Pyrimidine-fused Derivatives: Synthetic Strategies and Medicinal Attributes.

Pyrimidine-fused derivatives traits the inextricable part of DNA and RNA, exhibit indispensable role in numerous biological processes, possessing momentous chemical and biological importance. Pyrimidine-condensed derivatives as the pharmacophore exhibit broad spectrum of biological activities encompassing antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, anticancer and anti-HIV. Several retrosynthetic approaches, are available for the synthesis of pyrimidine-fused analogues which offers enormous scope in the field of medicinal chemistry. Ring fused pyrimidine and their innumerable derivatives continue to hold the attention of chemists since their presence in the biologically active resources have been known to elicit additive effects on the bio-efficacy of the molecules. The present review is a concerted effort to congregate information mainly focusing on the comprehensive categorization of pyrimidine ring based on their fusion with five, six, seven and eight-membered ring(s). Moreover, it also puts forward their systematic nomenclature, synthetic strategies, and bioactivities including SAR studies. This review is being put forwarded with an incentive to provide researchers with a comprehensive and updated literature. In addition, the manuscript also brings to light the various pharmacophore designs based on fusedpyrimidine ring system, delving deeper into synthesis and the subsequent generation of new libraries of pyrimidine-fused derivatives including their biological assessments.

Missing link between microRNA and prostate cancer.

MicroRNAs are the non-coding RNAs which regulate endogenous gene expression in animal and plant cells. Alterations in the level of micro-ribonucleic acids (miRNAs) involving the deletions, overexpression, mutations, epigenetic silencing, or dysregulation of transcription factors that target specific miRNAs may culminate in various diseases including cancer. Recent findings demonstrate the role of miRNAs in prostate cancer. Numerous discoveries of miRNAs have marked the research and development surrounding prostate cancer management, diagnosis, and therapy which has made prediction easy, but the effective treatment strategy remains a mystery. This review seeks to draw a link between miRNA and prostate cancer through an understanding of the numerous signaling pathways that these miRNAs control, which may prove to be helpful in identifying therapeutically interesting molecular targets.

Imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole: Microwave-assisted synthesis and anticancer activity via selective topoisomerase-II-α inhibition.

Microwave-accelerated synthesis and anticancer activity of novel imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole against a panel of seven cancer cell lines are reported for the first time. Compounds ARK-4, 10 and 12 in the series show promising in vitro anti proliferative activity with low micromolar IC50 values against A-459 (lung), Hep-G2 (liver) and H-460 (liver) cancer cell lines. Compounds caused the increase in ROS levels as well as mitochondrial membrane depolarization, which might induce apoptosis. Further, mechanistic interventions on biological and molecular modeling data supported that compounds inhibited topoisomerase-II selectively.

Design, microwave-mediated synthesis and biological evaluation of novel 4-aryl(alkyl)amino-3-nitroquinoline and 2,4-diaryl(dialkyl)amino-3-nitroquinolines as anticancer agents.

Design, microwave-assisted synthesis of novel 4-aryl (alkyl)amino-3-nitroquinoline (1a-1l) and 2,4-diaryl (dialkyl)amino-3-nitroquinolines (2a-2k and 3a) via regioselective and complete nucleophilic substitution of 2,4-dichloro-3-nitroquinoline, respectively in water are presented. The newly synthesized compounds were evaluated for the first time for antiproliferative activity against EGFR overexpressing human lung (A-549 and H-460) and colon (HCT-116-wild type and HCT-116-p53 null) cancer cell lines. Some notions about structure-activity relationships (SAR) are presented. Compounds 2e, 2f, 2j and 3a overall exhibited excellent anticancer activity comparable to erlotinib which was used as a positive control. Molecular modeling studies disclosed the recognition pattern of the compounds and also supported the observed SAR.

Pyrazoloquinazolines: Synthetic strategies and bioactivities.

Numerous N-heterocycles are indisputably evidenced to exhibit myriad biological activities. In the recent past, attempts made to condense the various heterocycles have resulted in derivatives possessing better bioactivities. Among many such condensed heterocycles, pyrazoloquinazolines have managed to hold the attention of many researchers, owing to the broad spectrum of activities they portray. This review is the first of its kind to congregate the various pyrazoloquinazolines reported until now and categorizes these structurally isomeric classes into eleven different groups based on the fusion pattern of the ring such as [1,5-c], [5,1-b], [4,3-h], etc. Furthermore, this review is a concerted effort to highlight design, synthetic strategies as well as biological activities of each class of this condensed heterocycle. Structure-activity relationship studies and in silico approaches wherever reported have also been discussed. In addition, manuscript also offers scope for design, synthesis and generation of libraries of unreported classes of pyrazoloquinazolines for the biological evaluation.

Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer.

Insulin and insulin-like growth factor (IGF) signaling system, commonly known for fine-tuning numerous biological processes, has lately made its mark as a much sought-after therapeutic targets for diabetes and cancer. These receptors make an attractive anticancer target owing to their overexpression in variety of cancer especially in prostate and breast cancer. Inhibitors of IGF signaling were subjected to clinical cancer trials with the main objective to confirm the effectiveness of these receptors as a therapeutic target. However, the results that these trials produced proved to be disappointing as the role played by the cross talk between IGF and insulin receptor (IR) signaling pathways at the receptor level or at downstream signaling level became more lucid. Therapeutic strategy for IGF-1R and IR inhibition mainly encompasses three main approaches namely receptor blockade with monoclonal antibodies, tyrosine kinase inhibition (ATP antagonist and non-ATP antagonist), and ligand neutralization via monoclonal antibodies targeted to ligand or recombinant IGF-binding proteins. Other drug-discovery approaches are employed to target IGF-1R, and IR includes antisense oligonucleotides and recombinant IGF-binding proteins. However, therapies with monoclonal antibodies and tyrosine kinase inhibition targeting the IGF-1R are not evidenced to be satisfactory as expected. Factors that are duly held responsible for the unsuccessfulness of these therapies include (a) the existence of the IR isoform A overexpressed on a variety of cancers, enhancing the mitogenic signals to the nucleus leading to the endorsement of cell growth, (b) IGF-1R and IR that form hybrid receptors sensitive to the stimulation of all three IGF axis ligands, and (c) IGF-1R and IR that also have the potential to form hybrid receptors with other tyrosine kinase to potentiate the cellular transformation, tumorigenesis, and tumor vascularization. This mini review is a concerted effort to explore and fathom the well-recognized roles of the IRA signaling system in human cancer phenotype and the main strategies that have been so far evaluated to target the IR and IGF-1R.

4,5-Dihydro-1H-pyrazole: an indispensable scaffold.

Pyrazoles, categorized as nitrogen-containing heterocycles, are well known for their interminable participation in the field of perpetual research and development of therapeutical active agents. As a consequence pyrazoles became an inevitable core of numerous drugs having diverse activities. The broad spectrum of activities portrayed by the pyrazoles instigated the researchers to modify the pyrazole ring as 4,5-dihydro-1H-pyrazoles commonly known as 2-pyrazolines. The present review is a concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis. This endeavor culminated in revelation that inhibitory potential varied when the substituents in particular N-substituents of 2-pyrazolines were altered.