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1.
Molecules ; 27(21)2022 Oct 26.
Article in English | MEDLINE | ID: mdl-36364103

ABSTRACT

Although many antibiotics are active against Gram-positive bacteria, fewer also show activity against Gram-negative bacteria. Here, we present a combination of in silico (electron ion-interaction potential, molecular docking, ADMET), NMR, and microbiological investigations of selected macrolides (14-membered, 15-membered, and 16-membered), aiming to discover the pattern of design for macrolides active against Gram-negative bacteria. Although the conformational studies of 14-membered and 15-membered macrolides are abundant in the literature, 16-membered macrolides, and their most prominent representative tylosin A, have received relatively little research attention. We therefore report the complete 1H and 13C NMR assignment of tylosin A in deuterated chloroform, as well as its 3D solution structure determined through molecular modelling (conformational search) and 2D ROESY NMR. Additionally, due to the degradation of tylosin A in deuterated chloroform, other species were also detected in 1D and 2D NMR spectra. We additionally studied the anti-bacterial activity of tylosin A and B against selected Gram-positive and Gram-negative bacteria.


Subject(s)
Macrolides , Tylosin , Tylosin/pharmacology , Tylosin/chemistry , Macrolides/chemistry , Anti-Bacterial Agents/chemistry , Chloroform , Escherichia coli/metabolism , Gram-Positive Bacteria/metabolism , Molecular Docking Simulation , Gram-Negative Bacteria/metabolism
2.
J Med Chem ; 65(6): 4783-4797, 2022 03 24.
Article in English | MEDLINE | ID: mdl-35290041

ABSTRACT

A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibitors of N-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound 4 bound well into the colchicine-binding pocket of tubulin. Indeed, 4 suppressed tubulin polymerization, caused G2/M cell cycle arrest, and induced apoptosis. Also, 4 inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with para analogue 5. In accordance with this, the computed free energy of binding of 5 to tubulin was lower in magnitude than that for 4 and appeared to arise in part from the inability of the para substituent to occupy a tubulin subpocket, which is possible in the meta orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (meta versus para). The meta-substituted isoquinolinone 4 is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features.


Subject(s)
Antineoplastic Agents , Tubulin , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation , Colchicine/metabolism , Drug Screening Assays, Antitumor , Microtubules , Molecular Structure , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemistry
3.
Eur J Med Chem ; 182: 111649, 2019 Nov 15.
Article in English | MEDLINE | ID: mdl-31514018

ABSTRACT

(NRH):quinone oxidoreductase 2 (NQO2) is associated with various processes involved in cancer initiation and progression probably via the production of ROS during quinone metabolism. Thus, there is a need to develop inhibitors of NQO2 that are active in vitro and in vivo. As part of a strategy to achieve this we have used the 4-aminoquinoline backbone as a starting point and synthesized 21 novel analogues. The syntheses utilised p-anisidine with Meldrum's acid and trimethyl orthoacetate or trimethyl orthobenzoate to give the 4-hydrazin-quinoline scaffold, which was derivatised with aldehydes or acid chlorides to give hydrazone or hydrazide analogues, respectively. The hydrazones were the most potent inhibitors of NQO2 in cell free systems, some with low nano-molar IC50 values. Structure-activity analysis highlighted the importance of a small substituent at the 2-position of the 4-aminoquinoline ring, to reduce steric hindrance and improve engagement of the scaffold within the NQO2 active site. Cytotoxicity and NQO2-inhibitory activity in vitro was evaluated using ovarian cancer SKOV-3 and TOV-112 cells (expressing high and low levels of NQO2, respectively). Generally, the hydrazones were more toxic than hydrazide analogues and further, toxicity is unrelated to cellular NQO2 activity. Pharmacological inhibition of NQO2 in cells was measured using the toxicity of CB1954 as a surrogate end-point. Both the hydrazone and hydrazide derivatives are functionally active as inhibitors of NQO2 in the cells, but at different inhibitory potency levels. In particular, 4-((2-(6-methoxy-2-methylquinolin-4-yl)hydrazono)methyl)phenol has the greatest potency of any compound yet evaluated (53 nM), which is 50-fold lower than its toxicity IC50. This compound and some of its analogues could serve as useful pharmacological probes to determine the functional role of NQO2 in cancer development and response to therapy.


