scholarly journals Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1078
Author(s):  
Ning Wang ◽  
Diana Brickute ◽  
Marta Braga ◽  
Chris Barnes ◽  
Haonan Lu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Cathepsin L ◽  
Cancer Therapeutics ◽  
Choline Kinase ◽  
Biological Profile ◽  
Structure Activity ◽  
Promising Target ◽  
Derivatives Of ◽  
Specific Membrane

Choline kinase alpha (CHKA) is a promising target for the development of cancer therapeutics. We have previously reported ICL-CCIC-0019, a potent CHKA inhibitor with high cellular activity but with some unfavorable pharmacological properties. In this work, we present an active analogue of ICL-CCIC-0019 bearing a piperazine handle (CK146) to facilitate further structural elaboration of the pharmacophore and thus improve the biological profile. Two different strategies were evaluated in this study: (1) a prodrug approach whereby selective CHKA inhibition could be achieved through modulating the activity of CK146, via the incorporation of an ε-(Ac) Lys motif, cleavable by elevated levels of histone deacetylase (HDAC) and cathepsin L (CTSL) in tumour cells; (2) a prostate-specific membrane antigen (PSMA) receptor targeted delivery strategy. Prodrug (CK145) and PSMA-targeted (CK147) derivatives were successfully synthesized and evaluated in vitro. While the exploitation of CK146 in those two strategies did not deliver the expected results, important and informative structure-activity relationships were observed and have been reported.

Therapeutic Journey of 5-Pyrazolones as a Versatile Scaffold: A Review

2021 ◽  
Vol 21 ◽  
Author(s):  
Ravinder Sharma ◽  
Pooja A. Chawla ◽  
Viney Chawla ◽  
Rajeev Verma ◽  
Nandita Nawal ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Protease Inhibitor ◽  
Medicinal Chemistry ◽  
Membered Ring ◽  
Present Review ◽  
Biological Profile ◽  
3C Protease ◽  
Structure Activity ◽  
Derivatives Of ◽  
Heterocyclic Moiety

Abstract: A sizeable proportion of currently marketed drugs come from heterocycles. The heterocyclic moiety 5-pyrazolone is well known five membered ring containing nitrogen. Derivatives of this wonder nucleus have exhibited activities as diverse as antimicrobial, anti-inflammatory, analgesic, antidepressant, anticonvulsant, antidiabetic, antihyperlipidemic, antiviral, antitubercular, antioxidant, anticancer and antiviral including action against severe acute respiratory syndrome (SARS) or 3C protease inhibitor. A number of drugs based on this motif have already made it to the market. Standard texts and literature on medicinal chemistry cite different approaches for the synthesis of 5-pyrazolones. The present review provides an insight view to 5-pyrazolone synthesis, their biological profile and structure activity relationship studies.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Synthesis, Antitumor Activity, and Docking Analysis of New Pyrido[3’,2’:4,5]furo(thieno)[3,2-d]pyrimidin-8-amines

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3952 ◽  
Author(s):  
Sirakanyan ◽  
Spinelli ◽  
Geronikaki ◽  
Hakobyan ◽  
Sahakyan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Heterocyclic Compounds ◽  
Phosphorus Oxychloride ◽  
Docking Analysis ◽  
Structure Activity ◽  
Biological Tests ◽  
Amino Derivatives ◽  
Chloro Derivatives ◽  
Derivatives Of

Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3’,2’:4,5](furo)thieno[3,2-d]pyrimidines as well as of two new heterocyclic systems: furo[2–e]imidazo[1,2-c]pyrimidine and furo[2,3-e]pyrimido[1,2-c]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3’,2’:4,5]thieno(furo)[3,2-d]pyrimidines with various amines, the relevant pyrido[3’,2’:4,5]thieno(furo)[3,2-d]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2-c]pyrimidine and pyrimido[1,2-c]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure–activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds.

scholarly journals From in vitro to in cellulo: structure–activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa

2014 ◽  
Vol 12 (32) ◽  
pp. 6094-6104 ◽  
Author(s):  
Michael P. Storz ◽  
Giuseppe Allegretta ◽  
Benjamin Kirsch ◽  
Martin Empting ◽  
Rolf W. Hartmann
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Relationship Of ◽  
Derivatives Of

More than 60 derivatives of (2-nitrophenyl)methanol were synthesized and evaluated regarding their potency to inhibit PqsD. In vitro and in cellulo structure–activity relationships were derived.

