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1.
Inorg Chem ; 62(3): 1218-1225, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36630536

RESUMO

The organo-functionalization of metal oxides is a key strategy to introduce new functionalities. Often, phosphonates are used to anchor organic moieties to a range of metal oxides. Despite their widespread use, there is a lack of understanding of the parameters which enable selective and efficient formation of organophosphonate-metal oxide hybrids. Here, we report fundamental insights into the mechanism of phosphonate anchoring to a molecular metal oxide model. Specifically, we use in situ 31P NMR spectroscopy to follow the acid-catalyzed deprotection of a model phosphonate and its subsequent condensation to form a phosphonate-functionalized Dawson-polyoxometalate. Our study shows that the nucleophilicity of the acid anion is a key parameter which controls the clean and selective deprotection and polyoxometalate attachment of phosphonates. This insight will allow researchers to expand the scope of phosphonate anchoring to metal oxides by enabling the development of mild and scalable syntheses.


Assuntos
Organofosfonatos , Organofosfonatos/química , Ácidos Fosforosos/química , Óxidos/química , Catálise
2.
Braz. j. biol ; 83: e242830, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1278540

RESUMO

Abstract Pesticide residues that contaminate the environment circulate within the hydrological cycle can accumulate within the food chain and cause problems to both environmental and human health. Microbes, however, are well known for their metabolic versatility and the ability to degrade chemically stable substances, including recalcitrant xenobiotics. The current study focused on bio-prospecting within Amazonian rainforest soils to find novel strains fungi capable of efficiently degrading the agriculturally and environmentally ubiquitous herbicide, glyphosate. Of 50 fungal strains isolated (using culture media supplemented with glyphosate as the sole carbon-substrate), the majority were Penicillium strains (60%) and the others were Aspergillus and Trichoderma strains (26 and 8%, respectively). All 50 fungal isolates could use glyphosate as a phosphorous source. Eight of these isolates grew better on glyphosate-supplemented media than on regular Czapek Dox medium. LC-MS revealed that glyphosate degradation by Penicillium 4A21 resulted in sarcosine and aminomethylphosphonic acid.


Resumo Resíduos de agrotóxicos que contaminam o meio ambiente circulam no ciclo hidrológico, podendo se acumular na cadeia alimentar e causar problemas tanto à saúde ambiental quanto humana. Por sua vez, microrganismos são bem conhecidos por sua versatilidade metabólica e capacidade de degradar substâncias quimicamente estáveis, incluindo xenobióticos recalcitrantes. O estudo atual se concentrou na bioprospecção nos solos da floresta amazônica para encontrar novas linhagens de fungos capazes de degradar com eficiência o herbicida onipresente na agricultura e no meio ambiente, o glifosato. Entre os 50 fungos isolados (usando meio de cultura suplementado com glifosato como única fonte de carbono), a maioria eram isolados do gênero Penicillium (60%) e os outros eram isolados de Aspergillus e Trichoderma (26 e 8%, respectivamente). Todos os 50 isolados de fungos foram capazes de usar glifosato como fonte de fósforo. Oito desses isolados cresceram melhor em meio suplementado com glifosato do que em meio Czapek Dox regular. LC-MS revelou que a degradação do glifosato por Penicillium 4A21 resultou nos metabólitos sarcosina e ácido aminometilfosfônico.


Assuntos
Humanos , Penicillium , Trichoderma , Herbicidas/toxicidade , Aspergillus , Solo , Microbiologia do Solo , Biodegradação Ambiental , Organofosfonatos , Fungos , Glicina/análogos & derivados
3.
Eur J Med Chem ; 245(Pt 1): 114891, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36343412