Subject(s)
Aminoquinolines/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Hydrazones/pharmacology , Quinone Reductases/antagonists & inhibitors , Aminoquinolines/chemical synthesis , Aminoquinolines/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Models, Molecular , Molecular Structure , Quinone Reductases/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured
4.
J Radioanal Nucl Chem ; 317(2): 977-984, 2018.
Article in English | MEDLINE | ID: mdl-30100651

ABSTRACT

N-Methyl carbamoylimidazole is a safe and practical alternative to methyl isocyanate for carbamoylation reactions. We have developed a new chemical route for its synthesis from methyl iodide and applied this to the synthesis of N-[11C]methyl carbamoylimidazole as a new [11C]synthon to radiolabel biomolecules for PET imaging research. N-[11C]methyl carbamoylimidazole was prepared from [11C]methyl iodide in 70-74% radiochemical yield (decay corrected) and can be used in situ for further reaction without purification. The reactivity of N-[11C]methyl carbamoylimidazole was demonstrated in a series of [11C]carbamoylation reactions.

5.
Bioorg Med Chem Lett ; 28(8): 1292-1297, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29567345

ABSTRACT

Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3 µM.


Subject(s)
Amidines/pharmacology , Enzyme Inhibitors/pharmacology , Furans/pharmacology , Quinone Reductases/antagonists & inhibitors , Amidines/chemical synthesis , Amidines/chemistry , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Furans/chemical synthesis , Furans/chemistry , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Oxazoles/pharmacology , Oximes/chemical synthesis , Oximes/chemistry , Oximes/pharmacology , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacology
6.
Cell Chem Biol ; 24(11): 1321-1335.e5, 2017 Nov 16.
Article in English | MEDLINE | ID: mdl-28943355

ABSTRACT

NLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.


Subject(s)
Boron/chemistry , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Animals , Bone Marrow Cells/cytology , Boron/pharmacology , Boron Compounds/chemistry , Boron Compounds/metabolism , Boron Compounds/pharmacology , Calcium/metabolism , Cells, Cultured , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Molecular Conformation , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Structure-Activity Relationship
7.
J Radioanal Nucl Chem ; 311(1): 727-732, 2017.
Article in English | MEDLINE | ID: mdl-28111488

ABSTRACT

Meta-iodobenzylguanidine (mIBG) has been radiolabelled at the no-carrier-added level with [124I] for a proof of concept study to assess the diagnostic accuracy of [124I]mIBG PET/CT in detecting metastatic deposits in patients diagnosed with metastatic neuroblastoma. Radiolabelling of mIBG was achieved via the iododesilylation reaction between [124I]sodium iodide and meta-trimethylsilylbenzylguanidine. [124I]mIBG was produced in 62-70 % radioiodide incorporation yield from [124I]sodium iodide. The average amount of formulated [124I]mIBG was 359 MBq (range 344-389 MBq) with an average specific radioactivity of 4.1 TBq µmol-1 (range 1.8-5.9 TBq µmol-1) at end of synthesis.

