The Role of Free Radicals in the Aging Brain and Parkinson’s Disease: Convergence and Parallelism

Kumar, Hemant,Lim, Hyung-Woo,More, Sandeep Vasant,Kim, Byung-Wook,Koppula, Sushruta,Kim, In Su,Choi, Dong-Kug Molecular Diversity Preservation International (MD 2012 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.13 No.8

<P>Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5–10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD.</P>

1-Benzyl indazole derivative-based 18F-labeled PET radiotracer: Radiosynthesis and cell uptake study in cancer cells

MORE KUNAL NANDKUMAR,장동조,Jun-Young Lee,Jeong-Hoon Park 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1

Hypoxia-inducible factor-1 (HIF-1α) is a transcription factor activated in response to low oxygen level, and ishighly expressed in many solid tumors. Moreover, HIF-1α is a representative biomarker of hypoxia and alsohelps to maintain cell homeostasis under hypoxic condition. Most solid tumors show hypoxia, which inducespoor prognosis and resistance to conventional cancer therapies. Thus, early diagnosis of hypoxia with positronemission tomography (PET) radiotracer would be highly beneficial for management of malignant solid tumorswith effective cancer therapy. YC-1 is a most promising candidate among several HIF-1α inhibitors. As an effortto develop a hypoxia imaging tool as a PET radiotracer, we designed and synthesized [18F]DFYC based onpotent derivative of YC-1 and performed preliminary in vitro cell uptake study. [18F]DFYC showed a significantaccumulation in SKBR-3 cells among other cancer cells, proving as a good lead to develop a hypoxic solidtumor such as breast cancer.

1-Benzyl indazole derivative-based ¹⁸F-labeled PET radiotracer: Radiosynthesis and cell uptake study in cancer cells

More, Kunal N.,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo Korean Society of Radiopharmaceuticals and Molecul 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1

Hypoxia-inducible factor-1 ($HIF-1{\alpha}$) is a transcription factor activated in response to low oxygen level, and is highly expressed in many solid tumors. Moreover, $HIF-1{\alpha}$ is a representative biomarker of hypoxia and also helps to maintain cell homeostasis under hypoxic condition. Most solid tumors show hypoxia, which induces poor prognosis and resistance to conventional cancer therapies. Thus, early diagnosis of hypoxia with positron emission tomography (PET) radiotracer would be highly beneficial for management of malignant solid tumors with effective cancer therapy. YC-1 is a most promising candidate among several $HIF-1{\alpha}$ inhibitors. As an effort to develop a hypoxia imaging tool as a PET radiotracer, we designed and synthesized [$^{18}F$]DFYC based on potent derivative of YC-1 and performed preliminary in vitro cell uptake study. [$^{18}F$]DFYC showed a significant accumulation in SKBR-3 cells among other cancer cells, proving as a good lead to develop a hypoxic solid tumor such as breast cancer.

Characteristics of new bioreductive fluorescent probes based on the xanthene fluorophore: Detection of nitroreductase and imaging of hypoxic cells

More, Kunal N.,Lim, Tae-Hwan,Kim, So-Young,Kang, Julie,Inn, Kyung-Soo,Chang, Dong-Jo Applied Science Publishers 2018 Dyes and pigments Vol.151 No.-

<P><B>Abstract</B></P> <P>Hypoxia is a common feature of many solid tumors and is known to cause the resistance to chemotherapy and radiotherapy. Nitroreductase (NTR), a common biomarker of hypoxia, is an attractive target for the design of therapeutics and imaging agents targeting hypoxia. Under hypoxic condition, nitroreductase can reduce an aromatic nitro group conjugated to a drug or fluorophore to amine, which leads to release a free drug or fluorophore through the subsequent 1,6-rearrangment elimination. This type of 1,6-rearrangement elimination to release a drug or fluorophore has been widely used in the development of activity-based “turn on” fluorescent probes as well as targeted therapeutics such as antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs). In this paper, novel “turn on” NTR-responsive fluorescent probes diversely linked to a 4-nitrobenzyl moiety via ether, carbonate, amine and carbamate linkages have been developed. The effect of variation in linkage on the release of fluorophore has been studied by the analysis of spectroscopic properties, temperature and pH stability, kinetics and concentration-dependency of the probes during NTR reaction. Fluorescent probes with an ether (<B>10</B>) or a carbamate (<B>16</B>) linkage showed biocompatible nature, high sensitivity (working below 1 μM of concentration) and strong fluorescence emission in the presence of NTR whereas they showed very low quantum yields in the absence of NTR. Finally, the probes (<B>10, 16)</B> were successfully applied to <I>in vitro</I> imaging of hypoxic cancer cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> “Turn on” fluorescent probes linked to NTR-sensing moiety via ether, carbonate, amines and carbamate linkages were prepared. </LI> <LI> The Effect of variation in the linkage between fluorophore and NTR-responsive moiety was evaluated by NTR reaction. </LI> <LI> The probes with an ether or carbamate linkage exhibited fast responses to NTR and strong fluorescent images in hypoxic cells. </LI> <LI> This study can be applied to not only activity-based fluorescent probes but also therapeutics to release a drug such as ADCs. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Acetazolamide-based [¹⁸F]-PET tracer: <i>In vivo</i> validation of carbonic anhydrase IX as a sole target for imaging of CA-IX expressing hypoxic solid tumors