RESUMO

Unique coumarin aminophosphonates as new antibacterial agents were designed and synthesized to combat severely bacterial resistance. Bioactivity assessment identified that 3-hydroxylphenyl aminophosphonate 6f with low hemolytic activity not only exhibited excellent inhibition potency against Staphylococcus aureus at low concentration (0.5 µg/mL) in vitro but also showed considerable antibacterial potency in vivo. Meanwhile, the active compound 6f was capable of eradicating the S. aureus biofilm, thus alleviating the development of S. aureus resistance. Furthermore, the drug combination of compound 6f with norfloxacin could enhance the antibacterial efficacy. Mechanistic explorations manifested that molecule 6f was able to destroy the integrity of cell membrane, which resulted in the leakage of protein and metabolism inhibition. The cellular redox homeostasis was interfered through inducing the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to the reduction of glutathione (GSH) activity and lipid peroxidation. Furthermore, compound 6f could intercalate into DNA base pair to hinder normal biological function. The above results provided powerful information for the further development of coumarin aminophosphonates as antibacterial agents.


Assuntos
Aminocumarinas , Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Organofosfonatos , Antibacterianos/química , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Aminocumarinas/química , Aminocumarinas/farmacologia , Farmacorresistência Bacteriana , Organofosfonatos/química , Organofosfonatos/farmacologia
4.
Mol Pharm ; 20(1): 370-382, 2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36484496

RESUMO

DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize ß-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC50 for 24 h. These experiments identified a novel lead candidate, NPP-669. NPP-669 demonstrated efficacy against CMV infections in mice and AdV infections in hamsters following oral (p.o.) dosing at a dose of 1 mg/kg BID and 0.1 mg/kg QD, respectively. We further showed that NPP-669 at 30 mg/kg QD did not exhibit histological signs of toxicity in mice or hamsters. These data suggest that NPP-669 is a promising lead candidate for a broad-spectrum antiviral compound.


Assuntos
Infecções por Citomegalovirus , Organofosfonatos , Pró-Fármacos , Camundongos , Humanos , Animais , Antivirais/farmacocinética , Disponibilidade Biológica , Pró-Fármacos/farmacologia , Citosina , Cidofovir
5.
Molecules ; 27(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36500224

RESUMO

Two silver(I) complexes, bis{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3:κN4-amino) (4-trifluoromethylphenyl)methyl]phosphonate-(tetrafluoroborato-κF)}-di-silver(I) and tetrakis-{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3-amino)(4-trifluoromethylphenyl)methyl]phosphonate} silver(I) tetrafluoroborate, were prepared starting from the diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-amino)(4-trifluoromethylphenyl)methyl]phosphonate (1) ligand and AgBF4 salt in Ag/ligand ratios of 1/1 and 1/4, respectively. The structure, stoichiometry, and geometry of the silver complexes were fully characterized by elemental analyses, infrared, single-crystal X-ray diffraction studies, multinuclear NMR, and mass spectroscopies. The binuclear complex ([Ag2(1)2(BF4)2]; 2) crystallizes in the monoclinic asymmetric space group P21/c and contains two silver atoms adopting a {AgN2F} planar trigonal geometry, which are simultaneously bridged by two oxadiazole rings of two ligands, while the mononuclear complex ([Ag(1)4]BF4; 3) crystallizes in the non-usual cubic space group Fd-3c in which the silver atom binds to four distinct electronically enriched nitrogen atoms of the oxadiazole ring, in a slightly distorted {AgN4} tetrahedral geometry. The α-aminophosphonate and the monomeric silver complex were evaluated in vitro against MCF-7 and PANC-1 cell lines. The silver complex is promising as a drug candidate for breast cancer and the pancreatic duct with half-maximal inhibitory concentration (IC50) values of 8.3 ± 1.0 and 14.4 ± 0.6 µM, respectively. Additionally, the interactions of the ligand and the mononuclear complex with Vascular Endothelial Growth Factor Receptor-2 and DNA were evaluated by molecular docking methods.


