Synthetic strategies in curcumin chemistry focused on anticancer applications

In spite of having received considerable interest as a potential anticancer agent over the past two decades, curcumin has not been developed into a sturdy drug candidate yet, mainly due to the challenges imposed by its rapidly metabolizable structure, leading to bioavailability and stability issues, and its aspecific activity. To circumvent these obstacles, chemical modification of the parent scaffold has been shown to involve an eligible approach for the construction of curcuminoids with improved properties. This review article provides a compilation of curcumin modifications and the effect thereof on the anticancer activity displayed by the resulting new analogs

Synthesis of Novel Aza‐aromatic Curcuminoids with Improved Biological Activities towards Various Cancer Cell Lines

Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, displays pronounced anticancer properties but lacks good bioavailability and stability. In a previous study, we initiated structure modification of the curcumin scaffold by imination of the labile -diketone moiety to produce novel -enaminone derivatives. These compounds showed promising properties for elaborate follow-up studies. In this work, we focused on another class of nitrogen-containing curcuminoids with a similar objective: to address the bioavailability and stability issues and to improve the biological activity of curcumin. This paper thus reports on the synthesis of new pyridine-, indole-, and pyrrole-based curcumin analogues (aza-aromatic curcuminoids) and discusses their water solubility, antioxidant activity, and antiproliferative properties. In addition, multivariate statistics, including hierarchical clustering analysis and principal component analysis, were performed on a broad set of nitrogen-containing curcuminoids. Compared to their respective mother structures, that is, curcumin and bisdemethoxycurcumin, all compounds, and especially the pyridin-3-yl -enaminone analogues, showed better water solubility profiles. Interestingly, the pyridine-, indole-, and pyrrole-based curcumin derivatives demonstrated improved biological effects in terms of mitochondrial activity impairment and protein content, in addition to comparable or decreased antioxidant properties. Overall, the biologically active N-alkyl -enaminone aza-aromatic curcuminoids were shown to offer a desirable balance between good solubility and significant bioactivity

Synthesis of non‐symmetrical nitrogen‐containing curcuminoids in the pursuit of new anticancer candidates

Curcumin is known to display pronounced anticancer effects and a variety of other biological activities. However, the low bioavailability and fast metabolism of this molecule present an issue of concern with respect to its medicinal applications. To address this issue, structural modifications of the curcumin scaffold can be envisioned as a strategy to improve both the solubility and stability of this chemical entity, without compromising its biological activities. Previous work in our group targeted the synthesis of symmetrical azaheteroaromatic curcuminoids, which showed better solubility and cytotoxicity profiles compared to curcumin. In continuation of that work, we now focused on the synthesis of non-symmetrical nitrogen-containing curcuminoids bearing both a phenolic and an azaheteroaromatic moiety. In that way, we aimed to combine good solubility, antioxidant potential and cytotoxic properties into one molecule. Some derivatives were selected for further chemical modification of their rather labile beta-diketone scaffold to the corresponding pyrazole moiety. In this way, thirteen new non-symmetrical aza-aromatic curcuminoids and four pyrazolebased analogues were successfully synthesized in a yield of 11-69%. All newly synthesized analogues were evaluated for their antioxidant properties, reactive oxygen species (ROS) production, water solubility and anticancer activities. Several novel derivatives displayed good cytotoxicity profiles compared to curcumin, in combination with an improved water solubility and stability, and were thus identified as potential hit scaffolds for further optimization studies

Synthesis and first line in vitro evaluation of novel curcumin derivatives as anti-tumoral agents

Curcumin is known to display pronounced anticancer effects and a variety of other biological activities. However, the lack of bioavailability and the fast metabolism of this molecule present issues with respect to medicinal applications. To address these issues, structure modifications were pursued in this PhD research to improve both the solubility and stability of (bisdemethoxy)curcumin without compromising their biological activities. The structural modification of these compounds may pave the way toward new classes of curcuminoid pharmaceuticals to be used in cancer therapy or other medical applications. This structure revision aimed at modifying the (bisdemethoxy)curcumin framework, consisting of β-diketone, aromatic and enone moieties, through convenient, robust and green procedures to produce novel curcuminoids. The first scaffold modification concerned the imination of the labile β-diketone moiety to generate novel β-enaminone analogs upon reaction of (bisdemethoxy/3-pyridinyl)curcumin with different amines using microwave irradiation procedures (Chapter 1). When ethanol was used as the solvent, this method resulted in dihydropyridin-4-ones (via cyclization) in some cases. In the second approach, the aromatic rings in curcumin were replaced by aza-aromatic analogs in order to create symmetrical and non-symmetrical pyridine-, indole-, quinoline-, isoquinoline, and pyrrole-based curcumin derivatives (Chapter 2). A third structure modification relied on the curcumin enone moiety as a potential Michael acceptor. Particularly, the tandem imination/conjugate addition of amino thiols was explored, which culminated in unprecedented 1,4-thiazepane-based curcumin systems (Chapter 3). The reaction conditions for the three sets of experiments were optimized to provide unique structural compounds. In the fourth modification, a series of monocarbonyl curcumin analogs with different aromatic substituents was synthesized, and further structural variation was implemented by transforming them into pyrazoline scaffolds to generate a new set of compounds (Chapter 4). Additionally, to delve into the core of our research, the biological activities, water solubility and stability of all new analogs were evaluated and compared to their parent structures. In this way, several novel derivatives were identified as potential hit scaffolds for further optimization studies

New cysteine-analogue strategies for bioengineered peptide stapling and helical stabilization

Protein-protein interactions (PPIs) play critical roles in inter- and intracellular cell signalling pathways. Furthermore, PPIs are considered as novel therapeutic targets. Macrocyclization, an essential process in peptide drug discovery and peptide chemistry, is an efficient method to restrict peptide conformation, improve stability and bioavailability, enhance drug-like properties, and reduce polarity. Given these advantages there is an urgent need to develop new straightforward stapling techniques to constrain peptides. In this work, we describe the use of SSPS for preparing a diverse range of linear sequence peptides incorporating two cysteine amino acids in different positions in order to connect them. The thiol group of cysteine is prone to SN2 nucleophilic substitution, which leads, with the help of a staple, to constrained cyclic peptides. In case of a non-symmetrical staple, two regio-isomeric peptides are generated. Therefore, two new strategies are being explored based on functionalized-cysteine moieties, either L-penicillamine (Pen) or S-tert-butylthio-L-cysteine (StBu), to generate the target peptides in a selective fashion. We describe our advances in the development of selective stapling methodologies through a one-pot reaction (via Pen amino acids) or a two-pot reaction (via Cys-StBu amino acids). Interestingly, the outcome of our recent developments has highlighted how to achieve single regioisomers of target peptide by pre-designing the linear peptide sequences

Type 1 resistant starch: Nutritional properties and industry applications

Type 1 resistant starch (RS1) has recently received tremendous attention from various research areas such as food science, nutrition, microbiology, and pharmaceutical technology due to its ability to resist digestion in the upper gastrointestinal tract. The protective barriers of RS1 play a vital role in the reduction of starch hydrolysis, glucose absorption, and the glycemic response that has the potential to limit the prevalence of some diseases by delaying the reaction of the digestive enzymes and extending glucose release. This work aims to provide a comprehensive review of RS1 mechanisms in controlling starch digestion and a summary of its industrial applications in relation to health benefits. Despite extensive research in this area, the review exposed some unrevealed aspects of RS1 that would require further study