Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression

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.

Synthetic Studies with the Brevicidine and Laterocidine Lipopeptide Antibiotics Including Analogues with Enhanced Properties and in vivo Efficacy

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assay and in vivo infection models.

Rational Design of Carborane-Based Cu2-paddle wheel Coordination Polymers for Increased Hydrolytic Stability

A new unsymmetric carborane based dicarboxylic linker provided a 1D Cu2-paddle wheel coordination polymer (2) with much higher hydrolytic stability than the corresponding 2D Cu2-paddle wheel polymer (1), obtained from...

The Influence of Different Carbonate Ligands on the Hydrolytic Stability and Reduction of Platinum(IV) Prodrugs

Pt(IV) complexes bearing axial carbonate linkages have drawn much attention recently. A synthetic method behind it allows to attach the hydroxyl group of bioactive ligands to the available hydroxyl group...

Influence of Alkali Activator Type on the Hydrolytic Stability and Intumescence of Inorganic Polymers Based on Waste Glass

The main objective of this study is the synthesis and characterization of low cost alkali-activated inorganic polymers based on waste glass (G-AAIPs) using a mixture of NaOH and Ca(OH)2 as alkali activators, in order to improve their hydrolytic stability. This paper also presents detailed information about the influence of composition determined by X Ray Diffraction (XRD), microstructure determined by Scanning Electronic Microscopy (SEM) and processing parameters on the main properties of G-AAIP pastes. The main factors analyzed were the glass fineness and the composition of the alkaline activators. The influence on intumescent behavior was also studied by heat treating of specimens at 600 °C and 800 °C. The use of Ca(OH)2 in the composition of the alkaline activator determines the increase of the hydrolytic stability (evaluated by underwater evolution index) of the G-AAIP materials compared to those obtained by NaOH activation. In this case, along with sodium silicate hydrates, calcium silicates hydrates (C-S-H), with good stability in a humid environment, were also formed in the hardened pastes. The highest intumescence and an improvement of hydrolytic stability (evaluated by underwater evolution index and mass loss) was achieved for the waste glass powder activated with a solution containing 70% NaOH and 30% Ca(OH)2. The increase of the waste glass fineness and initial curing temperature of G-AAIPs have a positive effect on the intumescence of resulted materials but have a reduced influence on their mechanical properties and hydrolytic stability.

RESEARCH OF THERMAL AND THERMOMECHANICAL PROPERTIES OF COPOLYMERS BASED ON PYROMELLITE DIANHYDRIDE, 4,4'-DIAMINODIPHENYLOXIDE AND [2-(AMINOMETHYL)BICYCLO[2.2.1]HEPT-3-YL]ANILINES

The thermal and thermomechanical properties of copolyimides based on pyromellitic dianhydride, 4,4'-diaminodiphenyloxide and [2-(aminomethyl)bicyclo [2.2.1]hept-3-yl]anilines in an inert medium have been studied for the first time. It is shown that the introduction into the structure of aromatic polyimides up to 20 mol %. asymmetric vicinally substituted bicyclic diamines allows to obtain materials with increased hydrolytic stability in comparison with fully aromatic polyimides while maintaining a high level of thermomechanical characteristics.

Oxyamine Linkers for the Protecting Group Free Synthesis of Glycoconjugates

<p>Glycoconjugates, such as glycolipids and glycoproteins, are involved in a variety of cellular functions including cell-to-cell signalling and carbohydrate-protein recognition. Accordingly, glycoconjugates play important roles in health and disease and are promising new leads as carbohydrate-based therapeutics. However, for the development of glycoconjugates to study biological processes, or for the use of these adducts as therapeutics, the glycan needs to be conjugated to the carrier molecule or scaffold of choice. Many procedures for the conjugation of glycans involve lengthy protecting group strategies that install the aglycone at the start of glycan total synthesis and are therefore unsuitable for naturally derived sugars. Other glycan conjugation strategies can affect the integrity of the reducing end sugar or lead to adducts where the reducing end sugar adopts the ring-opened rather than the ring-closed form. N,O-Dialkyl oxyamine linkers, however, can be attached to the free reducing end of sugars in a single step without the need for protecting groups. This thesis therefore explores the synthesis and application of oxyamine linkers for the synthesis of glycoconjugates. First, the synthesis of an O-alkyl-N-methyl oxyamine linker (“Type A”) containing an amine at its terminus was improved by reducing the number of synthetic steps from six to four and by increasing the overall yield from 8% to 38%. This oxyamine linker was then conjugated to GlcNAc in 83% yield. The hydrolytic stability of this glycosyloxyamine was then compared to that of the analogous N-alkyl-O-methyl glycosyloxyamine (“Type B”). The stability of the two types of glycosyloxyamines has never been directly compared. Accordingly, it was not known whether the difference in substitution pattern between the two linkers affects their hydrolytic stability. To this end, the hydrolysis rates of the GlcNAc conjugated linkers were assessed at various pH values, glycoconjugate concentrations and buffer concentrations. In all instances, the “Type B” glycoside was found to have marginally better kinetic stability, while the “Type A” glycoside had marginally better thermodynamic stability, but overall, these differences were negligible. The pKa of the conjugate acid of these glycosyloxyamines was also determined to provide insight into the mechanism of hydrolysis. By considering this data, along with the observation that the rate of hydrolysis of these glycoconjugates increases with increasing buffer concentration, it was proposed that the hydrolysis of the oxyamines occurs via general acid catalysis at pH 4-6. A novel dithiol functionalised oxyamine linker was also designed and synthesised for the multivalent display of glycans on gold nanoparticles. With the successful attachment of this thiol linker to GlcNAc, the monomer unit of chitin, this work has paved the way for the future syntheses of chitin-functionalised gold nanoparticles. Such chitinfunctionalised AuNPs can be used to assess chitin’s ability to invoke the asthma allergic immune response, thereby bringing the possibility of an anti-asthma vaccine a step closer to fruition.</p>

