Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments

2019 ◽  
Vol 19 (4) ◽  
pp. 463-472 ◽  
Author(s):  
Evgenii S. Mozhaitsev ◽  
Alexandra L. Zakharenko ◽  
Evgeniy V. Suslov ◽  
Dina V. Korchagina ◽  
Olga D. Zakharova ◽  
...  
Keyword(s):  
Dna Repair ◽  
Carboxylic Acid ◽  
Simultaneous Action ◽  
Cancer Drug ◽  
Repair Enzyme ◽  
Carboxylic Acid Chloride ◽  
Toxic Dose ◽  
Lung Adenocarcinoma Cell Line ◽  
Ic50 Values ◽  
Human Lung Adenocarcinoma Cell

Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. Methods: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21–94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86–4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

scholarly journals Synthesis and evaluation of some novel derivatives of 2-propoxybenzylidene isonicotinohydrazide for their potential antimicrobial activity

2012 ◽  
Vol 77 (5) ◽  
pp. 589-597 ◽  
Author(s):  
Manav Malhotra ◽  
Manu Arora ◽  
Abdul Samad ◽  
Kapendra Sahu ◽  
Priyanka Phogat ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Mannich Bases ◽  
Dependent Manner ◽  
Lung Adenocarcinoma Cell Line ◽  
Ic50 Values ◽  
Nmr Methods ◽  
Human Lung Adenocarcinoma Cell ◽  
Dose Dependent ◽  
Derivatives Of

A novel series of Mannich which contained isoniaside were prepared. First by the reaction of 2-propoxybenzaldehyde with isoniazid corresponding hydrazone (2a) was obtained. After that, product 2a after mannich reaction of aminomethylation with formaldehyde and secondary give amines (2b-2k). The inhibitory potencies of the synthesized compounds were assayed in vitro against a panel of microorganisms and against A549 human lung adenocarcinoma cell line. Compounds 2c and 2k displayed moderate to potent antimicrobial activity against all the tested strains and they also exhibited significant cytotoxicity in a dose-dependent manner with an IC50 values ranging from 2.84 to 8.55 (?g) and 0.007-0.030 (?M). The structures of newly synthesized compounds were evaluated by elemental and spectral (IR, 1HNMR, 13C-NMR) methods. The result demonstrates the potential and importance of developing new mannich bases which would be effective against resistant microbial strain and they may be useful leads for anticancer drug development in the future.

scholarly journals The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

2019 ◽  
Vol 9 (13) ◽  
pp. 2767 ◽  
Author(s):  
Arina A. Chepanova ◽  
Evgenii S. Mozhaitsev ◽  
Aldar A. Munkuev ◽  
Evgeniy V. Suslov ◽  
Dina V. Korchagina ◽  
...  
Keyword(s):  
Cytotoxic Effect ◽  
Binding Mode ◽  
Catalytic Site ◽  
Clinical Use ◽  
Adenocarcinoma Cell Line ◽  
Repair Enzyme ◽  
Topoisomerase 1 ◽  
Lung Adenocarcinoma Cell Line ◽  
Ic50 Value ◽  
Ic50 Values

Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 M. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 M concentration, displaying strong synergism. This effect was only seen for 46a (IC50—3.3 M) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

Long-term efficacy of a new medical device containing Fernblock® and DNA repair enzyme complex in the treatment and prevention of cancerization field in patients with actinic keratosis.

2019 ◽  
Vol 2 (02) ◽  
pp. 80-89
Author(s):  
Blanca De Unamuno Bustos ◽  
Natalia Chaparr´´o Aguilera ◽  
Inmaculada Azorín García ◽  
Anaid Calle Andrino ◽  
Margarita Llavador Ros ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Medical Device ◽  
Actinic Keratosis ◽  
Statistical Significance ◽  
Dna Lesions ◽  
Enzyme Complex ◽  
Repair Enzyme ◽  
P53 Expression ◽  
Cancerization Field

Actinic keratosis (AKs) are part of the cancerization field, a region adjacent to AKs containing subclinical and histologically abnormal epidermal tissue due to Ultraviolet (UV)-induced DNA damage. The photoproducts as consequence of DNA damage induced by UV are mainly cyclobutane pyrimidine dimers (CPDs). Fernblock® demonstrated in previous studies significant reduction of the number of CPDs induced by UV radiation. Photolyases are a specific group of enzymes that remove the major UV-induced DNA lesions by a mechanism called photo-reactivation. A monocentric, prospective, controlled, and double blind interventional study was performed to evaluate the effect of a new medical device (NMD) containing a DNA-repair enzyme complex (photolyases, endonucleases and glycosilases), a combination of UV-filters, and Fernblock® in the treatment of the cancerization field in 30 AK patients after photodynamic therapy. Patients were randomized into two groups: patients receiving a standard sunscreen (SS) andpatients receiving the NMD. Clinical, dermoscopic, reflectance confocal microscopy (RCM) and histological evaluations were performed. An increase of AKs was noted in all groups after three months of PDT without significant differences between them (p=0.476). A significant increase in the number of AKs was observed in SS group after six (p=0.026) and twelve months of PDT (p=0.038); however, this increase did not reach statistical significance in the NMD group. Regarding RCM evaluation, honeycomb pattern assessment after twelve months of PDT showed significant differences in the extension and grade of the atypia in the NMD group compared to SS group (p=0.030 and p=0.026, respectively). Concerning histopathological evaluation, keratinocyte atypia grade improved from baseline to six months after PDT in all the groups, with no statistically significant differences between the groups. Twelve months after PDT, p53 expression was significantly lower in the NMD group compared to SS group (p=0.028). The product was well-tolerated, with no serious adverse events reported. Our results provide evidence of the utility of this NMD in the improvement of the cancerization field and in the prevention of the development of new AKs.  

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

The Development of Tyrosyl-DNA Phosphodyesterase 1 (TDP1) Inhibitors Based on the Amines Combining Aromatic/Heteroaromatic and Monoterpenoid Moieties

2019 ◽  
Vol 16 (5) ◽  
pp. 597-605 ◽  
Author(s):  
Evgenii Mozhaitsev ◽  
Evgenii Suslov ◽  
Yuliya Demidova ◽  
Dina Korchagina ◽  
Konstantin Volcho ◽  
...  
Keyword(s):  
Dna Repair ◽  
Tumor Cell ◽  
13C Nmr ◽  
Inhibitory Activity ◽  
Secondary Amines ◽  
Repair Enzyme ◽  
1H And 13C Nmr ◽  
Chemical Structures ◽  
Natural Substances ◽  
Micromolar Range

Background: Inhibition of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), may increase the efficacy of cancer drugs that cause damage to tumor cell DNA. Among the known TDP1 inhibitors, there are compounds containing moieties of natural substances, e.g., monoterpenoids. In this work, we synthesized several compounds containing aromatic/ heteroaromatic amines and monoterpenoid groups and assessed their TDP1 inhibition potential. Methods: Structures of all the synthesized compounds were confirmed by 1H and 13C NMR as well as HRMS. The TDP1 inhibitory activity of the amines was determined by real-time fluorescence oligonucleotide biosensor. Results: The synthesized secondary amines had TDP1 inhibitory activity IC50 in the range of 0.79-9.2 µM. The highest activity was found for (–)-myrtenal derivatives containing p-bromoaniline or m-(trifluoromethyl)aniline residue. Conclusion: We synthesized 22 secondary amines; of these, 17 amines are novel chemical structures. Many of the amines inhibit TDP1 activity in the low micromolar range. Therefore, these compounds are promising for further study of their antiproliferative activity in conjunction with DNA damaging drugs.

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