It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer ...chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
Inhibition of thiamine pyrophosphate (TPP)-dependent enzymes with thiamine/TPP analogues that have the central thiazolium ring replaced with other rings is well established, but a limited number of ...central rings have been reported. We report a novel analogue, pyrrothiamine, with a central pyrrole ring. We further develop pyrrothiamine derivatives as potent and selective inhibitors of pyruvate dehydrogenase, which might have anti-cancer potential.
Pyrrothiamine, a new thiamine analogue with the S replaced by CH, has been synthesised and is a moderate inhibitor of a range of thiamine pyrophosphate-dependent enzymes. Its ester
19
is a potent and selective inhibitor of pyruvate dehydrogenase.
A common approach to studying thiamine pyrophosphate (TPP)-dependent enzymes is by chemical inhibition with thiamine/TPP analogues which feature a neutral aromatic ring in place of the positive ...thiazolium ring of TPP. These are potent inhibitors but their preparation generally involves multiple synthetic steps to construct the central ring. We report efficient syntheses of novel, open-chain thiamine analogues which potently inhibit TPP-dependent enzymes and are predicted to share the same binding mode as TPP. We also report some open-chain analogues that inhibit pyruvate dehydrogenase E1-subunit (PDH E1) and are predicted to occupy additional pockets in the enzyme other than the TPP-binding pockets. This opens up new possibilities for increasing the affinity and selectivity of the analogues for PDH, which is an established anti-cancer target.
Flexible open-chain analogues of thiamine can occupy various different pockets in pyruvate dehydrogenase E1 subunit, depending on whether they have a metal-binding group or not.
•A multi-cues integration framework is proposed using a hierarchical neural network.•Bottleneck representations are effective in multi-cues feature fusion.•Shearlet is utilized to perform face image ...quality assessment.•Motion-based face liveness features are automatically learned using autoencoders.
Many trait-specific countermeasures to face spoofing attacks have been developed for security of face authentication. However, there is no superior face anti-spoofing technique to deal with every kind of spoofing attack in varying scenarios. In order to improve the generalization ability of face anti-spoofing approaches, an extendable multi-cues integration framework for face anti-spoofing using a hierarchical neural network is proposed, which can fuse image quality cues and motion cues for liveness detection. Shearlet is utilized to develop an image quality-based liveness feature. Dense optical flow is utilized to extract motion-based liveness features. A bottleneck feature fusion strategy can integrate different liveness features effectively. The proposed approach was evaluated on three public face anti-spoofing databases. A half total error rate (HTER) of 0% and an equal error rate (EER) of 0% were achieved on both REPLAY-ATTACK database and 3D-MAD database. An EER of 5.83% was achieved on CASIA-FASD database.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pyruvate dehydrogenase complex (PDHc) is suppressed in some cancer types but overexpressed in others. To understand its contrasting oncogenic roles, there is a need for selective PDHc inhibitors. Its ...E1-subunit (PDH E1) is a thiamine pyrophosphate (TPP)-dependent enzyme and catalyses the first and rate-limiting step of the complex. In a recent study, we reported a series of ester-based thiamine analogues as selective TPP-competitive PDH E1 inhibitors with low nanomolar affinity. However, when the ester linker was replaced with an amide for stability reasons, the binding affinity was significantly reduced. In this study, we show that an amino-oxetane bioisostere of the amide improves the affinity and maintains stability towards esterase-catalysed hydrolysis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Suppression of pyruvate dehydrogenase complex (PDHc) is a mechanism for cancer cells to manifest the Warburg effect. However, recent evidence suggests that whether PDHc activity is suppressed or ...activated depends on the type of cancer. The PDHc E1 subunit (PDH E1) is a thiamine pyrophosphate (TPP)-dependent enzyme, catalysing the first and rate-limiting step of PDHc; thus, there is a need for selective PDH E1 inhibitors. There is, however, inadequate understanding of the structure-activity relationship (SAR) and a lack of inhibitors specific for mammalian PDH E1. Our group have reported TPP analogues as TPP-competitive inhibitors to study the family of TPP-dependent enzymes. Most of these TPP analogues cannot be used to study PDHc in cells because (a) they inhibit all members of the family and (b) they are membrane-impermeable. Here we report derivatives of thiamine/TPP analogues that identify elements distinctive to PDH E1 for selectivity. Based on our SAR findings, we developed a series of furan-based thiamine analogues as potent, selective and membrane-permeable inhibitors of mammalian PDH E1. We envision that our SAR findings and inhibitors will aid work on using chemical inhibition to understand the oncogenic role of PDHc.
