Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological ...systems. As a way to address this issue, this study investigates the design of synthetic prodrugs that are not only tuned to be harmless, but can be robustly transformed in vivo to reach therapeutically relevant levels. To accomplish this, retrosynthetic prodrug design highlights the potential of naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization. Structural adjustments will also be done to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. The developed prodrug therapy is found to possess excellent anticancer activities in cell-based assays. Furthermore, in vivo activation by intravenously administered glycosylated artificial metalloenzymes can also induce significant reduction of implanted tumor growth in mice.
In Vivo Gold Complex Catalysis within Live Mice Tsubokura, Kazuki; Vong, Kenward K. H.; Pradipta, Ambara R. ...
Angewandte Chemie International Edition,
March 20, 2017, Letnik:
56, Številka:
13
Journal Article
Recenzirano
Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin–AuIII complex was designed and developed that enables organ‐specific, ...localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5‐ and TAMRA‐linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.
The first metal‐catalyzed reaction that proceeds within live mice is based on a targeting approach with glycans. Glycoalbumin–AuIII complexes can be accumulated in specific organs where they catalyze amide bond formation between a propargyl ester probe and amine groups on nearby proteins. The selective targeting was confirmed by whole body fluorescence imaging and analysis of dissected tissues.
Neoglycoconjugates mimicking natural compounds and possessing a variety of biological functions are very successful tools for researchers to understand the general mechanisms of many biological ...processes in living organisms. These substances are characterized by high biotolerance and specificity, with low toxicity. Due to the difficult isolation of individual glycoclusters from biological objects, special interest has been directed toward synthetic analogs. This review is mainly focused on the one-pot, double-click methodology (containing alkyne-azide click cycloaddition with the following 6π-azaelectrocyclization reactions) used in the synthesis of
-glycoconjugates. Homogeneous (including one type of biantennary
-glycan fragments) and heterogeneous (containing two to four types of biantennary
-glycan fragments) glycoclusters on albumin were synthesized via this strategy. A series of cell-, tissue- and animal-based experiments proved glycoclusters to be a very promising class of targeted delivery systems. Depending on the oligosaccharide units combined in the cluster, their amount, and arrangement relative to one another, conjugates can recognize various cells, including cancer cells, with high selectivity. These results open new perspectives for affected tissue visualization and treatment.
causes various infectious diseases, from skin impetigo to life-threatening bacteremia and sepsis, thus appearing an important target for antimicrobial therapeutics. In turn, the rapid development of ...antibiotic resistance and biofilm formation makes it extremely robust against treatment. Here, we unravel the molecular mechanism of the antimicrobial activity of the recently unveiled
consisting of three pharmacophores: chlorinated 2(5
)-furanone, sulfone, and
-menthol moieties.
demonstrates highly selective activity against Gram-positive bacteria and biofilm-embedded
and exhibits low risk of resistance development. We show explicitly that the fluorescent analogue of
rapidly penetrates into Gram-positive bacteria independently of their cell integrity and viability and accumulates there. By contrast, Gram-negative bacteria remain impermeable and, therefore, insusceptible to
. Apparently, in bacterial cells,
induces reactive oxygen species (ROS) formation and nonspecifically interacts with a number of proteins, including ROS-utilizing ones. Using native and 2D PAGE, we confirm that
changes the charge of some proteins by either oxidation or direct interaction with them. Therefore, it seems justified to conclude that being simultaneously a ROS inducer and damaging proteins responsible for ROS utilization,
impairs the cellular anti-ROS defense representing a prospective ROS-inducing antibacterial agent.
A previously unknown reduction of carbonyl compounds with dicyclopentylzinc is reported. Aldehydes react in mild conditions yielding corresponding primary alcohols and cyclopentene. Although ...cyclohexanone and acetophenone are inert to dicyclopentylzinc, a variety of heterocyclic ketones reacted readily, yielding reasonable to high yields of corresponding secondary alcohols. When the reaction was catalyzed with (-)-(1
,2
)-ephedrine, 3-acetylpyridine (
) resulted in a high yield of (
)-1-(pyridin-3-yl)ethanol (
) with >99% ee. 5-Acetyl-2-bromopyridine (
) also provided the corresponding optically active alcohol
, albeit with a much lower optical yield. When 10% of
with 92% ee was used as an autocatalyst, 55% yield of the same compound was obtained, with 95% ee and 96% ee in two independent experiments. A three-stage reaction sequence starting from "no chirality" reaction yielded
with 6% ee. Thus, amplifying autocatalysis was detected in the reaction of ketone
with dicylopentylzinc.
