Mini Reviews in Medicinal Chemistry - Volume 19, Issue 18, 2019

Thiazolidin-2,4-dione (TZD) possessing an active methylene constitute an important chemical class of compounds for the development of new drugs. So, many scholars have synthesized these derivatives as target molecules and evaluated their biological potential. Currently, some of the TZDs are synthesized to treat human cancers stating high levels of PPARγ because it is expected that activation of PPARγ arbitrates their anticancer activity because PPARγ ligands have recently been established to affect differentiation, cell proliferation and apoptosis of different cell types. In the present review, the synthesis of various derivatives of thiazolidine-2,4-diones, their mechanism of action and anticancer activity have been highlighted.

At present, cancers have been causing deadly fears to humans and previously unpredictable losses to health. Especially, lung cancer is one of the most common causes of cancer-related mortality accounting for approximately 15% of all cancer cases worldwide. While Non-Small Cell Lung Carcinomas (NSCLCs) makes up to 80% of lung cancer cases. The patient compliance has been weakening because of serious drug resistance and adverse drug effects. Therefore, there is an urgent need for the development of novel structural agents to inhibit NSCLCs. Nitrogen-containing heterocyclic compounds exhibit wide range of biological properties, especially antitumor activity. We reviewed some deadly defects of clinical medicines for the lung cancer therapy and importance of nitrogen based heterocyclic derivatives against NSCLCs. Nitrogen heterocycles exhibit significant antitumor activity against NSCLCs. Nitrogen heterocyclic hybrids could be developed as multi-target-directed NSCLC inhibitors and it is believed that the review is significant for rational designs and new ideas in the development of nitrogen heterocyclic-based drugs.

The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn’t been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.