Many neutral derivatives of the furan analogue of thiamine were tested to explore the SAR of the two thiamine pyrophosphate (TPP)-binding pockets and the substrate-binding C2-pocket: the optimum inhibitor bound 77-fold more tightly than TPP.
Hox genes encode evolutionarily conserved transcription factors that specify regional identities along the anterior-posterior (A-P) axis. Although some Hox genes are known to regulate the ...differentiation of certain neurons, to what extent Hox genes are involved in the terminal specification of the entire nervous system is unclear. Here, we systematically mapped the expression of all six Hox genes in C. elegans nervous system and found Hox expression in 97 (32%) of the 302 neurons in adult hermaphrodites. Our results are generally consistent with previous high-throughput expression mapping and single-cell transcriptomic studies. Detailed analysis of the fate markers for these neurons revealed that Hox genes regulate the differentiation of 29 (25%) of the 118 classes of C. elegans neurons. Hox genes not only regulate the specification of terminal neuronal fates through multiple mechanisms but also control subtype diversification along the A-P axis. The widespread involvement of Hox genes in neuronal differentiation indicates their roles in establishing complex nervous systems.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA ...highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease.
Hydrogels are able to exhibit optical transitions in the presence of external stimuli such as temperature, driven by the lower critical solution temperature (LCST) phenomena. However, they suffer ...from inherent thermal instability, requiring reswelling for repeated utilisation. Ionogels possess greater thermal stability over conventional hydrogels. However, thermally driven optical transitions via LCST phenomena in ionic liquid incorporated polymer networks have not been studied in-depth. In this work, we incorporated a low amount of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide in a polymer matrix, to trigger the desired reversible optical transitions based on the LCST phenomenon. The composition of the ionic liquid elastomer hybrid is in contrast to conventional hydrogels which possess high amounts of liquid. We present NMR and UV-vis spectroscopic studies to reveal the underlying reversible hydrogen bonding based mechanism behind this optical transition. Unlike conventional hydrogels, our hybrids show excellent thermal and ambient stability along with repeatable optical transitions with comparable response time, indicative of their long term use in harsher environments. Improvements in the mechanical properties with the inclusion of ionic liquid in our hybrids were also observed (40% increase in ultimate strain, 34% decrease in Young's modulus). The enhanced properties and optical transition of the ionic liquid elastomer hybrids allowed them to serve as a patternable smart display and a stretchable & flexible device.
A series of derivatives of a triazole analogue of thiamine has been synthesised. When tested as inhibitors of porcine pyruvate dehydrogenase, the benzoyl ester derivatives proved to be potent ...thiamine pyrophosphate (TPP) competitive inhibitors, with the affinity of the most potent analogue (
K
i
= 54 nM) almost matching the affinity of TPP itself. When tested as antiplasmodials, most of the derivatives showed modest activity (IC
50
value >60 μM), except for a 4′-
N
-benzyl derivative, which has an IC
50
value in the low micromolar range. This activity was not affected by increasing the extracellular concentration of thiamine in the culture medium for any of the compounds (except a modest increase in the IC
50
for the unfunctionalized benzoyl ester), nor by overexpressing thiamine pyrophosphokinase in the parasite, making it unlikely to be due to an effect on thiamine transport or metabolism.
A series of derivatives of a triazole analogue of thiamine has been synthesised.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
PDF