HuR as Therapeutic Target in Cancer: What the Future Holds

2021 ◽  
Vol 28 ◽  
Author(s):  
Dimitrios Goutas ◽  
Alexandros Pergaris ◽  
Constantinos Giaginis ◽  
Stamatios Theocharis
Keyword(s):  
Therapeutic Target ◽  
Rna Binding ◽  
Cancer Therapeutics ◽  
Scientific Data ◽  
Promising Target ◽  
Pubmed Database ◽  
Increased Risk ◽  
Major Player

: ELAV-like protein 1, or HuR (human antigen R), is an RNA-binding protein encoded by the ELAVL1 gene in humans. One of its best functions is to stabilize mRNAs in order to regulate gene expression. HuR protein overexpression has undoubtedly been linked to an increased risk of tumor growth, progression, and metastasis, rendering it a potential therapeutic target candidate in cancer. Novel agents interfering with HuR expression have been tested, both in vitro and in vivo, with promising results. The aim of this paper is to review the existing literature regarding the potential agents that could actively act on and inhibit HuR expression. HuR molecule controls the expression of various proto-oncogenes, cytokines and growth factors, representing a major player in tumor progression, invasion, and metastasis and constituting an emerging target for cancer therapy. PubMed database was thoroughly searched, and all published articles providing scientific data on molecules that can exhibit antitumorigenic effects via HuR inhibition were included. According to these data, HuR inhibition should be a promising target in cancer therapeutics.

Synthesis, in Vitro Anti-Human Immunodeficiency Virus Structure—Activity Relationships and Biological Stability of 5′-O-Myristoyl Analogue Derivatives of 3′-Azido-2′,3′-Dideoxythymidine (AZT) as Potential Prodrugs

1998 ◽  
Vol 9 (4) ◽  
pp. 28-40 ◽  
Author(s):  
K Parang ◽  
LI Wiebe ◽  
EE Knaus
Keyword(s):  
Human Immunodeficiency Virus ◽  
Brain Homogenate ◽  
Rat Plasma ◽  
Log P ◽  
Porcine Liver ◽  
Liver Esterase ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Derivatives Of

5′- O-Myristoyl analogue derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure–activity paradigms were developed. 3′-Azido-2′,3′-dideoxy-5′- O-(4-oxate-tradecanoyl)thymidine (EC50=1.4 nM) and 3′-azido-2′,3′-deoxy-5′- O-(12-bromododecanoyl)thymidine (EC50=3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50=10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P=4.5–8.1 range) than the parent compound AZT (log P=0.06), and a linear correlation between their log P and HPLC log retention timeswas observed. The ester cleavage half-lives ( t1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the α-substituent (H, Br, F), of the 5′- O-myristoyl analogue moiety. 3′-Azido-2′,3′-dideoxy-5′- O-(11-(4-iodophenoxy) undecanoyl)-thymidine exhibited t1/2 values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.

An update on chemical classes targeting ERK1/2 for the management of cancer

2020 ◽  
Author(s):  
Shelly Pathania ◽  
Ravindra K Rawal
Keyword(s):  
Cancer Research ◽  
Acquired Resistance ◽  
Chemotherapeutic Agents ◽  
Anticancer Effect ◽  
Structure Activity ◽  
Promising Target ◽  
Multiple Signaling ◽  
Resistance To Chemotherapy

Cancer, still in the limelight due to its dreadful nature, shows overexpression of multiple signaling macromolecules leading to failure of many chemotherapeutic agents and acquired resistance to chemotherapy. These factors highlight the significance of shifting toward targeted therapy in cancer research. Recently, ERKs (ERK1 and 2) have been established as a promising target for the management of various types of solid tumors, due to their aberrant involvement in cell growth and progression. Several ERKs inhibitors have reached clinical trials for the management of cancer and their derivatives are being continuously reported with noteworthy anticancer effect. This review highlights the recent reports on various chemical classes involved in the development of ERKs inhibitors along with their in vitro and  in vivo activity and structure–activity relationship profile.

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