Current Medicinal Chemistry - Volume 26, Issue 41, 2019

Glycolysis is a tightly regulated process in which several enzymes, such as Hexokinases (HKs), play crucial roles. Cancer cells are characterized by specific expression levels of several isoenzymes in different metabolic pathways and these features offer possibilities for therapeutic interventions. Overexpression of HKs (mostly of the HK2 isoform) have been consistently reported in numerous types of cancer. Moreover, deletion of HK2 has been shown to decrease cancer cell proliferation without explicit side effects in animal models, which suggests that targeting HK2 is a viable strategy for cancer therapy. HK2 inhibition causes a substantial decrease of glycolysis that affects multiple pathways of central metabolism and also destabilizes the mitochondrial outer membrane, ultimately enhancing cell death. Although glycolysis inhibition has met limited success, partly due to low selectivity for specific isoforms and excessive side effects of the reported HK inhibitors, there is ample ground for progress. The current review is focused on HK2 inhibition, envisaging the development of potent and selective anticancer agents. The information on function, expression, and activity of HKs is presented, along with their structures, known inhibitors, and reported effects of HK2 ablation/inhibition. The structural features of the different isozymes are discussed, aiming to stimulate a more rational approach to the design of selective HK2 inhibitors with appropriate drug-like properties. Particular attention is dedicated to a structural and sequence comparison of the structurally similar HK1 and HK2 isoforms, aiming to unveil differences that could be explored therapeutically. Finally, several additional catalytic- and non-catalytic roles on different pathways and diseases, recently attributed to HK2, are reviewed and their implications briefly discussed.

More than half of all human tumors express mutant forms of p53, with the ovary, lung, pancreas, and colorectal cancers among the tumor types that display the highest prevalence of p53 mutations. In addition, the expression of mutant forms of p53 in tumors is associated with poor prognosis due to increased chemoresistance and invasiveness. Therefore, the pharmacological restoration of wild-type-like activity to mutant p53 arises as a promising therapeutic strategy against cancer. This review is focused on the most relevant mutant p53 small molecule reactivators described to date. Despite some of them have entered into clinical trials, none has reached the clinic, which emphasizes that new pharmacological alternatives, particularly with higher selectivity and lower adverse toxic side effects, are still required.

Heterocyclic compounds represent a significant target for anti-cancer research and drug discovery, due to their structural and chemical diversity. Oxazoles, with oxygen and nitrogen atoms present in the core structure, enable various types of interactions with different enzymes and receptors, favoring the discovery of new drugs. Aim of this review is to describe the most recent reports on the use of oxazole-based compounds in anticancer research, with reference to the newly discovered iso/oxazole-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives. The corresponding dehydrogenated derivatives, i.e. iso/oxazolines and iso/oxazolidines, are also reported.

This review covers the chemistry and biological aspects of goniothalamin-related styryl lactones isolated from natural sources. This family of secondary metabolites has been reported to display diverse uses in folk medicine, but only a limited number of these compounds have been throughly investigated regarding their biological profile. Herein, we cover the goniothalamin-related styryl lactones having a C6-C3-C4 framework which appeared in the literature for the first time in the period 2000-2017, and the reports on the synthesis, biological activity and mechanism of action which were published from 2007-2017.

The development of safe and effective chemotherapeutic agents is one of the uppermost priorities and challenges of medicinal chemistry and new transition metal complexes are being continuously designed and tested as anticancer agents. Scorpionate ligands have played a great role in coordination chemistry, since their discovery by Trofimenko in the late 1960s, with significant contributions in the fields of catalysis and bioinorganic chemistry. Scorpionate metal complexes have also shown interesting anticancer properties, and herein, the most recent (last decade) and relevant scorpionate complexes reported for application in medicinal chemistry as chemotherapeutic agents are reviewed. The current progress on the anticancer properties of transition metal complexes bearing homo- or hetero- scorpionate ligands, derived from bis- or tris-(pyrazol-1-yl)-borate or -methane moieties is highlighted.

Transition metal complexes, of which the platinum(II) complex cisplatin is an example, have been used in medicine to treat cancer for more than 40 years. Although many successes have been achieved, there are problems associated with the use of these drugs, such as side effects and drug resistance. Converting them into prodrugs, to make them more inert, so that they can travel to the tumour site unchanged and release the drug in its active form only there, is a strategy which is the subject of much research nowadays. The new prodrugs may be activated and release the cytotoxic agent by differences in oxygen concentration or in pH, by the action of overexpressed enzymes, by differences in metabolic rates, etc., which characteristically distinguish cancer cells from normal ones, or even by the input of radiation, which can be visible light. Converting a metal complex into a prodrug may also be used to improve its pharmacological properties. In some cases, the metal complex is a carrier which transports the active drug as a ligand. Some platinum prodrugs have reached clinical trials. So far platinum, ruthenium and cobalt have been the most studied metals. This review presents the recent developments in this area, including the types of complexes used, the mechanisms of drug action and in some cases the techniques applied to monitor drug delivery to cells.

The unique properties of ionic liquids make them quite appealing for diverse applications, from “green” solvents (1st generation ionic liquids) to finely tuned materials (2nd generation ionic liquids). A decade ago, a 3rd generation of ionic liquids emerged which is focused on their prospective clinical applications, either as drugs per se or as adjuvants in drug formulations. In recent years, research focused on the use of ionic liquids for topical drug delivery has been increasing and holds great promise towards clinical application against skin cancers. This article highlights the growing relevance of ionic liquids in medicinal chemistry and pharmaceutical technology, which is opening new windows of opportunity.