Current Topics in Medicinal Chemistry - Volume 17, Issue 28, 2017

There is a great demand for the development of novel anticancer drugs, due to the increasing morbidity and high mortality of cancer. To date, chemotherapy still plays a central role in the clinical treatment of cancer, but this role is being reduced by targeted therapies. Since cancer is a complicated and multiple genes involved disease, drugs that act at multiple targets can enhance efficacy and lower drug resistance, and are thought to be the future of novel anticancer drug development. In this paper, we discuss the recent development of “single molecule, multi-target” anticancer agents that combine two or more pharmacophores in a single molecule, including organic multitargeted anticancer agents and metal based complexes such as platinum, ruthenium, iridium and rhodium complexes. These efforts will contribute to clinical cancer therapy and benefit patients in the future.

Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include Vascular Endothelial Growth Factor Receptors (VEGFRs), Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), Epidermal Growth Factor Receptors (EGFRs), Insulin-Like Growth Factor 1 Receptor (IGF-1R), Fmslike Tyrosine Kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include Checkpoint Kinases (Chks), Cyclin- Dependent Kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include Matrix Metalloproteinases (MMPs), LIM kinase (Limk), Nicotinamide Phosphoribosyltransferase (Nampt), and Histone Deacetylase (HDAC); (6) arylureas from the rational modification of natural products. This review focuses on the Structure-Activity Relationships (SARs) of these arylureas. The structural evolution and current status of some typical anti-cancer agents used in clinic and/or in clinical trials are emphasized.

There has been a growing interest in the rational design of multi-targeted drugs with the aim of enhancing overall efficacy and/or improving safety. The development of multi-targeted drugs might yield new avenues in the treatment of cancers that involve multiple pathogenic factors. In this review, we focus on the multi-targeted metal-based anticancer agents, which include platinum, ruthenium, rhodium, gold, silver, copper, cobalt, zinc, and nickel complexes. Future directions for the development of multi-targeted metal-based anticancer agents are also proposed.

Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like Cyclooxygenase (COX), Lipooxygenase (LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Leukotriene D4 (LTD4), Nuclear Factor-ΚB (NF- ΚB), Intracellular Cell Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and TLR4/MD-2, etc. The chalcone scaffold with hydroxyl, methoxyl, carboxyl, prenyl group and/or heterocyclic ring substitution like thiophene/furan/indole showed promising anti-inflammatory activity. In this review, a comprehensive study (from the year 1991 to 2016) on multi-targets of inflammatory interest, related inflammation reactions and their treatment by chalcone-based inhibitors acting on various molecular targets entailed in inflammation, Structure-Activity Relationships (SARs), Mechanism of Actions (MOAs), and patents are highlighted.