Background
Vitamin K antagonists (VKAs), such as warfarin, have remained the cornerstone of oral anticoagulation therapy in the prevention and treatment of thromboembolism for more than half a ...century. They function by impairing the biosynthesis of vitamin K‐dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially the result of genetic variations of VKOR.
Objectives
The goal of this study was to search for an improved VKA that is tolerant to the genetic variations of its target enzyme.
Methods
A series of vitamin K derivatives with benzyl and related side‐chain substitutions at the 3‐position of 1,4‐naphthoquinone were synthesized. The role of these compounds in VKD carboxylation was evaluated by mammalian cell‐based assays and conventional in vitro activity assays.
Results
Our results showed that replacing the phytyl side‐chain with a methylene cyclooctatetraene (COT) moiety at the 3‐position of vitamin K1 converted it from a substrate to an inhibitor for VKD carboxylation. Strikingly, this COT‐vitamin K derivative displayed a similar inhibition potency in warfarin‐resistant VKOR mutations whose warfarin resistance varied more than 400‐fold. Further characterization of COT‐vitamin K for the inhibition of VKD carboxylation suggested that this compound targets multiple enzymes in the vitamin K redox cycle. Importantly, the anticoagulation effect of COT‐vitamin K can be rescued with high doses of vitamin K1.
Conclusion
We discovered a vitamin K analogue that functions as a VKA and is tolerant to genetic variations in the target enzyme.
Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse ...translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.
An efficient nitro-Mannich type direct α-C(sp(3))-H functionalisation of N-aryl-1,2,3,4-tetrahydroisoquinolines catalysed by simple iron salts in combination with O2 as the terminal oxidant is ...described. The use of a Teflon AF-2400 membrane Tube-in-Tube reactor under continuous flow conditions allowed for considerable process intensification to be achieved relative to previous batch methods.
Cubane: 50 Years Later Biegasiewicz, Kyle F; Griffiths, Justin R; Savage, G. Paul ...
Chemical reviews,
07/2015, Letnik:
115, Številka:
14
Journal Article
Recenzirano
The synthesis of cubane and it's derivatives is examined. Structurally complex cage molecules are also discussed.
Highlights • We use a novel structural–functional covariance network analysis to investigate effects of aging. • Findings show that young adults activate the fronto-parietal and salience networks ...more consistently. • Older adults compensate for gray and white matter degradation by engaging prefrontal network nodes.
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Synthesis and biological evaluation of a small, focused library of 1,3-disubstituted-1,2,4-triazin-6-ones for in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) ...and androgen-receptor independent (PC3) castration-resistant prostate cancer (CRPC) cells led to highly active compounds with in vitro IC50 values against 22Rv1 cells of <200 nM, and with apparent selectivity for this cell type over PC3 cells. From metabolic/PK evaluations of these compounds, a 3–benzyl-1–(2,4-dichlorobenzyl) derivative had superior properties and showed considerably stronger activity, by nearly an order of magnitude, against AR–dependent LNCaP and C4–2B cells compared to AR–independent DU145 cells. This lead compound decreased AR expression in a dose and time dependent manner and displayed promising therapeutic effects in a 22Rv1 CRPC xenograft mouse model. Computational target prediction and subsequent docking studies suggested three potential known prostate cancer targets: p38a MAPK, TGF-β1, and HGFR/c–Met, with the latter case of c–Met appearing stronger, owing to close structural similarity of the lead compound to known pyridazin-3-one derivatives with potent c-Met inhibitory activity. RNA-seq analysis showed dramatic reduction of AR signalling pathway and/or target genes by the lead compound, subsequently confirmed by quantitative PCR analysis. The lead compound was highly inhibitory against HGF, the c–Met ligand, which fitted well with the computational target prediction and docking studies. These results suggest that this compound could be a promising starting point for the development of an effective therapy for the treatment of CRPC.
The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., ...bioisosterism). In recent years, bioisosteres such as cubane and bicyclo1.1.1pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.
The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s–1 at 25 °C) through scission of two bonds of the cube. The rearrangement ...has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C–H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cubane core ring-opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C–H abstraction and C–O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.
Formula 1 Composites Engineering Savage, G.
Engineering failure analysis,
2010, 2010-1-00, 20100101, Letnik:
17, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Any engineering structure, irrespective of its intended purpose, must be made of one or more materials. More often than not it is the choice and behaviour of those materials that determine its ...mechanical performance. The introduction of fibre reinforced composite chassis was one of the most significant developments in the history of Grand Prix motor racing. Technological advances gained from these advanced materials have produced cars that are lighter, faster and safer than ever before. The manufacture of Formula 1 cars is now dominated by composites. A short introduction to the science of composite materials will be followed by a history of their use and development within the sport. Design manufacture and operation of composite structures are reviewed. Reference is also made to their energy absorbing properties that have contributed so significantly to the improved safety record of Formula 1 and the more specialist composite materials, such as carbon–carbon, used in brakes and clutches.
Synthesis of the 6-aza1.0triblattane skeleton and the unexpected construction of the 7-azatetracyclo4.2.1.02,5.03,7nonane framework are reported, as inspired by the Wilder–Culberson ...1-aza1.1triblattane ring system. The key steps to assess the 6-aza1.0triblattane include accessing the 1,6-cycloaddition product from reaction of chlorosulfonyl isocyanate with cyclohept-1,3,5-triene followed by intramolecular electrocyclization and aminium radical cyclization.
PDF
![The (±)-6-Aza[1.0]triblatta...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1523-7060/small "The (±)-6-Aza[1.0]triblattane Skeleton: Contraction beyond the Wilder–Culberson Ring System")