Ahcène Boumendjel

Antimitotic and antiproliferative activities of chalcones: forward structure-activity relationship

A series of 59 chalcones was prepared and evaluated for the antimitotic effect against K562 leukemia cells. The most active chalcones were evaluated for their antiproliferative activity against a panel of 11 human and murine cell cancer lines. We found that three chalcones were of great interest as potential antimitotic drugs. In vivo safety studies conducted on one of the most active chalcones revealed that the compound was safe, allowing further in vivo antitumor evaluation.

Aurones: a subclass of flavones with promising biological potential.

Aurones [2-benzylidenebenzofuran-3(2H)-ones] are the secondary metabolites natural compounds belong to the flavonoids family, and structurally are the isomers of flavones, widely present in fruits and flowers where they play significant role in the pigmentation of the part of plant in which they occur. Literature survey clearly indicates that flavones, chalcones, flavonols and isoflavones have been studied largely for their therapeutical potential. Somehow, aurones still are less studied and it is only recently that these compounds have begun to be investigated. In this review, we report the recent advances made on the therapeutical potential of aurones in different biological areas. Their synthesis, structure-activity relationships, the importance of the substitution pattern will also be discussed. Finally, some aspects regarding the possible development of aurones will be highlighted briefly.

Targeting the Achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance.

The development of multidrug resistance (MDR) in patients suffering cancer remains a significant clinical challenge, with drug efflux by ABC (ATP-binding cassette) transporters contributing significantly. Strategies to circumvent the reduced drug accumulation conferred by these polyspecific efflux transporters have relied on attempts to develop drugs that bypass extrusion (often with a sacrifice in activity) or the exploration of clinical inhibitors that, although showing promise in vitro, have not translated to the clinic. Alterations that confer selective advantage during the evolution of cancer cells might also create vulnerabilities that can be exploited therapeutically.1 As defined by Szybalski and Bryson, collateral sensitivity is a “phenomenon in drug-resistant cells (prokaryotic or eukaryotic) identified during most in vitro studies... [whereby] the development of resistance in cells to one agent can confer higher sensitivity to an alternate agent than seen in the original (parental) line”.2 In other words, the resistant cell line is more sensitive to a cytotoxin than the parental line from which it is derived (Figure ​(Figure1).1). From this perspective, resistance can be interpreted as a trait that could be targeted by new drugs. In this review, we discuss general mechanisms underlying collateral sensitivity and focus on small molecules reported to elicit increased toxicity in cells overexpressing one of the three major multidrug transporters. Such molecules (termed MDR-selective compounds) target multidrug-resistant cycling cells, suggesting that MDR ABC transporters could be considered as the ultimate “Achilles’ heel”—the exquisite spot to fatally wound a multidrug-resistant cancer cell. Herein, we discuss the potential of this emerging technology, cataloging MDR-selective compounds reported in the literature and highlighting chemical features that are associated with MDR-selective toxicity. Figure 1 Collateral sensitivity. Changes accompanying acquired resistance to drug A can be beneficial, neutral, or detrimental in the presence of drug B. Cancer cells tend to increase their fitness through the overexpression of efflux transporters that keep the ...

Chalcones Derivatives Acting as Cell Cycle Blockers: Potential Anti Cancer Drugs?

Chalcones (1,3-diphenylpropen-1-ones) are naturally occurring compounds belonging to the flavonoid family and are largely investigated in various therapeutic area and especially as antitumor drugs. In the latter field, the literature survey indicates that effect on the cell cycle is one of the most important targets domains of chalcones. In this review, we will shed light on: a) the structural criteria responsible for the cell cycle perturbations, b) the activity of chalcones on cell cycle molecular players or regulators c) the correlation between the chalcone-structure and proteins involved directly or not in cell cycle regulation and apoptosis by enhancement of proapoptotic molecules expression. We will discuss some perspectives related on how can we deal with chemical modification of chalcones to come up with more potent compounds to provide new ways for cancer treatment.

Inhibitors of cancer cell multidrug resistance mediated by breast cancer resistance protein (BCRP/ABCG2)

Breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP-binding cassette (ABC) transporter superfamily. It is able to efflux a broad range of anti-cancer drugs through the cellular membrane, thus limiting their anti-proliferative effects. Due to its relatively recent discovery in 1998, and in contrast to the other ABC transporters P-glycoprotein (MDR1/ABCB1) and multidrug resistance-associated protein (MRP1/ABCC1), only a few BCRP inhibitors have been reported. This review summarizes the known classes of inhibitors that are either specific for BCRP or also inhibit the other multidrug resistance ABC transporters. Information is presented on structure–activity relationship aspects and how modulators may interact with BCRP.

Flavonoids as Promising Lead Compounds in Type 2 Diabetes Mellitus: Molecules of Interest and Structure-Activity Relationship

There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: α-glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development.

Substituted chromones as highly potent nontoxic inhibitors, specific for the breast cancer resistance protein.

A series of 13 disubstituted chromones was synthesized. Two types of substituents, on each side of the scaffold, contributed to both the potency of ABCG2 inhibition and the cytotoxicity. The best compound, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one (6g), displayed high-affinity inhibition and low cytotoxicity, giving a markedly high therapeutic index. The chromone derivative specifically inhibited ABCG2 versus other multidrug ABC transporters and was not transported. It constitutes a highly promising candidate for in vivo chemosensitization of ABCG2-expressing tumors.

A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models.

BackgroundOver the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect.MethodsThe in-vitro activities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity on in-vitro microtubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compound in vivo. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours.ResultsIn the four human and the murine glioblastoma cell lines tested, 10 μM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 × 105 M-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. These in vitro studies were reinforced by our in vivo investigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB.ConclusionThese in vitro and in vivo data suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model.

Recent Advances in the Medicinal Chemistry of Aurones

The first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of aurones. A special focus will be made on the structure-activity relationship aspects among aurones and especially in case where aurones were found highly active than the corresponding flavones and chalcones.

A new synthesis of α,β-unsaturated aldehydes

Abstract The two carbon homologation of carbonyl compounds to α,β-unsaturated aldehydes is achieved by the Wittig-Horner reaction with N-methoxy N-methyl diethylphosphonoacetamide 1 followed by lithium aluminum hydride reduction.