Number Of Lead Compounds Research Articles

(Invited, Digital Presentation) Molecular Nanocarbon Synthesis and Beyond

Our goal is the creation of super molecules, innovative functional molecules with significant properties and/or beautiful molecules. To this end, we have focused on catalyst-enabling synthetic chemistry with broad directions, including applications in molecular nanocarbons, pharmaceuticals, and plant/animal chemical biology, and the development of rapid molecule-assembly methods using unique catalysts. In particular, we have pioneered molecular nanocarbon science by the bottom-up synthesis of structurally uniform nanocarbons of fundamental and practical importance. Representative achievements include: (1) the development of single-step aromatic π-extension (APEX) methods for the rapid and programmable synthesis of nanocarbon molecules (Science 2018, Nature Commun. 2015, Nature Chem. 2015, Nature Commun. 2021); (2) the synthesis of carbon nanorings, nanobelts and pure nanotubes (ACIE 2009, Science 2017, Nature Chem. 2013, Nature Commun. 2018, Nature Commun. 2019, Nature Chem. 2021); and (3) the synthesis of topologically unique nanocarbons such as warped nanographenes, carbon nanocages, all-benzene catenanes, and trefoil knots (Science 2019, Nature Chem. 2013, Nature Catal. 2020). In this talk, most recent beautiful molecular nanocarbons will be presented. We will also describe about our exciting interdisciplinary research conducted at the Institute of Transformative Bio-Molecules (ITbM) in Nagoya University and Institute of Chemistry in Academia Sinica, Taiwan, where we aim at developing game-changing molecules for nanocarbon-based chemical biology. By using our original rapid molecule-assembling catalysts, a number of lead compounds were rapidly discovered.

Geoinformation modeling of soil pollution processes by lead compounds in highway geosystems

In this paper, we have worked out a method of geoinformation modeling of soil pollution by heavy metals in highway geosystems. Permanent process of contamination and redistribution of pollutants in highway geosystems causes difficulties in determining the degree of soil pollution and the speed of this process. This problem can be solved when using the method of geoinformation modeling of pollution by heavy metals compounds of soil. The method allows you to set the spatial parameters of the contamination field and the speed of the contamination process. The goal of the work is to test the method on the examples of lead compounds in the soils of the mixed forest zone. The methodology uses geoinformation and mathematical models. These models describe the behavior of lead compounds when forming the contamination field. These are models of spatial distribution of heavy metals in the atmospheric air, soil, «soil-plant system». Results: working out the provisions of the methodology took place at the test area. This area has plain fluvio-glacial and fluvial relief, close to the surface of the groundwater, the presence of wetlands, the soils are preferably of light mechanical composition with acid reaction and fulvatic type of humus, that are typical for the mixed forest zone. The modeling process is divided into two stages: 1. determining the amount of lead compounds brought in over a period of time and 2. determination of the number of lead compounds that have been removed from soil or removed from migration flows the same time period. At each stage, models and tools supported obtaining, storing data, analyzing and displaying results of modeling. During the modeling process, we determined the total number of lead compounds coming per unit of time into the geosystem. First of all, we have identified the number of lead compounds entering the atmospheric surface from vehicles as the main source of emissions. We used an atmospheric impurity scattering model and obtained a mapping of the distribution of lead compounds in the near-earth layers of atmospheric air at dangerous wind speeds. In the next step, we determined the amount of lead compounds that reach the soil surface. The constructed surface, reflecting the spatial characteristics and intensities of the primary contamination field, became the basis for modeling the “soil cleaning processes”, following the main migration scenarios: lateral, radial and biogenic migration processes. For next step of modeling, we used a method that calculates soil loss (and, accordingly, lead compounds) from the site due to erosion processes. The number of lead compounds recovered from soils during lateral migration was determined. The results showed that in the test site geosystems, natural factors create conditions for the slow lateral migration. Closed negative landforms were geosystems with the highest probability of accumulation. The next step was to determine the migration intensity of soluble forms of lead in soils during radial migration. We determined that due to the liming, these soils show a "very low" intensity of metal migration and, accordingly, a "low" risk of contamination of plants. Preferably this relates to the accumulation of soluble lead compounds in concentrator plants. In the next step, the amount of lead compounds that were transferred from soil to plants within the farmland was calculated. Scientific novelty: as a result of the step-by-step implementation of the methodology of modeling, a series of digital maps were created and areas with different levels of soil contamination (or self-cleaning) speed were determined. We have identified areas that can be self-cleaning under conditions typical of the mixed forest zone with the existing level of anthropogenic loading. We have identified areas that are potentially dangerous for agricultural production by lead contamination. Practical importance. This method can be applied to any heavy metal and other physical and geographical conditions. It allows to implement modeling in projects of ecological management, to determine the optimum level of anthropogenic load within highway geosystems.

