ABSTRACT
Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20⯵M, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81⯵M in the IDO1-based assay, a full biocompatibility at 10⯵M, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.
Subject(s)
Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Thiazoles/pharmacology , Catalytic Domain , Cell Line, Tumor , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Imidazoles/chemical synthesis , Imidazoles/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Molecular Docking Simulation , Molecular Structure , Oximes/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacology , Thiazoles/chemical synthesis , Thiazoles/chemistry , Tryptophan/analogs & derivatives , Tryptophan/pharmacologyABSTRACT
Aryne chemistry has recently received widespread attention and isocyanides have been reported as efficient nucleophilic partners in a set of multicomponent transformations. In this study, we demonstrate that tertiary α-monosubstituted α-isocyanoacetamides are efficaciously coupled with water and benzyne to offer a direct and metal-free access to densely functionalized α-benzoylamino amides, without competing with the intramolecular cyclization to 5-aminooxazoles. Despite the formation of the aryl anion as a key intermediate, the reaction displays a stereoconservative course, allowing for the preparation of enantiomerically pure α-benzoylamino amides. Finally, the synthetic utility of the reported MCR was exemplified by the preparation of proglumide, a cholecystokinin antagonist.
ABSTRACT
In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Animals , Benzimidazoles/blood , Cell Line, Tumor , Cells, Cultured , Enzyme Inhibitors/blood , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Male , Mice , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
Multicomponent transformations, such as Ugi and Passerini reactions, allow for the fast synthesis of libraries of medium complexity, avoiding the formation of waste residues and significantly reducing time and money expenditure. Although the Ugi reaction has found a vast number of uses in medicinal chemistry, the employment of the Passerini reaction has received scant attention due to the formation of an α-acyloxyamide, which hardly resists the hydrolytic enzymes in the body. On the other hand, an overlooked possibility with the Passerini products is to exploit the presence of an ester group in the design and synthesis of soft drugs. We started to fill this gap, designing and synthesizing a series of TRPV1 and TRPM8 agonists able to act as soft drugs by using the Passerini reaction.
Subject(s)
Cyanides/chemical synthesis , Drug Discovery/methods , TRPM Cation Channels/agonists , TRPV Cation Channels/agonists , Capsaicin/chemical synthesis , Menthol/chemical synthesis , Molecular StructureABSTRACT
Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.
Subject(s)
Capsaicin/administration & dosage , Capsaicin/chemistry , Drug Discovery , Inflammation/drug therapy , Keratinocytes/drug effects , Laurates/pharmacology , Skin Diseases/drug therapy , TRPV Cation Channels/antagonists & inhibitors , Administration, Topical , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/chemistry , Animals , Cells, Cultured , Female , Humans , Inflammation/chemically induced , Laurates/administration & dosage , Mice , Mice, Inbred C57BL , Skin Diseases/chemically inducedABSTRACT
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.
Subject(s)
Calcium/metabolism , Drug Design , Pancreatitis/drug therapy , Triazoles/chemistry , Triazoles/pharmacology , Acute Disease , Animals , Biological Transport/drug effects , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , HEK293 Cells , Humans , Mice , Triazoles/therapeutic useABSTRACT
Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.