pyrrolopyrimidine and Neoplasms

Pyrrolopyrimidine derivatives represent a class of biologically active heterocyclic compounds which can serve as promising scaffolds that display remarkable biological activities, such as anti-inflammatory, antimicrobial, antiviral and anticancer. In the last few years, several pyrrolopyrimidine derivatives have been approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Due to their inimitable antioxidant and anti-tumor properties, researchers were inspired to develop novel derivatives for the treatment of different types of cancer. The present review summarizes recent literature up to 2017 on the most recent development in the medicinal chemistry of pyrrolopyrimidine derivatives and their potential as anticancer therapeutics, especially compounds acting as kinase inhibitors.

Topics: Antineoplastic Agents; Drug Design; Humans; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Structure-Activity Relationship

The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure-activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of

Topics: Biomarkers; Cell Nucleolus; Cell Nucleus; Humans; Neoplasms; Pyrimidines; Pyrroles

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3-d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Human Umbilical Vein Endothelial Cells; Humans; Models, Molecular; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Urea; Vascular Endothelial Growth Factor Receptor-2

Epidermal growth factor receptor (EGFR) protein tyrosine kinases are over expressed in several human cancers and considered as a promising target for developing novel anticancer drugs. In this study, the ligand-based pharmacophore mapping and atom-based 3D-QSAR approach was carried out on a series of 40 novel pyrrolo[3, 2-d]pyrimidine derivatives acting as EGFR inhibitors. The best pharmacophore hypothesis AAADRR.295 was selected and an atom-based 3D-QSAR model was generated by applying partial least-squares algorithm. The developed model was validated and used as a 3D query in sequential virtual screening study to filter five chemical databases. The obtained compounds were further filtered according to Lipinski rule of five and fitness score. Subsequently, a multistep molecular docking study was employed on the retrieved hits and finally, 12 compounds were prioritized as potential leads against EGFR, which exhibited high docking scores, correlated binding mode to experimentally proven compounds and constructive drug-like properties. The results of this study provide detailed structural insights and emphasize the important binding features of these compounds, which may assists in the design and development of novel EGFR inhibitors.

Topics: Antineoplastic Agents; Binding Sites; ErbB Receptors; Humans; Molecular Docking Simulation; Neoplasms; Protein Binding; Pyrimidines; Pyrroles; Quantitative Structure-Activity Relationship; User-Computer Interface

A series of 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines have been synthesised, characterised and tested for their in vitro EGFR (ErbB1) tyrosine kinase inhibitory activity. The compounds were prepared from ethyl cyanoacetate and α-bromoacetophenones via the 2-amino-3-ethoxycarbonyl-5-aryl-pyrroles and 4-chloro-6-arylpyrrolopyrimidines. Aromatic substitution with benzylic amines was performed by conventional thermal substitution, and palladium catalysed coupling. The two methods resulted in similar yields, but the palladium coupling had the benefit of lower chemical consumption and reduced reaction times. Eight of the new compounds had IC(50) values in the range of 2.8-9.0 nM. Four of these have a fluorine atom positioned at sites otherwise potentially susceptible to oxidative metabolism. Structural variation of the 6-aryl group indicated that the inhibitory action was only moderately sensitive to modifications in this fragment. However, the potency depended strongly on the structure of the aromatic part of the 4-amino group, and any aromatic substitution except fluorine reduced the in vitro activity. The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Three fluorinated derivatives had a pronounced effect in inhibiting EGFR internalization.

Topics: Antineoplastic Agents; ErbB Receptors; HeLa Cells; Humans; Models, Molecular; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Structure-Activity Relationship