Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the “mutual prodrug” approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.     

Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a 5-year survival rate of less than 10% following diagnosis. The aggressive and invasive properties of pancreatic cancer tumors coupled with poor diagnostic options contribute to the high mortality rate since most patients present with late-stage disease. Accordingly, PDAC is linked to the highest rate of cancer-associated venous thromboembolic disease of all solid tumor malignancies. However, in addition to promoting clot formation, recent studies suggest that the coagulation system in PDAC mediates a reciprocal relationship, whereby coagulation proteases and receptors promote PDAC tumor progression and dissemination. Here, upregulation of tissue factor (TF) by tumor cells can drive local generation of the central coagulation protease thrombin that promotes cell signaling activity through protease-activated receptors (PARs) expressed by both tumor cells and multiple stromal cell subsets. Moreover, the TF-thrombin-PAR1 signaling axis appears to be a major mechanism of cancer progression in general and PDAC in particular. Here, we summarize the current literature regarding the role of PAR1 in PDAC and review possibilities for pharmacologically targeting PAR1 as a PDAC therapeutic approach.     

The AFLATOX® Project: Approaching the Development of New Generation,Natural-Based Compounds for the Containment of the Mycotoxigenic Phytopathogen Aspergillus flavus and Aflatoxin Contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox^® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.     

A Review on the Fundamentals of Palm Oil Fractionation: Processing Conditions and Seeding Agents

Fractionation is a well-established process adopted in the fats and oils industries. It involves the separation of low and high melting triacylglycerol under controlled cooling conditions into olein and stearin fractions with distinct chemical and physical properties. Amongst the other vegetable oils, palm oil is one of the most fractionated oils in the past few decades mainly attributed to its semisolid properties. The various fraction of palm oil allows it to be used in different types of food products such as margarine, frying oil, and cocoa butter substitute. In fractionation, proper control of the fractionation conditions is important to produce the fractions with desirable stearin and olein quality. The purpose of this paper is to critically review the fractionation conditions (crystallization temperature, agitation, cooling rate and crystallization time) that affect the yield and quality of the oil produced. Additionally, it also provides the latest updates on the influence of seeding agents (diacylglycerol, monoacylglycerol, hard fat, phytosterol, phospholipid, lecithin, essential oil, sugar, polyglycerol ester, and talc) used in fractionation. This article is useful to provide a fundamental understanding of fractionation to scientists from the industries or academia working in the fats and oils industries. Practical Applications: This paper provides an in-depth understanding of fractionation particularly on the parameters of fractionation in influencing the quality and yield of the stearin and olein produced. It also for the first time presents the effect of addition of various seeding agents on palm oil fractionation which can help the industry to select the appropriate seeding agents to improve the currently employed fractionation process. Thus, it can act as a guideline for the industry to understand and select the appropriate fractionation conditions when developing a new product using this approach. The fractionation conditions discussed here can also be used as a reference when fractionating other types of fats and oils as most of them share a common background.     

Preparation and Bioactivity of Iridium(III) Phenanthroline Complexes with Halide Ions and Pyridine Leaving Groups

A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl⁻, Br⁻, I⁻) and pyridine leaving groups ([(η⁵-Cp^X)Ir(Phen)Z](PF₆)_n, Cp^x: electron-rich cyclopentadienyl group, Z: leaving group) have been prepared. Target complexes, especially the Cp^xbiph (biphenyl-substituted cyclopentadienyl)-based one, showed favourable anticancer activity against human lung cancer (A549) cells; the best one ( Ir8 ) was almost five times that of cisplatin under the same conditions. Compared with complexes involving halide ion leaving groups, the pyridine-based one did not display hydrolysis but effectively caused lysosomal damage, leading to accumulation in the cytosol, inducing an increase in the level of intracellular reactive oxygen species and apoptosis; this indicated an anticancer mechanism of oxidation. Additionally, these complexes could bind to serum albumin through a static quenching mechanism. The data highlight the potential value of half-sandwich iridium(III) phenanthroline complexes as anticancer drugs.     

Luminescent Amphiphilic Aminoglycoside Probes to Study Transfection

We report the characterization of amphiphilic aminoglycoside conjugates containing luminophores with aggregation-induced emission properties as transfection reagents. These inherently luminescent transfection vectors are capable of binding plasmid DNA through electrostatic interactions; this binding results in an emission “on” signal due to restriction of intramolecular motion of the luminophore core. The luminescent cationic amphiphiles effectively transferred plasmid DNA into mammalian cells (HeLa, HEK 293T), as proven by expression of a red fluorescent protein marker. The morphologies of the aggregates were investigated by microscopy as well as ζ-potential and dynamic light-scattering measurements. The transfection efficiencies using luminescent cationic amphiphiles were similar to that of the gold-standard transfection reagent Lipofectamine® 2000.     

Metal Complexes as Antiviral Agents for SARS-CoV-2

The severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), the infectious agent responsible for COVID-19 – has caused more than 2.5 million deaths worldwide and triggered a global pandemic. Even with successful vaccines being delivered, there is an urgent need for novel treatments to combat SARS-CoV-2, and other emerging viral diseases. While several organic small molecule drug candidates are in development, some effort has also been devoted towards the application of metal complexes as potential antiviral agents against SARS-CoV-2. Herein, the metal complexes that have been reported to show antiviral activity against SARS-CoV-2 or one of its target proteins are described and their proposed mechanisms of action are discussed.     

聚丙烯改性技术进展

介绍了近年来聚丙烯改性技术研究方面的进展．研究内容包括用结晶成核剂对聚丙烯的晶型进行设计，用橡胶、矿物填料等对聚丙烯进行改性．     

化学镀Ni-Cu-P添加剂的研究

通过对化学镀Ni-Cu-P合金的稳定剂、表面活性剂、光亮剂对镀层性能及镀液稳定性的影响研究，得出最佳实验配方。     

我国木质素油田化学品的发展现状

本文综述了我国木质素类（碱木质素或木质素磺酸盐）油田化学品的最新进展，其中包括钻井液处理剂、油井水泥添加剂、堵水剂、调剖剂、稠油降粘剂和表面活性剂驱油的牺牲剂。目前我国木质素类堵水剂、调剖剂和稠油降粘剂的研究和应用方面已达到或超过世界先进水平，改性木质素磺酸盐的研究也接近国际先进水平，但钻井处理剂和水泥添加剂仅为美国的1／9，许多木质素化学品仍为空白。因此，这些油田化学品仍然是吸引人去研究的课题，期望不久的将来会有较大的进展。