Assuntos
Organofosfonatos , Prata , Prata/farmacologia , Prata/química , Ligantes , Oxidiazóis/farmacologia , Simulação de Acoplamento Molecular , Fator A de Crescimento do Endotélio Vascular , Organofosfonatos/farmacologia
6.
Molecules ; 27(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36500470

RESUMO

The cyclotron production of gallium-68 via the 68Zn(p,n)68Ga nuclear reaction in liquid targets is gaining significant traction in clinics. This work describes (1) the synthesis of new arylamino phosphonates via the Kabachnik-Fields reaction, (2) their use for liquid-liquid extraction of 68Ga from 1 M Zn(NO3)2/0.01 M HNO3 in batch and continuous flow, and (3) the use of Raman spectroscopy as a process analytical technology (PAT) tool for in-line measurement of 68Zn. The highest extraction efficiencies were obtained with the extractants functionalized with trifluoromethyl substituents and ethylene glycol ponytails, which were able to extract up to 90% of gallium-68 in batch and 80% in flow. Only ppm amounts of zinc were co-extracted. The extraction efficiency was a function of pKa and the aqueous solubility of the extractant and showed marked concentration, solvent, and temperature dependence. Raman spectroscopy was found to be a promising PAT tool for the continuous production of gallium-68.


Assuntos
Gálio , Organofosfonatos , Radioisótopos de Gálio/química , Zinco/química , Extração Líquido-Líquido
7.
Acta Chim Slov ; 69(4): 735-755, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36562156

RESUMO

Several multicomponent synthetic approaches were elaborated for plenty of novel nitrogen or oxygen heterocycles containing a phosphonate or a phosphine oxide moiety. All multicomponent reactions were optimized through a model reaction in respect of the heating mode, molar ratio of the starting materials, atmosphere, catalyst, temperature, reaction time and solvent applied, and then, the extended preparation of small libraries of structurally-related compounds was performed. Most of the reactions could be considered as "green syntheses", as they were carried out in the absence of any catalyst and/or solvent using microwave (MW) irradiation or even at ambient temperature. The scaling-up of a MW-assisted synthesis was also elaborated in a continuous flow MW system. Altogether more than 150 heterocyclic organophosphorus compounds were synthesized, among them several derivatives showed moderate or promising activity against the HL-60 cell line and Bacillus subtilis bacteria.


Assuntos
Compostos Heterocíclicos , Organofosfonatos , Óxidos , Solventes
8.
Viruses ; 14(11)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36366582

RESUMO

That cidofovir, an acyclic nucleoside phosphonate (ANP), was inhibitory to the replication of poxviruses was first demonstrated by De Clercq et al.. That its active metabolite, the diphosphate, was found to be inhibitory to the molluscum contagiosum (M. contagiosum) DNA polymerase was demonstrated by Watanabe and Tamaki. Twelve different independent observations have then indicated that cidofovir administered intravenously, topically or intralesionally is efficacious in the treatment of M. contagiosum mostly in immunosuppressed patients.


Assuntos
Molusco Contagioso , Vírus do Molusco Contagioso , Organofosfonatos , Humanos , Cidofovir/uso terapêutico , Citosina , Organofosfonatos/uso terapêutico , Molusco Contagioso/tratamento farmacológico
9.
J Pharmacol Sci ; 150(4): 223-232, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36344044

RESUMO

Oroxylin-A (OroA), a flavonoid isolated from Scutellariae baicalensis, alleviates cardiovascular dysfunction. Several procedures for synthesizing OroA have been developed but show low production yield and regioselectivity. We synthesized OroA from baicalin using a one-pot reaction to increase its overall yield. We also determined the chemical properties and mechanism of action of the synthesized OroA and OroA phosphate diethyl ester (OroA-OET) in vascular function. The induction of vascular reactivity by OroA and OroA-OET was evaluated using blood vessel myography and biochemical analysis to assess nitric oxide synthase-mediated nitric oxide production in mouse aortic arteries. OroA and OroA-OET (0.1-30 µM) induced sustained vasorelaxation, which was partly mediated by the endothelium in isolated normal arteries pre-contracted with phenylephrine. OroA and OroA-OET significantly attenuated vasoconstrictors-induced contractile responses. Dilation effects were blocked by the non-selective nitric oxide synthase inhibitor N (omega)-nitro-l-arginine methyl ester but not by tetraethylammonium or 1H-(1,2,4)oxadiazolo [4,3-a]quinoxalin-1-one. Notably, preincubation with OroA and OroA-OET potentiated acetylcholine-induced relaxation and endothelial nitric oxide production in the arteries with the endothelium. OroA and OroA-OET protected against cardiovascular dysfunction. The synthesis and lead compounds used not only improved the yield of OroA from natural sources but also potentially regulated vascular tone.