Oxyamine Linkers for the Protecting Group Free Synthesis of Glycoconjugates

<p>Glycoconjugates, such as glycolipids and glycoproteins, are involved in a variety of cellular functions including cell-to-cell signalling and carbohydrate-protein recognition. Accordingly, glycoconjugates play important roles in health and disease and are promising new leads as carbohydrate-based therapeutics. However, for the development of glycoconjugates to study biological processes, or for the use of these adducts as therapeutics, the glycan needs to be conjugated to the carrier molecule or scaffold of choice. Many procedures for the conjugation of glycans involve lengthy protecting group strategies that install the aglycone at the start of glycan total synthesis and are therefore unsuitable for naturally derived sugars. Other glycan conjugation strategies can affect the integrity of the reducing end sugar or lead to adducts where the reducing end sugar adopts the ring-opened rather than the ring-closed form. N,O-Dialkyl oxyamine linkers, however, can be attached to the free reducing end of sugars in a single step without the need for protecting groups. This thesis therefore explores the synthesis and application of oxyamine linkers for the synthesis of glycoconjugates. First, the synthesis of an O-alkyl-N-methyl oxyamine linker (“Type A”) containing an amine at its terminus was improved by reducing the number of synthetic steps from six to four and by increasing the overall yield from 8% to 38%. This oxyamine linker was then conjugated to GlcNAc in 83% yield. The hydrolytic stability of this glycosyloxyamine was then compared to that of the analogous N-alkyl-O-methyl glycosyloxyamine (“Type B”). The stability of the two types of glycosyloxyamines has never been directly compared. Accordingly, it was not known whether the difference in substitution pattern between the two linkers affects their hydrolytic stability. To this end, the hydrolysis rates of the GlcNAc conjugated linkers were assessed at various pH values, glycoconjugate concentrations and buffer concentrations. In all instances, the “Type B” glycoside was found to have marginally better kinetic stability, while the “Type A” glycoside had marginally better thermodynamic stability, but overall, these differences were negligible. The pKa of the conjugate acid of these glycosyloxyamines was also determined to provide insight into the mechanism of hydrolysis. By considering this data, along with the observation that the rate of hydrolysis of these glycoconjugates increases with increasing buffer concentration, it was proposed that the hydrolysis of the oxyamines occurs via general acid catalysis at pH 4-6. A novel dithiol functionalised oxyamine linker was also designed and synthesised for the multivalent display of glycans on gold nanoparticles. With the successful attachment of this thiol linker to GlcNAc, the monomer unit of chitin, this work has paved the way for the future syntheses of chitin-functionalised gold nanoparticles. Such chitinfunctionalised AuNPs can be used to assess chitin’s ability to invoke the asthma allergic immune response, thereby bringing the possibility of an anti-asthma vaccine a step closer to fruition.</p>

Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid β-Ala and Conjugates with Second Pharmacophore

(1) Background: Peptides are good candidates for anticancer drugs due to their natural existence in the body and lack of secondary effects. (KLAKLAK)2 is an antimicrobial peptide that also shows good anticancer properties. (2) Methods: The Solid Phase Peptide Synthesis (Fmoc-strategy) was used for the synthesis of target molecules, analogs of (KLAKLAK)2-NH2. The purity of all compounds was monitored by HPLC, and their structures were proven using mass spectrometry. Cytotoxicity and antiproliferative effects were studied using 3T3 NRU and MTT tests, respectively. For determination of antimicrobial activity, the disc-diffusion method was used. Hydrolytic stability at three pH values, which mimic the physiological pH in the body, was investigated by means of the HPLC technique. (3) Results: A good selective index against MCF-7 tumor cell lines, combined with good cytotoxicity and antiproliferative properties, was revealed for conjugates NphtG-(KLAKLAK)2-NH2 and Caf-(KLAKLAK)2-NH2. The same compounds showed very good antifungal properties and complete hydrolytic stability for 72 h. The compound Caf-(KLβ-AKLβ-AK)2-NH2 containing β-Ala in its structures exhibited good antimicrobial activity against Escherichia coli K12 407 and Bacillus subtilis 3562, in combination with very good antiproliferative and cytotoxic properties, as well as hydrolytic stability. (4) Conclusions: The obtained results reveal that all synthesized conjugates could be useful for medical practice as anticancer or antimicrobial agents.