectroscopic analysis. All the synthesized compounds were examined for their cytotoxic effectsin vitro,some of which showed significant cytotoxic activities against HCT-15 human colon cancer cell line.

Design, Synthesis, and Evaluation of WC5 Analogues as Inhibitors of Human Cytomegalovirus Immediate-Early 2 Protein, a Promising Target for Anti-HCMV Treatment

ChemMedChem ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. 1403-1414 ◽  
Author(s):  
Serena Massari ◽  
Beatrice Mercorelli ◽  
Luca Sancineto ◽  
Stefano Sabatini ◽  
Violetta Cecchetti ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Protein A ◽  
Immediate Early ◽  
Design Synthesis ◽  
Promising Target

scholarly journals Cytotoxic and Apoptotic-inducing Effect of Fraction Containing Brazilein from Caesalpinia sappan L. and Cisplatin on T47D Cell Lines

2017 ◽  
Vol 6 (3) ◽  
pp. 89
Author(s):  
Prisnu Tirtanirmala ◽  
Annisa Novarina ◽  
Rohmad Yudi Utomo ◽  
Raisatun Nisa Sugiyanto ◽  
Riris Istighfari Jenie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Annexin V ◽  
T47d Cell ◽  
Breast Cancer Cell Lines ◽  
Cytotoxic Effects ◽  
Caesalpinia Sappan ◽  
Main Compound ◽  
T47d Breast Cancer Cell ◽  
Ic50 Value

Anticancer activity of secang’s heartwood (Caesalpinia sappan L.) is based on its main compound: brazilin and brazilein. Brazilin, brazilein, and other compounds such as caesalpiniaphenol can affect proteins that have a role in apoptosis. In this study, we observed cytotoxic activity of fraction containing brazilein (FCB) alone or in combination with chemotherapeutic agent, cisplatin and the ability of the combination to induce apoptosis in T47D breast cancer cell lines. Cytotoxicity assay was determined using MTT assay, whereas the detection apoptosis induction was conducted using flow cytometry using Annexin-V and propidium iodide. FCB and cisplatin showed cytotoxic effect on T47D cells with IC50 value of 68 µg/mL and 16 µM, respectively. Combination of FCB and cisplatin result synergistic combination at the concentration ratio of 1/2 IC50 with CI value of 0.66. Its combination also able to induce apoptosis on T47D cell population 13% larger than the single treatment. Based on this study, we conclude that FCB is able to enhance the cytotoxic effects of cisplatin by inducing apoptosis.Keywords:  Caesalpinia sappan L., cisplatin, apoptosis, breast cancer

scholarly journals Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

2021 ◽  
Author(s):  
Julia Stille ◽  
Jevgenijs Tjutrins ◽  
Guanyu Wang ◽  
Felipe A. Venegas ◽  
Christopher Hennecker ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Antiviral Drugs ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Promising Target ◽  
Starting Point ◽  
Covalent Inhibitors ◽  
Screening Platform ◽  
And Function ◽  
Synthesis And Biological Evaluation

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

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