More, Kunal N.,Lee, Jun Young,Kim, Dong-Yeon,Cho, Nam-Chul,Pyo, Ayoung,Yun, Misun,Kim, Hyeon Sik,Kim, Hangun,Ko, Kwangseok,Park, Jeong-Hoon,Chang, Dong-Jo Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.5

<P><B>Abstract</B></P> <P>Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [<SUP>18</SUP>F]-PET tracer (<B>1</B>) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 <I>in vivo</I> models other than SKRC-52. [<SUP>18</SUP>F]-acetazolamide (<B>1</B>) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand <I>in vivo</I> behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Fluorimetric Study on the Interaction between Norfloxacin and Proflavine Hemisulphate

More, Vishalkumar R.,Anbhule, Prashant V.,Lee, Sang H.,Patil, Shivajirao R.,Kolekar, Govind B. Springer-Verlag 2011 Journal of fluorescence Vol.21 No.4

Synthesis and Characterization of Potentiostatically Electrodeposited Tungsten Oxide Thin Films for Smart Window Application

More, A. J.,Patil, R. S.,Dalavi, D. S.,Suryawanshi, M. P.,Burungale, V. V.,Kim, J. H.,Patil, P. S. Springer Science + Business Media 2017 Journal of electronic materials Vol.46 No.2

<P>Tungsten oxide (WO3) thin films have been synthesized using electrodeposition in potentiostatic mode and the effect of different deposition potentials on their structural, morphological, optical, and electrochromic (EC) properties investigated. The deposition potential versus saturated calomel electrode (SCE) was varied from -0.35 V to -0.50 V in steps of -0.05 V for 20 min each. The electrodeposited WO3 thin films were characterized using x-ray diffraction analysis, micro-Raman spectroscopy, field-emission scanning electron microscopy, and ultraviolet-visible (UV-Vis) spectrophotometry, revealing amorphous nature with nanograins having average size from 40 nm to 60 nm. The EC performance of the WO3 thin films exhibited response times of 1.35 s for bleaching (t (b)) and 3.1 s for coloration (t (c)) with excellent reversibility of 64.36%. The highest coloration efficiency of the electrodeposited WO3 thin films was found to be 87.95 cm(2)/C. The electrochemical reversibility and stability of the WO3 thin films obtained in this study make them promising for use in smart window applications.</P>

Toxin-Induced Experimental Models of Learning and Memory Impairment

More, Sandeep Vasant,Kumar, Hemant,Cho, Duk-Yeon,Yun, Yo-Sep,Choi, Dong-Kug MDPI 2016 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.17 No.9

<P>Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson’s disease dementia and Alzheimer’s disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.</P>

Atractylenolide-I Protects Human SH-SY5Y Cells from 1-Methyl-4-Phenylpyridinium-Induced Apoptotic Cell Death

More, Sandeep Vasant,Choi, Dong-Kug MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.5

<P>Oxidative stress and apoptosis are the major mechanisms that induce dopaminergic cell death. Our study investigates the protective effects of atractylenolide-I (ATR-I) on 1-methyl-4-phenylpyridinium (MPP<SUP>+</SUP>)-induced cytotoxicity in human dopaminergic SH-SY5Y cells, as well as its underlying mechanism. Our experimental data indicates that ATR-I significantly inhibits the loss of cell viability induced by MPP<SUP>+</SUP> in SH-SY5Y cells. To further unravel the mechanism, we examined the effect of ATR-I on MPP<SUP>+</SUP>-induced apoptotic cell death characterized by an increase in the Bax/Bcl-2 mRNA ratio, the release of cytochrome-c, and the activation of caspase-3 leading to elevated levels of cleaved poly(ADP-ribose) polymerase (PARP) resulting in SH-SY5Y cell death. Our results demonstrated that ATR-I decreases the level of pro-apoptotic proteins induced by MPP<SUP>+</SUP> and also restored Bax/Bcl-2 mRNA levels, which are critical for inducing apoptosis. In addition, ATR-I demonstrated a significant increase in the protein expression of heme-oxygenase in MPP<SUP>+</SUP>-treated SH-SY5Y cells. These results suggest that the pharmacological effect of ATR-I may be, at least in part, caused by the reduction in pro-apoptotic signals and also by induction of anti-oxidant protein.</P>

Synthesis of (3-(2-Aminopyrimidin-4-yl)-4-hydroxyphenyl)phenyl Methanone Analogues as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 Kinase

MORE KUNAL NANDKUMAR,이진호 대한화학회 2017 Bulletin of the Korean Chemical Society Vol.38 No.1

Angiogenesis is critical for tumor growth and mediated mainly by vascular endothelial growth factor (VEGF) signaling. Inhibition of the VEGF signaling pathway has emerged as one of the promising approaches for cancer therapy. VEGF receptor 2 (VEGFR-2) is considered as a major mediator of angiogenic effects of VEGF. We describe herein the discovery of a series of potent VEGFR-2 tyrosine kinase (KDR) inhibitors from a new 2-(2-aminopyrimidin-4-yl)phenol scaffold. The KDR activity was reduced appreciably by a series of compounds with a benzoyl group at position 4 of phenol ring. The structure–activity relationships for a series of (3-(2-aminopyrimidin-4-yl)-4-hydroxyphenyl)phenyl methanones revealed compound 9 (KDR IC50 = 25 nM) as the most potent inhibitor in the series. Compound 22 had a potent cellular activity on VEGF-induced HUVEC cell growth (IC50 < 0.1 μM) with high selectivity over HCT116.