Abstract 513: Investigating stress-response pathways in pancreatic cancer cells using novel PERK inhibitors

Abstract An adaptive stress response mechanism, termed the unfolded protein response (UPR), is highly activated in a variety of tumor types to cope with ER stress and maintain protein homeostasis. PERK (PKR-like endoplasmic reticulum kinase) is one of the key components of the UPR. PERK is a Ser/Thr protein kinase whose active homodimer phosphorylates and inactivates eukaryotic initiation factor 2α (eIF2α), thereby inhibiting protein translation globally and reducing the load of newly synthesized proteins entering the ER. Previous studies demonstrated that cells with a compromised PERK signaling pathway are sensitive to hypoxic stress in vitro and form tumors that grow more slowly in vivo. Thus, selective inhibitors of PERK activity may be useful therapeutic candidates for the treatment of cancer. Using an HTS approach a number of lead compounds were identified with demonstrated ability to inhibit PERK kinase activity in vitro. The potent PERK inhibitors were further tested in pancreatic cancer cells to evaluate the modulation of the PERK-eIF2α-ATF4-CHOP signaling pathway. The effect of PERK inhibitors on cell viability was determined by an MTS assay. PERK inhibitors had dose-dependent effects on suppression of pancreatic cancer cell proliferation. Inhibitor-mediated PERK inhibition is associated with the down-regulation of PERK signaling and with the suppression of pancreatic cancer cell proliferation, suggesting their potential anticancer activities. Here we present new findings implicating additional inputs into this stress response. Citation Format: Jihyun Park, Qiantao Wang, Tamer S. Kaoud, Clint D. J Tavares, Ramakrishna Edupuganti, Pengyu Ren, Kevin N. Dalby. Investigating stress-response pathways in pancreatic cancer cells using novel PERK inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 513. doi:10.1158/1538-7445.AM2014-513

Development of dual inhibitors targeting DprE1 and AHAS for treatment of Mycobacterium tuberculosis infection

Background The emerging multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (MTB) infection is increasing with greater complexity, estimated 220000-400000 tuberculosis cases emerged in 2011 globally. A number of lead compounds have been developed for treatment of MDR and XDR TB, but no new chemical entity has emerged for clinical use. Recently DprE1 and AHAS have been identified as promising drug targets.

Abstract 4542: Towards the identification of PKR-like endoplasmic reticulum kinase (PERK) inhibitors.

Abstract During tumorgenesis cancer cells must tolerate cellular stresses such as DNA damage, hypoxia, and oxidative stress. In order to adapt to and overcome such stresses, tumor cells remodel transcriptional and translational programs by activating pro-survival signaling pathways. PERK (PKR-like endoplasmic reticulum kinase) is one of the key components of the unfolded protein response (UPR). Many studies report that the UPR is activated in a variety of tumor types. Previous studies demonstrated that cells with a compromised PERK-eIF2α-ATF4 signaling pathway are sensitive to hypoxic stress in vitro and form tumors that grow more slowly in vivo. Together, these data suggest a substantial role for PERK and the UPR in tumor cell survival and adaptation to stress. Thus, selective inhibitors of PERK activity may be useful therapeutic candidates for the treatment of cancer. Using a high-throughput screening (HTS) approach a number of lead compounds were identified with demonstrated ability to inhibit PERK kinase autophosphorylation and activity in cells. Using a publically available structure of Apo PERK a PERK-ATP complex structure was generated by means of molecular dynamics (MD) simulation. Evidence is presented to support the notion that the simulation-generated structure represents a useful model for computer-aided lead optimization. Citation Format: Jihyun Park, Qiantao Wang, Pengyu Ren, Kevin N. Dalby. Towards the identification of PKR-like endoplasmic reticulum kinase (PERK) inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4542. doi:10.1158/1538-7445.AM2013-4542

Chemotherapy against human African trypanosomiasis: Is there a road to success?

For over fifty years, human African trypanosomiasis (HAT, sleeping sickness) has been treated with suramin, pentamidine and the very toxic organo-arsenical melarsoprol that was the only drug available for effective treatment of the second stage of the disease. Recently there have been significant efforts using molecular and biochemical approaches to drug design, including high-throughput screening, but the number of lead compounds with promising activity against T. brucei spp. and an acceptable toxicity index has remained astonishingly small. Clinical research continues to be difficult due to the economic constraints and the complexity of trials on a low prevalence disease in remote and impoverished African regions. Despite those limitations the situation for the patients is improving thanks to the combination of a number of critical factors. By the late 1990s the disease had reached epidemic levels that triggered political support. WHO would sign a donation agreement with the manufacturers for all drugs to treat HAT. A result of this agreement was that eflornithine which is much safer than melarsoprol became available and widely used by non-governmental organizations. The Impamel I and II programmes demonstrated that against all odds the conduct of clinical trials on HAT was feasible. This allowed the initiation of trials on combination therapies which eventually resulted in the nifurtimox-eflornithine combination treatment (NECT). This combination is currently being introduced as first line treatment, and there is even the prospect of having a new compound, fexinidazole, in the development pipeline. This review summarizes the key information about the existing drugs and gives a comprehensive summary about the recent and currently ongoing efforts towards new drugs.

Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of respiratory disease

Asthma and chronic obstructive pulmonary disease (COPD) are two of the most common chronic diseases worldwide, yet the classes of drug licensed to treat these conditions have not changed appreciably over the last 20 years. Inhaled bronchodilators and glucocorticosteroids (often in combination) form the mainstay of therapy for respiratory diseases, but many patients (including the elderly and children) can have problems using inhaler devices and there is a clear preference for oral therapy. The prevalence of these respiratory diseases is on the increase worldwide and continues to represent an area of medicine with unmet medical needs, particularly in the treatment of COPD. Despite this increase, very few new classes of drugs have been introduced into clinical practice. Phosphodiesterase-4 inhibitors are a novel class of drugs in development for the treatment of respiratory diseases and there are a number of lead compounds in late clinical development. This review focuses on one of the most promising drugs in development, roflumilast, which has undergone extensive clinical evaluation.