Covalent Modification of p53 by ()-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one.

is commonly mutated in cancer, giving rise to loss of wild-type tumor suppressor function and increases in gain-of-function oncogenic roles. Thus, inhibition of mutant p53 and reactivation of wild-type function represents a potential means to target diverse tumor types. ()-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984), first identified from a high-throughput screen, induces wild-type p53 signaling and antiproliferative effects while inhibiting mutant p53 gain-of-function activities.

Prodrug Strategy Extends the Use of Anti-HIV Sulfanylbenzamides for Application .

Sulfanylbenzamide thioesters are molecules with anti-HIV activity that disrupt zinc coordination in the viral protein NCp7. These molecules are useful as topical microbicides; however, they are too unstable to be used systemically. In this article, a nitroimidazole prodrug was used to protect the sulfanylbenzamide to convey blood stability and oral bioavailability to the molecule.

Indol-3-ylglyoxylamide as Privileged Scaffold in Medicinal Chemistry.

In recent years, indolylglyoxylamide-based derivatives have received much attention due to their application in drug design and discovery, leading to the development of a wide array of compounds that have shown a variety of pharmacological activities. Combining the indole nucleus, already validated as a "privileged structure," with the glyoxylamide function allowed for an excellent template to be obtained that is suitable to a great number of structural modifications aimed at permitting interaction with specific molecular targets and producing desirable therapeutic effects. The present review provides insight into how medicinal chemists have elegantly exploited the indolylglyoxylamide moiety to obtain potentially useful drugs, with a particular focus on compounds exhibiting activity in in vivo models or reaching clinical trials.

Alkyl-substituted N-methylaryl-N'-aryl-4-aminobenzamides: A new series of small molecule inhibitors for Wip1 phosphatase.

The wild-type p53 induced phosphatase 1 (Wip1), a member of the serine/threonine-specific PP2C family, is overexpressed in numerous human cancers. Wip1 dephosphorylates p53 as well as several kinases (such as p38 MAPK, ATM, Chk1, and Chk2) in the DNA damage response pathway that are responsible for maintaining genomic stability and preventing oncogenic transformation. As a result, Wip1 is an attractive target for synthetic inhibitors that could be further developed into therapeutics to treat some cancers.

The Alpha Keto Amide Moiety as a Privileged Motif in Medicinal Chemistry: Current Insights and Emerging Opportunities.

Over the years, researchers in drug discovery have taken advantage of the use of privileged structures to design innovative hit/lead molecules. The α-ketoamide motif is found in many natural products, and it has been widely exploited by medicinal chemists to develop compounds tailored to a vast range of biological targets, thus presenting clinical potential for a plethora of pathological conditions. The purpose of this perspective is to provide insights into the versatility of this chemical moiety as a privileged structure in drug discovery.

An update into the medicinal chemistry of translocator protein (TSPO) ligands.

The Translocator Protein 18 kDa (TSPO) has been discovered in 1977 as an alternative binding site for the benzodiazepine diazepam. It is an evolutionary well-conserved and tryptophan-rich 169-amino acids protein with five alpha helical transmembrane domains stretching the outer mitochondrial membrane, with the carboxyl-terminus in the cytosol and a short amino-terminus in the intermembrane space of mitochondrion. At this level, together with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT), it forms the mitochondrial permeability transition pore (MPTP).

Multiple Topoisomerase I (TopoI), Topoisomerase II (TopoII) and Tyrosyl-DNA Phosphodiesterase (TDP) inhibitors in the development of anticancer drugs.

DNA Topoisomerases (Topos) are ubiquitous nuclear enzymes involved in regulating the topological state of DNA and, in eukaryotic organisms, Topos can be classified into two structurally and functionally different main classes: TopoI and TopoII. Both these enzymes proved to be excellent targets of clinically significant classes of anticancer drugs. Actually, TopoI or II inhibitors show considerable wide spectrum antitumor activities, an important feature to be included in many chemotherapeutic protocols.

The structure-activity profile of mercaptobenzamides' anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target.

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed.

Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases.

New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH) at R-R positions and protonatable R-dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI values spanning from 0.31 to 6.93 μM) and pro-apoptotic effect.

Novel fluorescent triazinobenzimidazole derivatives as probes for labelling human A and A adenosine receptor subtypes.

The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N (1,2) or N (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized.

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N-Dialkyl-2-arylindol-3-ylglyoxylamides.

Targeting the biosynthetic pathway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligands may be a viable therapeutic approach for a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between binding affinity and in vitro steroidogenic efficacy has limited the identification of lead compounds by traditional affinity-based drug discovery strategies. Our recent research indicates that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends in the target, namely its residence time (RT).

Toward PET imaging of A2B adenosine receptors: a carbon-11 labeled triazinobenzimidazole tracer: Synthesis and imaging of a new A2B PET tracer.

Introduction: A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target.