8.
Medchemcomm ; 8(3): 551-558, 2017 Mar 01.
Article in English | MEDLINE | ID: mdl-30108771

ABSTRACT

Natural prenylated indoles have been proposed as potential anticancer agents. To exploit this discovery for developing new peptide therapeutics, we report the first studies whereby incorporation of prenylated indoles into primary sequences has been achieved. We developed a route to synthesise Nα-Fmoc-protected tryptophan derivatives in which the prenyl group is linked to the N-indole core, using Pd(ii)-mediated C-H functionalisation of 2-methyl-2-butene. Based on the Substance P antagonist G (SPG), a well-known Small Cell Lung Cancer (SCLC) anticancer agent, we designed a new penta-peptide sequence to include a prenyl moiety on one of the tryptophan residues. The N-tert-prenylated tryptophan analogue was assembled into the pentameric peptide using standard solid phase peptide synthesis or liquid phase synthesis by fragment coupling. In vitro screening showed that the N-tert-prenylation of the indole ring on the tryptophan residue located near the C-terminal of the penta-peptide enhanced the cytotoxicity against H69 (IC50 = 2.84 ± 0.14 µM) and DMS79 (IC50 = 4.37 ± 0.44 µM) SCLC cell lines when compared with the unmodified penta-peptide (H69, IC50 = 30.74 ± 0.30 µM and DMS79, IC50 = 23.00 ± 2.07 µM) or the parent SPG sequence (IC50 > 30 µM, both cell lines). SCLC almost invariably relapses with therapy-resistant disease. The DMS79 cell line was established from a patient following treatment with a number of chemotherapeutics (cytoxan, vincristine and methotrexate) and radiation therapy. Treating DMS79 tumour-bearing nude mice provided a human xenograft model of drug resistance to test the efficacy of the prenylated peptide. A low dose (1.5 mg kg-1) of the prenylated peptide was found to reduce tumour growth by ∼30% (P < 0.05) at day 7, relative to the control group receiving vehicle only. We conclude that the availability of the Fmoc-Trp(N-tert-prenyl)-OH amino acid facilitates the synthesis of prenylated-tryptophan-containing peptides to explore their therapeutic potential.

9.
Eur J Med Chem ; 111: 33-45, 2016 Mar 23.
Article in English | MEDLINE | ID: mdl-26854376

ABSTRACT

NRH:quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer and neurodegenerative diseases, with roles in either chemoprevention or chemotherapy. Here we report the design, synthesis and evaluation of non-symmetrical furan-amidines and their analogues as novel selective NQO2 inhibitors with reduced adverse off-target effects, such as binding to DNA. A pathway for the synthesis of the non-symmetrical furan-amidines was established from the corresponding 1,4-diketones. The synthesized non-symmetrical furan-amidines and their analogues showed potent NQO2 inhibition activity with nano-molar IC50 values. The most active compounds were non-symmetrical furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15 nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized non-symmetrical furan-amidines showed no affinity towards DNA, as demonstrated by DNA melting temperature experiments. In addition, Plasmodium parasites, which possess their own quinone oxidoreductase PfNDH2, were inhibited by the non-symmetrical furan-amidines, the most active possessing a para-fluoro substituent (IC50 9.6 nM). The high NQO2 inhibition activity and nanomolar antimalarial effect of some of these analogues suggest the lead compounds are worthy of further development and optimization as potential drugs for novel anti-cancer and antimalarial strategies.


Subject(s)
Amidines/pharmacology , Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Furans/pharmacology , Malaria/drug therapy , Plasmodium/drug effects , Amidines/chemical synthesis , Amidines/chemistry , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Furans/chemical synthesis , Furans/chemistry , Humans , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship
10.
Nat Commun ; 5: 3742, 2014 Apr 29.
Article in English | MEDLINE | ID: mdl-24776982

ABSTRACT

Variation of mutation rate at a particular site in a particular genotype, in other words mutation rate plasticity (MRP), can be caused by stress or ageing. However, mutation rate control by other factors is less well characterized. Here we show that in wild-type Escherichia coli (K-12 and B strains), the mutation rate to rifampicin resistance is plastic and inversely related to population density: lowering density can increase mutation rates at least threefold. This MRP is genetically switchable, dependent on the quorum-sensing gene luxS--specifically its role in the activated methyl cycle--and is socially mediated via cell-cell interactions. Although we identify an inverse association of mutation rate with fitness under some circumstances, we find no functional link with stress-induced mutagenesis. Our experimental manipulation of mutation rates via the social environment raises the possibility that such manipulation occurs in nature and could be exploited medically.


