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1.
Med Chem Res ; 31(7): 1154-1175, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36389181

RESUMEN

Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-Bromo (GRG-1-34, 6e), 4-Chloro (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1-34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5 hours after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.

2.
J Biol Chem ; 293(8): 2755-2769, 2018 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-29301937

RESUMEN

An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of cyclipostins and cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex (i.e. Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC7ß, CyC8ß, and CyC17 bind covalently to the catalytic Ser124 residue in Ag85C; inhibit mycolyltransferase activity (i.e. the transfer of a fatty acid molecule onto trehalose); and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC8ß disclosed that this inhibitor occupies Ag85C's substrate-binding pocket. Importantly, metabolic labeling of M. tuberculosis cultures revealed that the CyC compounds impair both trehalose dimycolate synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex in vitro and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against M. tuberculosis.


Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Antituberculosos/farmacología , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Mycobacterium tuberculosis/efectos de los fármacos , Compuestos Organofosforados/farmacología , Acilación/efectos de los fármacos , Aciltransferasas/genética , Aciltransferasas/metabolismo , Sustitución de Aminoácidos , Antígenos Bacterianos/genética , Antígenos Bacterianos/metabolismo , Antituberculosos/química , Antituberculosos/metabolismo , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Ligandos , Viabilidad Microbiana/efectos de los fármacos , Conformación Molecular , Mutación , Mycobacterium tuberculosis/citología , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/metabolismo , Compuestos Organofosforados/química , Compuestos Organofosforados/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Serina/química
3.
J Am Soc Mass Spectrom ; 30(11): 2306-2317, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31399941

RESUMEN

We investigate the gas-phase structures and fragmentation pathways of model compounds of anthracene derivatives of the general formula CcHhN1 utilizing tandem mass spectrometry and computational methods. We vary the substituent alkyl chain length, composition, and degree of branching. We find substantial experimental and theoretical differences between the linear and branched congeners in terms of fragmentation thresholds, available pathways, and distribution of products. Our calculations predict that the linear substituents initially isomerize to form lower energy branched isomers prior to loss of the alkyl substituents as alkenes. The rate-determining chemistry underlying these related processes is dominated by the ability to stabilize the alkene loss transition structures. This task is more effectively undertaken by branched substituents. Consequently, analyte lability systematically increased with degree of branching (linear < secondary < tertiary). The resulting anthracen-9-ylmethaniminium ion generated from these alkene loss reactions undergoes rate-limiting proton transfer to enable expulsion of either hydrogen cyanide or CNH. The combination of the differences in primary fragmentation thresholds and degree of radical-based fragmentation processes provide a potential means of distinguishing compounds that contain branched alkyl chain substituents from those with linear ones.

4.
Sci Rep ; 7(1): 11751, 2017 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-28924204

RESUMEN

A new class of Cyclophostin and Cyclipostins (CyC) analogs have been investigated against Mycobacterium tuberculosis H37Rv (M. tb) grown either in broth medium or inside macrophages. Our compounds displayed a diversity of action by acting either on extracellular M. tb bacterial growth only, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth with very low toxicity towards host macrophages. Among the eight potential CyCs identified, CyC 17 exhibited the best extracellular antitubercular activity (MIC50 = 500 nM). This compound was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 23 potential candidates, most of them being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA and HsaD, have previously been reported as essential for in vitro growth of M. tb and/or survival and persistence in macrophages. Overall, our findings support the assumption that CyC 17 may thus represent a novel class of multi-target inhibitor leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes participating in important physiological processes.


Asunto(s)
Antituberculosos , Macrófagos/microbiología , Mycobacterium tuberculosis/crecimiento & desarrollo , Compuestos Organofosforados , Tuberculosis/tratamiento farmacológico , Antituberculosos/química , Antituberculosos/farmacología , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Tuberculosis/metabolismo , Tuberculosis/patología
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