Assuntos
Organofosfonatos , Vasoconstritores , Camundongos , Animais , Vasoconstritores/farmacologia , Óxido Nítrico/farmacologia , Organofosfonatos/farmacologia , Óxido Nítrico Sintase Tipo III , Aorta , Flavonoides/farmacologia , Óxido Nítrico Sintase , Vasodilatação , Endotélio Vascular , NG-Nitroarginina Metil Éster/farmacologia
10.
Mar Drugs ; 20(11)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36354981

RESUMO

The first total synthesis of loroxanthin (1) was accomplished by Horner-Wadsworth-Emmons reaction of C25-apocarotenal 8 having a silyl-protected 19-hydroxy moiety with C15-phosphonate 25 bearing a silyl-protected 3-hydroxy-ε-end group. Preparation of apocarotenal 8 was achieved via Stille coupling reaction of alkenyl iodide 10 with alkenyl stananne 9, whereas phosphonate 25 was prepared through treatment of ally alcohol 23 with triethyl phosphite and ZnI2. The ally alcohol 23 was derived from the known (3R,6R)-3-hydroxy C15-aldehyde 20, which was obtained by direct optical resolution of racemate 20 using a semi-preparative chiral HPLC column.


Assuntos
Carotenoides , Organofosfonatos , Estereoisomerismo
11.
Org Biomol Chem ; 20(45): 8843-8848, 2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-36326057

RESUMO

Catalytic asymmetric hydrogenation of α- and ß-enamido phosphonates was developed using a complex formed in situ through a chiral hybrid phosphine-bicyclic bridgehead phosphoramidite ligand and rhodium metal precursor as the catalyst. This strategy afforded a wide variety of substrates in excellent yield (96-99%) and enantiomeric excess (≤99%) with very low catalyst loading (S/C up to 10 000) and relatively mild reaction conditions. Further investigations suggested that the hydrogenation reaction occurred only at the CC bond of the enamido phosphate stage without tautomerization to the imine form. Tandem hydrolysis reactions of hydrogenated products gave the corresponding α- and ß-amino phosphonic acids in fairly high yield, which could be multipurpose building blocks for bioorganic chemistry, medicinal chemistry and organic synthesis.


Assuntos
Organofosfonatos , Ródio , Organofosfonatos/química , Hidrogenação , Ródio/química , Estereoisomerismo , Aminoácidos , Aminas , Catálise
12.
Curr Protoc ; 2(11): e602, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36440983

RESUMO

We present an improved synthesis of (S)-HPMPA (1) from an easily accessible and commercially available compound, (S)-3-(benzyloxy)propane-1,2-diol (10). Tritylation of primary alcohol 10 was highly selective, and pure product was isolated in good yield. Alkylation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) with diethyl p-toluenesulfonyloxymethyl phosphonate (6) using sodium hydride in tetrahydrofuran followed by detritylation afforded the desired chiral synthon 12. Tosylation of the primary alcohol and subsequent reaction with sodium adeninate afforded protected S-HPMPA (14). Global deprotection using concentrated hydrochloric acid in a sealed tube afforded S-HPMA (1), and the deprotected 1 was crystallized from water and acetone to obtain a 99% pure product. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) Basic Protocol 2: Preparation of diethyl (S)-(((1-(benzyloxy)-3-hydroxypropan-2-yl)oxy)methyl)phosphonate (12) Basic Protocol 3: Preparation of (R)-3-(benzyloxy)-2-((diethoxyphosphoryl)methoxy)propyl-4-methylbenzenesulfonate (13) Basic Protocol 4: Preparation of diethyl (S)-(((1-(6-amino-9H-purin-9-yl)-3-(benzyloxy)propan-2-yl)oxy)methyl)phosphonate (14) Support Protocol 1: Preparation of sodium adeninate Basic Protocol 5: Preparation of (S)-(((1-(6-amino-9H-purin-9-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid (1).