Subject(s)
Drug Resistance, Bacterial/genetics , Escherichia coli/physiology , Genetic Variation , Microbial Interactions/physiology , Mutation Rate , Rifampin , Analysis of Variance , Bacterial Proteins/metabolism , Carbon-Sulfur Lyases/metabolism , DNA Primers/genetics , Escherichia coli/genetics , Genetic Fitness/genetics , Population Density , Real-Time Polymerase Chain Reaction
11.
Chem Commun (Camb) ; 50(39): 5000-2, 2014 May 21.
Article in English | MEDLINE | ID: mdl-24637781

ABSTRACT

(S)-4,5-Dihydroxypentane-2,3-dione [(S)-DPD, (1)] is a precursor for , a quorum sensing signalling molecule for inter- and intra-species bacterial communication. The synthesis of its fluoro-analogue, 4-fluoro-5-hydroxypentane-2,3-dione () is reported. An intermediate in this route also enables a new, shorter synthesis of the native (S)-DPD. 4-Fluoro-DPD (2) completely inhibited bioluminescence and bacterial growth of Vibrio harveyi BB170 strain at 12.5 µM and 100 µM, respectively.


Subject(s)
Bacterial Physiological Phenomena/drug effects , Biofilms/drug effects , Pentanones/pharmacology , Quorum Sensing/drug effects , Signal Transduction/drug effects , Vibrio/drug effects , Biofilms/growth & development , Luminescent Measurements , Molecular Structure , Pentanones/chemistry , Vibrio/physiology
12.
Bioorg Med Chem ; 22(1): 341-9, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24290974

ABSTRACT

The diethyl ester of [(18)F]ML-10 is a small molecule apoptotic PET probe for cancer studies. Here we report a novel multi-step synthesis of the diethyl ester of ML-10 in excellent yields via fluorination using Xtal-Fluor-E. In addition, a one-pot radiosynthesis of the diethyl ester of [(18)F]ML-10 from nucleophilic [(18)F]fluoride was completed in 23% radiochemical yield (decay corrected). The radiochemical purity of the product was ≥99%. The diethyl ester of [(18)F]ML-10 was used in vivo to detect apoptosis in the testes of mice. In parallel studies, the dansyl-ML-10 diethyl ester was prepared and used to detect apoptotic cells in an in vitro cell based assay.


Subject(s)
Fluorine Radioisotopes , Positron-Emission Tomography/methods , Radiopharmaceuticals , Tomography, X-Ray Computed/methods , Animals , Apoptosis , Esters , Halogenation , Humans , Male , Mice , Radiochemistry
13.
Microb Cell ; 1(7): 250-252, 2014 Jun 25.
Article in English | MEDLINE | ID: mdl-28357250

ABSTRACT

We do not need to rehearse the grim story of the global rise of antibiotic resistant microbes. But what if it were possible to control the rate with which antibiotic resistance evolves by de novo mutation? It seems that some bacteria may already do exactly that: they modify the rate at which they mutate to antibiotic resistance dependent on their biological environment. In our recent study [Krasovec, et al. Nat. Commun. (2014), 5, 3742] we find that this modification depends on the density of the bacterial population and cell-cell interactions (rather than, for instance, the level of stress). Specifically, the wild-type strains of Escherichia coli we used will, in minimal glucose media, modify their rate of mutation to rifampicin resistance according to the density of wild-type cells. Intriguingly, the higher the density, the lower the mutation rate (Figure 1). Why this novel density-dependent 'mutation rate plasticity' (DD-MRP) occurs is a question at several levels. Answers are currently fragmentary, but involve the quorum-sensing gene luxS and its role in the activated methyl cycle.

