Pyrimidine-fused Dinitrogenous Penta-heterocycles as a Privileged Scaffold for Anti-Cancer Drug Discovery

Pyrimidine-fused derivatives that are the inextricable part of DNA and RNA play a key role in the normal life cycle of cells. Pyrimidine-fused dinitrogenous penta-heterocycles including pyrazolopyrimidines and imidazopyrimidines is a special class of pyrimidine-fused compounds contributing to an important portion in anti-cancer drug discovery, which have been discovered as core structure for promising anti-cancer agents used in clinic or clinical evaluations. Pyrimidine-fused dinitrogenous penta-heterocycles have become one privileged scaffold for anti-cancer drug discovery. This review consists of the recent progress of pyrimidine-fused dinitrogenous penta-heterocycles as anti-cancer agents and their synthetic strategies. In addition, this review also summarizes some key structure-activity relationships (SARs) of pyrimidine-fused dinitrogenous penta-heterocycle derivatives as anti-cancer agents.

Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma

Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.

Targeting PI3K/Akt signal transduction for cancer therapy

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.

Frontiers in Anti-cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-angiogenic Add-on Therapy in Glioblastoma

Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin’s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.

1,3,4-Oxadiazole as a Potential Anti-Cancer Scaffold: A Review

1,3,4-oxadiazole is an aromatic heterocycle with –N=C=O- linkage. 1,3,4-oxadiazole derivatives possess remarkable biological properties; antimicrobial anti-inflammatory, anti-cancer, antitubercular, antioxidant, antiviral, and anti-diabetic. This scaffold is present in many marketed drugs, such as Raltegravir, Tiodazosin, Nesapidil, and Zibotentan. 1,3,4-oxadiazole derivatives have displayed significant anti-cancer potential with a diverse mode of actions viz. growth factors, enzymes, kinases, etc. The present review gives an overview of the anti-cancer potential of 1,3,4-oxadiazoles derivatives in cancer drug discovery and development from the last ten years.