In mixed infections, the bacterial susceptibility differs significantly compared to monocultures of bacteria, and generally the concentrations of antibiotics required for the treatment increases ...drastically. For S. aureus and P. aeruginosa dual species biofilms, it has been numerously reported that P. aeruginosa decreases S. aureus susceptibility to a broad range of antibiotics, including beta-lactams, glycopeptides, aminoglycosides, macrolides, while sensitizes to quinolones via secretion of various metabolites. Here we show that S. aureus also modulates the susceptibility of P. aeruginosa to antibiotics in mixed cultures. Thus, S. aureus-P. aeruginosa consortium was characterized by tenfold increase in susceptibility to ciprofloxacin and aminoglycosides compared to monocultures. The same effect could be also achieved by the addition of cell-free culture of S. aureus to P. aeruginosa biofilm. Moreover, similar increase in antibiotics efficacy could be observed following addition of S. aureus suspension to the P. aeruginosa mature biofilm, compared to P. aeruginosa monoculture, and vice versa. These findings open promising perspectives to increase the antimicrobial treatment efficacy of the wounds infected with nosocomial pathogens by the transplantation of the skin residential microflora.
The phenomenon of amplifying asymmetric autocatalysis (AAA) has recently been restricted to alkylation of several specific substrates with diisopropyl zinc (Soai reaction). Targeting the extension of ...the scope of this phenomenon, we studied the reaction of triazolic aldehydes with diisopropyl zinc. Experiments demonstrated a diversity of results for the dissipation of chirality, conserving the existent ee and spontaneous chirality generation. Computational analysis showed that depending on the level of oligomerization of the catalyst, one could expect amplification (monomeric catalyst) while maintaining the existing chirality (dimeric catalyst) or dissipation of chirality (tetrameric catalyst). These findings are promising for the elaboration of synthetic protocols controlling chirality generation. In addition, three optically active triazolic alcohols were characterized.
The frequency of mycoses caused by drug-resistant fungal pathogen
has increased drastically over the last two decades. The spread of drug-resistant strains, along with the limitations of currently ...available antifungals, complicates the management of fungal infections, thereby representing great challenges for clinical healthcare. Among various antimicrobial pharmacophores, 2(5
)-furanone derivatives have demonstrated antimicrobial, antifungal, and antibiofilm activities. In this study, we report the antifungal activity of the 2(5
)-furanone derivative
, consisting of three pharmacophores, namely chlorinated 2(5
)-furanone, sulfonyl group, and
-menthol moiety. Although exhibiting moderate antifungal activity alone with the minimum inhibitory concentration (MIC) values of 32-256 μg/mL,
potentiates the activity of fluconazole and terbinafine with fractional inhibitory concentration index (FICI) values of 0.27-0.50. Thus, 16 μg/mL of
reduced the MICs of these antifungals against fluconazole-resistant
isolates four-fold, achieving similar values as for the intermediately susceptible phenotype. Confocal laser scanning microscopy revealed that the fluorescent 2(5
)-furanone derivative
was also able to penetrate through biofilms formed by
. Indeed, in the presence of
, even sub-MIC concentrations of both fluconazole and terbinafine led to significant reduction of
CFUs in the mature biofilm. Thus,
appears to be a promising candidate for the development of novel antifungal agents as well as enhancers of current antifungal agents, particularly for the treatment of drug-resistant
infections.
Over the past decades, 2(5
)-furanone derivatives have been extensively studied because of their promising ability to prevent the biofilm formation by various pathogenic bacteria. Here, we report the ...synthesis of a series of optically active sulfur-containing 2(5
)-furanone derivatives and characterize their biological activity. Novel thioethers were obtained by an interaction of stereochemically pure 5-(
)-menthyloxy- or 5-(
)-bornyloxy-2(5
)-furanones with aromatic thiols under basic conditions. Subsequent thioethers oxidation by an excess of hydrogen peroxide in acetic acid resulted in the formation of the corresponding chiral 2(5
)-furanone sulfones. The structure of synthesized compounds was confirmed by IR and NMR spectroscopy, HRMS, and single crystal X-ray diffraction. The leading compound,
, possessing the sulfonyl group and
-borneol moiety, exhibited the prominent activity against
and
with MICs of 8 μg/mL. Furthermore, at concentrations of 0.4-0.5 μg/mL, the sulfone
increased two-fold the efficacy of aminoglycosides gentamicin and amikacin against
. The treatment of the model-infected skin wound in the rat with a combination of gentamicin and sulfone
speeded up the bacterial decontamination and improved the healing of the wound. The presented results provide valuable new insights into the chemistry of 2(5
)-furanone derivatives and associated biological activities.
Gram-positive bacteria can cause various infections including hospital-acquired infections. While in the biofilm, the resistance of bacteria to both antibiotics and the human immune system is ...increased causing difficulties in the treatment. Bacillus subtilis, a non-pathogenic Gram-positive bacterium, is widely used as a model organism for studying biofilm formation. Here we investigated the effect of novel synthesized chloro- and bromo-containing 2(5H)-furanones on biofilm formation by B. subtilis. Mucobromic acid (3,4-dibromo-5-hydroxy-2(5H)-furanone) and the two derivatives of mucochloric acid (3,4-dichloro-5-hydroxy-2(5H)-furanone)-F8 and F12-were found to inhibit the growth and to efficiently prevent biofilm formation by B. subtilis. Along with the low production of polysaccharide matrix and repression of the eps operon, strong repression of biofilm-related yqxM also occurred in the presence of furanones. Therefore, our data confirm that furanones affect significantly the regulatory pathway(s) leading to biofilm formation. We propose that the global regulator, Spo0A, is one of the potential putative cellular targets for these compounds.
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