An Appraisal on Synthetic and Medicinal Aspects of Fused Pyrimidines as Anti Neoplastic Agents.

Heterocyclic compounds are recognized to possess a high grade of structural diversity and a broad spectrum of therapeutic properties. About two-thirds of the New Chemical Entities approved by the FDA against cancer entail heterocyclic rings and are the foundation stone of medicinal chemistry. Pyrimidine being a major heterocyclic compound and a crucial base component of the genetic material, has emerged as the key structural component against cancer, the deadliest disease worldwide. Though many drugs are marketed against cancer, researchers are still investigating the more promising moieties against various malignancies due to the severity of this disease. In this review, an attempt has been made to assemble the reported literature of the previous five years on various synthetic procedures and the anti-cancer potential of various classes of fused pyrimidine analogs, which would help the researchers in designing new potent derivatives. Besides this, the review intends to focus on the comprehensive discussion on biological targets, modes of action, and structure-activity relationships of each class of fused pyrimidines as potential anticancer agents.

Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer.

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

Aspergillus nidulans natural product biosynthesis is regulated by mpkB, a putative pheromone response mitogen-activated protein kinase.

The Aspergillus nidulans putative mitogen-activated protein kinase encoded by mpkB has a role in natural product biosynthesis. An mpkB mutant exhibited a decrease in sterigmatocystin gene expression and low mycotoxin levels. The mutation also affected the expression of genes involved in penicillin and terrequinone A synthesis. mpkB was necessary for normal expression of laeA, which has been found to regulate secondary metabolism gene clusters.

Mating type and the genetic basis of self-fertility in the model fungus Aspergillus nidulans.

Sexual reproduction occurs in two fundamentally different ways: by outcrossing, in which two distinct partners contribute nuclei, or by self-fertilization (selfing), in which both nuclei are derived from the same individual. Selfing is common in flowering plants, fungi, and some animal taxa. We investigated the genetic basis of selfing in the homothallic fungus Aspergillus nidulans. We demonstrate that alpha and high-mobility group domain mating-type (MAT) genes, found in outcrossing species, are both present in the genome of A. nidulans and that their expression is required for normal sexual development and ascospore production. Balanced overexpression of MAT genes suppressed vegetative growth and stimulated sexual differentiation under conditions unfavorable for sex. Sexual reproduction was correlated with significantly increased expression of MAT genes and key genes of a pheromone-response MAP-kinase signaling pathway involved in heterothallic outcrossing. Mutation of a component MAP-kinase mpkB gene resulted in sterility. These results indicate that selfing in A. nidulans involves activation of the same mating pathways characteristic of sex in outcrossing species, i.e., self-fertilization does not bypass requirements for outcrossing sex but instead requires activation of these pathways within a single individual. However, unlike heterothallic species, aspects of pheromone signaling appeared to be independent of MAT control.