Introduction: Sulfonamide compounds are significant class of synthetic bacteriostatic antibiotics still which used today for the therapy of bacterial infections and those caused by other microorgan...

Sulfonamide inhibitors: a patent review 2013-present

Tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are eukaryotic enzymes that clean-up after aberrant topoisomerase activity. While TDP1 hydrolyzes phosphotyrosyl peptides emanating from trapped topoisomerase I (Top I) from the 3' DNA ends, topoisomerase 2 (Top II)-induced 5'-phosphotyrosyl residues are processed by TDP2. Even though the canonical functions of TDP1 and TDP2 are complementary, they exhibit little structural or sequence similarity. Homozygous mutations in genes encoding these enzymes lead to the development of severe neurodegenerative conditions due to the accumulation of transcription-dependent topoisomerase cleavage complexes underscoring the biological significance of these enzymes in the repair of topoisomerase-DNA lesions in the nervous system. TDP1 can promiscuously process several blocked 3' ends generated by DNA damaging agents and nucleoside analogs in addition to hydrolyzing 3'-phosphotyrosyl residues. In addition, deficiency of these enzymes causes hypersensitivity to anti-tumor topoisomerase poisons. Thus, TDP1 and TDP2 are promising therapeutic targets and their inhibitors are expected to significantly synergize the effects of current anti-tumor therapies including topoisomerase poisons and other DNA damaging agents. This review covers the structural aspects, biology and regulation of these enzymes, along with ongoing developments in the process of discovering safe and effective TDP inhibitors.

Tyrosyl-DNA phosphodiesterases: rescuing the genome from the risks of relaxation.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top1) cleavage complexes and other 3′-end DNA lesions. TDP1 is a perspective target for anticancer therapy based on Top1-poison-mediated DNA damage. Several novel usnic acid derivatives with an enamine moiety have been synthesized and tested as inhibitors of TDP1. The enamines of usnic acid showed IC50 values in the range of 0.16 to 2.0 μM. These compounds revealed moderate cytotoxicity against human tumor MCF-7 cells. These new compounds enhanced the cytotoxicity of the established Top1 poison camptothecin by an order of magnitude.

Tyrosyl-DNA Phosphodiesterase 1 Inhibitors: Usnic Acid Enamines Enhance the Cytotoxic Effect of Camptothecin

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential ☆

Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety.

Large-scale mining operations over 90 years at the Khibiny apatite-nepheline deposits that are characterized with the conspicuous gravity-tectonic type of the stress-strain state have transformed the initial stress field of the rock massif, which has led to the recurrent occurrence of rockbursts. This problem retains its relevance due to constant increasing intensity of mining operations at the apatite mines during the last two decades and complicated mining, geological and geomechanical conditions. Accordingly, the dynamic rock pressure is increasing. We have retrospectively analyzed data on the manifestations of geodynamic events in the Khibiny rockburst-hazardous deposits and determined a set of factors that influence the changes in seismic behavior and localization of hazardous zones in complicated mining and engineering systems. We have systematized the data of long-term observations on dynamic rock pressure manifestations at the Khibiny apatite mines, taking into account the seismicity parameters, the scale of mine damage, the mining-induced stress fields, and geological and geomechanical features of the rock massif at specific time points. A structural scheme has been developed and ranking of factors has been carried out, considering the time of impact on the rock massif.

Svetlana Zhukova

Papers

Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety.

Factors of seismic behavior change and localization of hazardous zones under a large-scale mining-induced impact

Seismic behavior of rock mass in mining rockburst-hazardous deposits in the Khibiny Massif