Leukotriene and prostaglandin pathways are controlled by the enzymes, LOX and COX/mPGES1 respectively and are responsible for inflammatory responses.

Mukesh Doble

Department Of Biotechnology

Shweta K. Sinha

Meera Ramanan

Puratchikody A

Gayathri Ramamoorthy

Umamaheswari E

Irfan N

Sinha S

Manju S L

Ramanan M

Ramamoorthy G

3 [4 (BENZYLOXY) 3,5 DIIODOPHENYL] 2 METHANESULFONAMIDO PROPANOIC ACID

3 {3 CHLORO 4 [(PYRIMIDIN 4 YL)METHOXY]PHENYL} 2 METHANE SULFONAMIDOPROPANOIC ACID

3 {3,5 DIIODO 4 [(1 H 1,2,3 TRIAZOL 5 YL)METHOXY]PHENYL} 2 METHANE SULFONAMIDOPROPANOIC ACID

3 {3,5 DIIODO 4 [(1,2 OXAZOL 3 YL)METHOXY]PHENYL} 2 METHANE SULFONAMIDOPROPANOIC ACID

3 {3,5 DIIODO 4 [(PYRIDIN 4 YL)METHOXY]PHENYL} 2 METHANE SULFONAMIDOPROPANOIC ACID

3 {3,5 DIIODO 4 [(PYRIMIDIN 4 YL)METHOXY]PHENYL} 2 METHANE SUFLONAMIDOPROPANOIC ACID

antineoplastic agent

ARACHIDONATE 5 LIPOXYGENASE

Ascorbic acid

BETA ACTIN

Chlorine

Cisplatin

CYCLOOXYGENASE 1

CYCLOOXYGENASE 2 INHIBITOR

enzyme inhibitor

Lanthanum

Lead

LEUKOTRIENE

LICOFELONE

messenger RNA

PROSTAGLANDIN

PROSTAGLANDIN E SYNTHASE 1

PROSTAGLANDIN E2

TYROSINE DERIVATIVE

unclassified drug

antineoplastic activity

antioxidant activity

article

controlled study

drug synthesis

enzyme activity

Enzyme inhibition

G2 phase cell cycle checkpoint

HeLa cell line

Human

human cell

in vitro study

MALIGNANT NEOPLASM

MRNA EXPRESSION LEVEL

oxidation reduction reaction

priority journal

S PHASE CELL CYCLE CHECKPOINT

IIT Madras is a public technical and research university located in Chennai, Tamil Nadu. Founded in 1959, it is recognised as an Institute of National Importance.

IIT Madras has been ranked as the top engineering institute in India for four years in a row by the National Institutional Ranking Framework of the MHRD

It currently offers undergraduate, postgraduate and research degrees across 16 disciplines in Engineering, Sciences, Humanities and Management. About 596 faculty belonging to science and engineering departments and centres of the Institute are engaged in teaching, research and industrial consultancy.

IIT Madras

New Journal of Chemistry

The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades. © 2019

Bioorganic and Medicinal Chemistry

5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach

Prostaglandins serve as the connecting link between inflammation and cancer. mPGES1, the downstream enzyme in the prostaglandin pathway is considered a better target than COX-2 against the progression of cancer due to the cardiovascular and other complications associated with the inhibition of the latter. Despite the discovery of several compounds that inhibit mPGES1 none could enter the market as drugs because of the problems concerning specificity and unacceptable pharmacokinetic properties. Expression of mPGES1 is inducible in conditions of inflammation and hypoxia and its expression is regulated by a number of transcriptional factors. Targeting these transcription factors could be an alternative approach in the drug discovery process. In this review, the characteristics of the transcription factors, their ability to bind to the promoter of mPGES1 gene and the inhibitors against them have been discussed. The Structure Activity Relationship of the reported inhibitors is highlighted. Finally, practical challenges to further the drug development and future research directions are discussed. These novel compounds that are inhibitors of the major transcription factors are promising candidates for further development as inhibitors of mPGES1. © 2017 Bentham Science Publishers.

Current Drug Targets

Transcriptional regulation of mPGES1 in cancer: An alternative approach to drug discovery?

The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE2in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE2is known to participate in cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX enzyme in vitro and PGE2production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC50of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE2production respectively. Another compound 7f, exhibits an IC50of 12.4 ± 0.14 μM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol (7c) exhibits IC50of 15.8 ± 0.03 μM against PGE2production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC50of 6.0 μM for mPGES1 &amp; 0.2 μM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as cancer. © 2016 Elsevier Masson SAS

European Journal of Medicinal Chemistry

Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins

Both the insoluble and soluble fibres have health benefits and could be used as food additive and in pharmaceutical and other industries. In the current study, the role of soluble dietary fibre fractions of marine red algae, Kappaphycus alvarezii (κ-carrageenan) against human colon cancer cells, was investigated. It comprises of D-galactose and 3,6-anhydro-D-galactose, linearly linked by α(1→3) and β(1→4) glycosidic linkages. Exposure of human colon cancer cells, HCT116, to the sulphated fractions (F1 and F2) resulted in apoptotic cell death, nuclear fragmentation, apoptosome formation, upregulation of the mRNA expression levels of Bcl-2, Bcl-xL and caspase3 and the downregulation of XIAP and PARP-1. The treatment also enhanced the intracellular mitochondrial ROS levels in HCT-116 but not in HEK293 and L6. The apoptosis in HCT116 is possibly induced through the ROS-mediated mitochondrial pathway combined with downregulation of XIAP and upregulation of caspase3. The former induces DNA damage leading to G1 cell cycle arrest and apoptosis. Low cytotoxicity and anticarcinogenic effects of the soluble dietary fibre fractions from K. alvarezii on HCT116 suggests an alternative approach to metastatic human colon cancer therapy and highlights the importance of marine dietary fibre as a food supplement. © 2015 Elsevier Ltd.

Journal of Functional Foods

κ-Carrageenan from marine red algae, Kappaphycus alvarezii - A functional food to prevent colon carcinogenesis

Synthesis, antioxidant activity, and quantitative structure-activity relationship (QSAR) of 25 of chalcone derivatives is reported here. They were synthesized by Claisen-Schmidt reaction and were characterized by FTIR, NMR, and mass spectroscopy. Antioxidant activity is evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide scavenging, reducing power, and DPPH radical-scavenging assays. Generally, compounds with -SCH3 and -OCH3 in the para position of the A-ring and -OH in the B-ring were more active than others. In few cases some of the compounds were more active than ascorbic acid or butylated hydroxytoluene. QSAR was developed correlating the antioxidant activity with the structural features of the compounds and the predictive capability of the models was estimated using internal and external validation methods. All the predictions were within the 99% confidence level. Spatial, structural, and lipophilic properties of the compounds determine their antioxidant properties. © 2011 Springer Science+Business Media, LLC.

Medicinal Chemistry Research

Synthesis, antioxidant evaluation, and quantitative structure-activity relationship studies of chalcones

Frontiers in Cell and Developmental Biology

Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer

A novel class of tyrosine derivatives as dual 5-LOX and COX-2/mPGES1 inhibitors with PGE 2 mediated anticancer properties

Journal	Data powered by TypesetNew Journal of Chemistry
Publisher	Data powered by TypesetRoyal Society of Chemistry
ISSN	11440546
Open Access	No