Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity

Abstract

The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions, and many small-molecule screens have sought to identify agents that prevent endothelial cell activation. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Yet, small-molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed that identifies activated endothelium by its capacity to trigger macrophage inflammatory protein 1 beta from primary monocytes. Subsequently, a 642-compound library of 39 distinctive scaffolds generated by a diversity-oriented synthesis based on the nucleophilic phosphine catalysis was screened for small molecules that activated the endothelium. Among the active compounds identified, the major classes were synthesized through the sequence of phosphine-catalyzed annulation, Tebbe reaction, Diels–Alder reaction, and in some cases, hydrolysis. Ninety-six analogs of one particular class of compounds, octahydro-1,6-naphthyridin-4-ones, were efficiently prepared by a solid-phase split-and-pool technique and by solution phase analog synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive octahydro-1,6-naphthyridin-4-one analogs identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.

Domino synthesis of functionalized 1,6-naphthyridines and their in vitro anti-inflammatory and anti-oxidant efficacies

“…2,3 These pyridine structures are the most significant because of their wide spectrum of promising biological activities such as anticonvulsants, 4 anti-inflammatory, 5 antimitotic, 6 agents antioxidant, 7,8 anticancer, 9,10 and antimicrobial activities. 11 Similarly, 1,6-naphthyridines [12][13][14][15][16][17] have established significant attention due to their broad range of bioactivities [18][19][20][21][22][23][24] such as antimicrobial, 25 anti-analgesic, 26 antifungal, 27,28 anticancer, [29][30][31] antioxidant, 31 anti-inflammatory, [27][28][29]32 antiarrhythmic, 33 antitumor 34 , anti HSV-1 35 anti-HIV 36,37 activities and act as inhibitors of acetylcholinesteras. 38 Structures of few previously reported biologically active 1,6-naphyridines (A-G) are shown in Figure 1.…”

Phosphine-catalyzed intramolecular γ-umpolung addition of α-aminoalkylallenic esters: facile synthesis of 3-carbethoxy-2-alkyl-3-pyrrolines

“…2 Of the various approaches toward functionalized 2,5-dihydropyrroles, Lu’s phosphine-catalyzed [3+2] annulation of allenes and imines has emerged as one of the premiere methodologies. 2 b ,3 Since its first report, this annulation has undergone many developments, including modifications, 4 applications, 5 and asymmetric renditions. 6 Despite the great utility of this phosphine-catalyzed allene–imine [3+2] annulation, it has its limitations—the most evident being the necessity for imines devoid of α-protons.…”

Stereoselective Cycloaddition Reactions

“…50 To examine their capability of antibacterial, antifungal, antitumoral, and anti-inflammatory properties. 58 Based on the bicyclic structure of the octahydro-1,6naphthyridin-4-one 92, a chemical library was prepared by employing a solid-phase synthesis technique and evaluated by an EC activation assay that measured the production of macrophage inflammatory protein 1 beta (MIP1b), a marker of EC activation by IFNg. [55][56][57] Recently, octahydro-1,6-naphthyridin-4-one framework 92 exerted an ability to promote endothelial cell (EC) activation that mediates leukocytes transmigration and subsequently participates in host defense by eradicating infections and some cancers after it is induced by proinflammatory cytokines like interferon gamma (IFNg) (Figure 16.8).…”

“…54 Among its six isomers, a 1,6-naphthyridine skeleton was found to have antidepressant and analgesic activities as well (Figure 16.8). 58 Reaction conditions were first established by using SynPhase lanterns as solid supports. 58 Based on the bicyclic structure of the octahydro-1,6naphthyridin-4-one 92, a chemical library was prepared by employing a solid-phase synthesis technique and evaluated by an EC activation assay that measured the production of macrophage inflammatory protein 1 beta (MIP1b), a marker of EC activation by IFNg.…”