Assuntos
Antivirais , Organofosfonatos , Antivirais/farmacologia , Adenina , 2-Propanol , Etanol , Sódio
13.
Molecules ; 27(22)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36432015

RESUMO

A series of pyrazolo[1,5-a]pyridine-3-ylphosphonates were prepared with moderate to good yields by the oxidative [3+2]cycloaddition of 2-subtituted ethynylphosphonates with in situ generated pyridinium-N-imines and their annulated analogs. 2-Aliphatic and 2-Ph acetylenes demonstrate low activity, and the corresponding pyrazolopyridines were achieved with a moderate yield in the presence of 10 mol% Fe(NO3)3·9H2O. At the same time, tetraethyl ethynylbisphosphonate, diethyl 2-TMS- and 2-OPh-ethynylphosphonates possess much greater reactivity and the corresponding pyrazolo[1,5-a]pyridines, and their annulated derivatives were obtained with good to excellent yields without any catalyst. 2-Halogenated ethynylphosphonates also readily reacted with pyridinium-N-imines, forming complex mixtures containing poor amounts of 2-halogenated pyrazolopyridines.


Assuntos
Iminas , Organofosfonatos , Reação de Cicloadição , Estrutura Molecular , Piridinas , Estresse Oxidativo
14.
Molecules ; 27(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36432120

RESUMO

An efficient general method for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid bearing tetrasubstituted carbons is reported through an aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates, in an umpolung process. In addition, the α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma). In view of the possibilities in the diversity of the substituents that offer the synthetic methodology, an extensive profile structure-activity is presented, measuring IC50 values up to 0.34 µM in the A549 and 9.8 µM in SKOV3 cell lines.


Assuntos
Antineoplásicos , Organofosfonatos , Humanos , Ácido Aspártico/farmacologia , Fósforo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral
15.
Int J Mol Sci ; 23(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36361974

RESUMO

Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (AcPMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine, and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. A comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in freezing time are most pronounced after administration of methyl acetylphosphinate and dimethyl acetylphosphonate. The PDHC inhibitors do not significantly change the levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation, but increase total protein succinylation and glutarylation, affecting sirtuin 5 expression. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compensated by increased degradation of amino acids through the activated OGDHC, increasing total protein succinylation/glutarylation. Simultaneously, parasympathetic activity and anxiety indicators decrease.


Assuntos
Aminoácidos , Organofosfonatos , Complexo Piruvato Desidrogenase/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Piruvatos/farmacologia , Homeostase , Encéfalo/metabolismo
16.
Curr Opin Infect Dis ; 35(6): 530-535, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36206151

RESUMO

PURPOSE OF REVIEW: This review summarizes the literature on acyclovir resistant herpes infections and the most recent data pertinent to diagnosis and treatment in the immunocompromised patient population. RECENT FINDINGS: Although fairly rare, acyclovir resistant herpes infections can be challenging to diagnose. Clinicians should be aware of this entity when facing refractory herpes infections. With updated diagnostics, the diagnosis is usually made through viral culture and sequencing. Therapeutic choices depend on the extent of disease. Topical therapy may be appropriate for mucocutaneous disease. Intravenous antiviral therapies such as foscarnet and cidofovir may be necessary for disseminated, ophthalmologic, central nervous system, or visceral disease. Experimental therapies such as pritelivir are in clinical trials. SUMMARY: Immunosuppressed patients are at risk for developing acyclovir-resistant herpes, which can be challenging to diagnose and treat, although emerging therapeutic options look promising.