14.
Carbohydr Res ; 355: 13-8, 2012 Jul 01.
Article in English | MEDLINE | ID: mdl-22578527

ABSTRACT

Ester prodrugs have the potential to eliminate the gastrotoxicity associated with the carboxylic acid group of indomethacin. 4,6-Bis-O-2'-[1'-(4″-chlorobenzoyl)-5'-methoxy-2'-methyl-1'H-indol-3'-acetyl]-myo-inositol-1,3,5-orthoacetate (2) was synthesised and evaluated as a COX-2 inhibitor. It adopts a conformationally restricted chair with two indomethacin groups in the sterically hindered 1,3-diaxial positions. Acid-induced cleavage of the orthoacetate lock of the prodrug leads to a ring flip of the myo-inositol ring with the two indomethacin groups now in 1,3-diequatorial positions. This increases the susceptibility of hydrolysis of the ester groups to release indomethacin under acidic conditions. The long half-life (152 min) of decomposition of (2) at ~pH 1-2 suggests that it may bypass the stomach with minimal hydrolysis upon oral administration. Indomethacin ester (2) was completely stable at pH 4.0-8.5 over 24h at 37°C and showed comparable activity to indomethacin in a COX-2 assay (pH 8.0).


Subject(s)
Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Esters/pharmacology , Indomethacin/analogs & derivatives , Indomethacin/pharmacology , Inositol/pharmacology , Animals , Cyclooxygenase 2 Inhibitors/chemical synthesis , Esters/chemical synthesis , Esters/chemistry , Hydrolysis , Indomethacin/chemistry , Inositol/chemistry , Molecular Structure , Sheep , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 20(8): 2625-8, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20307979

ABSTRACT

The autoinducer (4S)-4,5-dihydroxypentane-2,3-dione ((S)-DPD, AI-2) facilitates chemical communication, termed 'quorum sensing', amongst a wide range of bacteria, The synthesis of (S)-DPD is challenging in part due to its instability. Herein we report a novel synthesis of (S)-DPD via (2S)-2,3-O-isopropylidene glyceraldehyde, through Wittig, dihydroxylation and oxidation reactions, with a complimentary asymmetric synthesis to a key precursor. Its enantiomer (R)-DPD, was prepared from d-mannitol via (2R)-2,3-O-isopropylideneglyceraldehyde. The synthesized enantiomers of DPD have AI-2 bioluminescence-inducing properties in the Vibrio harveyi BB170 strain.


Subject(s)
Pentanones/chemical synthesis , Pentanones/pharmacology , Quorum Sensing , Luminescence , Magnetic Resonance Spectroscopy , Mass Spectrometry , Spectrophotometry, Infrared , Stereoisomerism
16.
Org Biomol Chem ; 6(11): 1966-72, 2008 Jun 07.
Article in English | MEDLINE | ID: mdl-18480912

ABSTRACT

2-O-tert-Butyldimethylsilyl-4,6-bis-O-pyrenoyl-myo-inositol-1,3,5-orthoformate (6) and 2-O-tert-butyldimethylsilyl-4-O-[4-(dimethylamino)benzoyl]-6-O-pyrenoyl-myo-inositol-1,3,5-orthoacetate (10) adopt conformationally restricted unstable chairs with five axial substituents. In the symmetrical diester 6, the two pi-stacked pyrenoyl groups are electron acceptor-donor partners, giving a strong intramolecular excimer emission. In the mixed ester 10, the pyrenoyl group is the electron acceptor and the 4-(dimethylamino)benzoyl ester is the electron donor, giving a strong intramolecular exciplex emission. The conformation of the mixed ester 10 was assessed using 1H NMR spectroscopy (1H-NOESY) and computational studies. which showed the minimum inter-centroid distance between the two aromatic systems to be approximately 3.9 A. Upon addition of acid, the orthoformate/orthoacetate trigger in 6 and 10 was cleaved, which caused a switch of the conformation of the myo-inositol ring to the more stable penta-equatorial chair, leading to separation of the aromatic ester groups and loss of excimer and exciplex fluorescence, respectively. This study provides proof of principle for the development of novel fluorescent molecular probes.


Subject(s)
Inositol/chemistry , Molecular Probes , Fluorescence , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Spectrometry, Mass, Electrospray Ionization
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