scholarly journals Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5170
Author(s):  
Mrunal Jadhav ◽  
Kaksha Sankhe ◽  
Richie R. Bhandare ◽  
Zehra Edis ◽  
Samir Haj Bloukh ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Kinases ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Antitumor Agents ◽  
Aurora Kinase ◽  
Pyrimidine Ring ◽  
Pyrimidine Derivatives ◽  
Comprehensive Overview

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

Synthesis and anticancer activity of some pyrido[2,3-d]pyrimidine derivatives as apoptosis inducers and cyclin-dependent kinase inhibitors

2019 ◽  
Vol 11 (18) ◽  
pp. 2395-2414 ◽  
Author(s):  
Safinaz E-S Abbas ◽  
Riham F George ◽  
Eman M Samir ◽  
Mostafa MA Aref ◽  
Hatem A Abdel-Aziz
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Cytotoxic Agents ◽  
Cyclin Dependent Kinase ◽  
Apoptosis Induction ◽  
Pyrimidine Derivatives ◽  
Induced Apoptosis ◽  
Emergence Of Resistance ◽  
Mcf 7

Aim: Due to emergence of resistance to available anticancer agents, there is a need to search for new cytotoxic agents. Methods: Pyrido[2,3- d]pyrimidines (4–6) and their tricyclic derivatives (7–13) were prepared and screened for their cytotoxicity against breast MCF-7, prostate PC-3 and lung A-549 cancer cell lines as well as normal fibroblasts WI-38. Results: The most active compounds were 6b, 6e and 8d compared with doxorubicin. Moreover, compounds 6b and 8d induced apoptosis in PC-3 and MCF-7, respectively via activation of CASP3 (in PC-3 only), Bax, p53 and down regulation of Bcl2 in addition to CDK4/6 inhibition. Conclusion: Pyrido[2,3- d]pyrimidine represents an important core for discovery of new potent cytotoxic agents acting on the cell cycle via apoptosis induction through either intrinsic or extrinsic pathways.

scholarly journals Assessment of utilization of anticancer drugs in cancer centre at tertiary care hospitals in Telangana region

2020 ◽  
Vol 11 (2) ◽  
pp. 1562-1570
Author(s):  
Praveen Kumar T ◽  
Nadeem Ahmed ◽  
Sravan Kumar B ◽  
Chinna Eswaraiah M
Keyword(s):  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Tertiary Care ◽  
Cost Effective ◽  
Prescribing Patterns ◽  
Female Patients ◽  
Rational Drug ◽  
Cost Effective Treatment ◽  
Life Threatening

Cancer is a life-threatening disease and is a major economic burden to families in India. Assessment of the utilization of anticancerdrugs promotes rational in using drugs.The main objective of the study was to identify theprevalence of various types of cancers, analyzing the prescribing patterns of anticancer drugs in cancer centers atthe tertiary care government hospital of Telangana. It was aProspective and observational study carried out in hospitals ofTelangana for a period of six months, which includes 300 patients. All the patients with respective to age, sex, diagnosis, and treatment, who were on anticancer prescription and were willing to give consent, were included in the study.Among 300 patients selected in our study, 111 (37 %) were males, and 189 (63 %) were female patients.170 (56.66 %) cancer cases were evident between 71 to 80 years of age. Hypertension is the major comorbidity observed in 68 cancer patients.54 drugs were prescribed for different cancers patients in our study.  The most commonly used class of anticancer agents wastyrosine kinase inhibitors (10drugs), monoclonal antibodies (10 drugs). 33 female patients were suffering from breast cancer, and Lungs cancer was found in 44 patients. Carboplatin was given to 30 (10%) patients, followed by Chlorambucil to 27 patients (9%).Assessment of utilization of Anticancer Drugs promotes education to a physician for rational drug use and can give better health care and also cost-effective treatment.

scholarly journals MN4-based G4-Ligands as Potential Antitumor Agents: A Review

2021 ◽  
Vol 12 (3) ◽  
pp. 3977-3988
Keyword(s):  
Metal Complexes ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Genomic Dna ◽  
Rational Design ◽  
Structural Engineering ◽  
Antitumor Agents ◽  
Medical Field ◽  
G Quadruplex ◽  
Potential Antitumor

Cisplatin-based metal drugs have been widely used clinically as anticancer agents. However, these drugs also harm ordinary tissues because cisplatin kills cancer cells by attacking genomic DNA. Therefore, it has been shown that cisplatin-based metal drugs have some serious side effects that cannot be avoided. In order to replace the target site of genomic DNA, G-quadruplex nucleic acid is considered to be an alternative and attractive target for anticancer agents because G-quadruplex always folds into a parallel topology and is, therefore, more important than DNA. This review discussed the recent advancements in the rational design and the development of metal complexes containing anticancer drugs to interact and stabilize or cleave the G4 structure selectively. Further, we also highlighted the G4-interacting transition metal complexes, interacting modes, and their potentials to serve as anticancer drugs in the medical field. The significance of this survey lies in designing the metallodrugs from the most fundamental characteristic of electronic structural engineering to an increasingly reasonable dimension of bio-science.

Targeting Protein Kinase Inhibitors with Traditional Chinese Medicine

2019 ◽  
Vol 20 (15) ◽  
pp. 1505-1516
Author(s):  
Yangyang Zhang ◽  
Minghua Liu ◽  
Jun Wang ◽  
Jianlin Huang ◽  
Mingyue Guo ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Protein Kinase ◽  
Traditional Chinese Medicine ◽  
Protein Kinases ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Specific Protein ◽  
Protein Kinase Inhibitors ◽  
Bioactive Substances ◽  
Phosphoinositide 3 Kinase

Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.

scholarly journals Diarylureas as Antitumor Agents

2021 ◽  
Vol 11 (1) ◽  
pp. 374
Author(s):  
Alessia Catalano ◽  
Domenico Iacopetta ◽  
Maria Stefania Sinicropi ◽  
Carlo Franchini
Keyword(s):  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Anticancer Agent ◽  
Kinase Inhibitors ◽  
Antitumor Agents ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
The Past ◽  
To Come ◽  
Come Into The Market

The diarylurea is a scaffold of great importance in medicinal chemistry as it is present in numerous heterocyclic compounds with antithrombotic, antimalarial, antibacterial, and anti-inflammatory properties. Some diarylureas, serine-threonine kinase or tyrosine kinase inhibitors, were recently reported in literature. The first to come into the market as an anticancer agent was sorafenib, followed by some others. In this review, we survey progress over the past 10 years in the development of new diarylureas as anticancer agents.

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