Assuntos
Herpes Simples , Infecções por Herpesviridae , Organofosfonatos , Humanos , Organofosfonatos/uso terapêutico , Citosina/uso terapêutico , Aciclovir/uso terapêutico , Foscarnet/uso terapêutico , Antivirais/uso terapêutico , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico
17.
J Med Chem ; 65(20): 13813-13832, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36251833

RESUMO

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.


Assuntos
Glioblastoma , Glioma , Organofosfonatos , Pró-Fármacos , Humanos , Pró-Fármacos/uso terapêutico , Pró-Fármacos/farmacocinética , Organofosfonatos/farmacologia , Homozigoto , Deleção de Sequência , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Glioblastoma/tratamento farmacológico , Ésteres , Lipídeos , Proteínas de Ligação a DNA , Biomarcadores Tumorais , Proteínas Supressoras de Tumor/genética
18.
J Org Chem ; 87(21): 14793-14808, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36283025

RESUMO

A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC50) 59 ± 17 µM), while the other prodrugs were inactive at 100 µM. A racemic bispivaloyloxymethyl methyl ester monophosphonate prodrug was also prepared to assess the suitability of the methyl ester as a carboxylic acid prodrug. This compound exhibited no activity against HIV in cellular assays.


Assuntos
Fármacos Anti-HIV , Organofosfonatos , Pró-Fármacos , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia , Nucleosídeos/farmacologia , Ésteres , Fármacos Anti-HIV/farmacologia
19.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234748

RESUMO

A series of 5'-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, H-phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the 1,2,3-triazole-4-yl-ß-D-ribofuranose fragment is attached via a methylene group or a butylene chain to the N-1 atom of the heterocycle moiety (uracil or quinazoline-2,4-dione) was synthesized. All compounds were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1). Antiviral assays revealed three compounds, 13b, 14b, and 17a, which showed moderate activity against influenza virus A (H1N1) with IC50 values of 17.9 µM, 51 µM, and 25 µM, respectively. In the first two compounds, the quinazoline-2,4-dione moiety is attached via a methylene or a butylene linker, respectively, to the 1,2,3-triazole-4-yl-ß-D-ribofuranosyl fragment possessing a 5'-diphenyl phosphate substituent. In compound 17a, the uracil moiety is attached via the methylene unit to the 1,2,3-triazole-4-yl-ß-D-ribofuranosyl fragment possessing a 5'-(phenyl methoxy-L-alaninyl)phosphate substituent. The remaining compounds appeared to be inactive against influenza virus A/PR/8/34/(H1N1). The results of molecular docking simulations indirectly confirmed the literature data that the inhibition of viral replication is carried out not by nucleoside analogues themselves, but by their 5'-triphosphate derivatives.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Organofosfonatos , Alcenos , Antivirais/farmacologia , Simulação de Acoplamento Molecular , Nucleosídeos/farmacologia , Fosfatos , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia , Uracila
20.
Molecules ; 27(19)2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36235061

RESUMO

Dipolar cycloaddition of the N-substituted C-(diethoxyphosphonyl)nitrones with N3-allyl-N1-benzylquinazoline-2,4-diones produced mixtures of diastereoisomeric 3-(diethoxyphosphonyl)isoxazolidines with a N1-benzylquinazoline-2,4-dione unit at C5. The obtained compounds were assessed for antiviral and antibacterial activities. Several compounds showed moderate inhibitory activities against VZV with EC50 values in the range of 12.63-58.48 µM. A mixture of isoxazolidines cis-20c/trans-20c (6:94) was found to be the most active against B. cereus PCM 1948, showing an MIC value 0.625 mg/mL, and also was not mutagenic up to this concentration.


Assuntos
Herpes Zoster , Organofosfonatos , Antibacterianos/farmacologia , Antivirais/farmacologia , Herpesvirus Humano 3 , Humanos , Quinazolinas/farmacologia
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