Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 56
Filtrar
1.
Cytokine ; 171: 156373, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37776719

RESUMEN

Leishmania major and L. donovani cause cutaneous leishmaniasis and visceral leishmaniasis, respectively. Available chemotherapies suffer from toxicity, drug-resistance or high cost of production prompting the need for the discovery of new anti-leishmanials. Here, we test a novel aminosteriodal compound- 3-alpha-amino-cholestane [3AC] - that shows selective inhibition of SHIP1, an inositol-5'-phosphate-specific phosphatase with potent effects on the immune system. We report that 3AC-sensitive SHIP1 expression increases in Leishmania-infected macrophages. Treatment of BALB/c mice, a Leishmania-susceptible host, with 3AC increased anti-leishmanial, but reduced pro-leishmanial, cytokines' production and reduced the parasite load in both L. major and L. donovani infections. These findings implicate SHIPi as a potential novel immunostimulant with anti-leishmanial function.


Asunto(s)
Leishmania donovani , Leishmaniasis Visceral , Animales , Ratones , Leishmaniasis Visceral/tratamiento farmacológico , Ratones Endogámicos BALB C
2.
Molecules ; 28(24)2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-38138538

RESUMEN

The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer's disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1. A series of similar SHIP1 activators have been synthesized and evaluated to determine structure-activity relationships and improve in vivo stability. Some new analogs have now been found with improved potency. In addition, both the thiophene and the thiomorpholine in the parent structure can be replaced by groups without a low valent sulfur atom, which provides a way to access activators that are less prone to oxidative degradation.


Asunto(s)
Monoéster Fosfórico Hidrolasas , Monoéster Fosfórico Hidrolasas/metabolismo
3.
J Cell Sci ; 133(5)2020 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-31780579

RESUMEN

We show here that both SHIP1 (Inpp5d) and its paralog SHIP2 (Inppl1) are expressed at protein level in microglia. To examine whether targeting of SHIP paralogs might influence microglial physiology and function, we tested the capacity of SHIP1-selective, SHIP2-selective and pan-SHIP1/2 inhibitors for their ability to impact on microglia proliferation, lysosomal compartment size and phagocytic function. We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size, and phagocytosis of dead neurons and amyloid beta (Aß)1-42 by microglia in vitro We show that one of the more-potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier. Consistent with this, K161 increases the capacity of CNS-resident microglia to phagocytose Aß and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible, and suggest that dual inhibition of the SHIP1 and 2 paralogs can provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's disease and, possibly, other types of dementia where increased microglial function could be beneficial.


Asunto(s)
Enfermedad de Alzheimer , Microglía , Péptidos beta-Amiloides , Homeostasis , Humanos , Fagocitosis
4.
Org Biomol Chem ; 20(10): 2131-2136, 2022 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-35229852

RESUMEN

N-Alkylation of isatins can be achieved utilizing trichloroacetimidate electrophiles and a Lewis acid catalyst. These reactions provide access to N-alkyl isatins, versatile scaffolds which are often employed in the synthesis of pharmaceutical lead structures as well as natural products. Secondary trichloroacetimidates that are precursors to stabilized carbocations provided excellent yields of the isatin product. Substitution was well tolerated on the isatin, although reduced reactivity was observed with C7-substitution, likely due to the steric effects. Solvent effects can be used to favor O-alkylation under similar reaction conditions.

5.
Org Biomol Chem ; 20(19): 4016-4020, 2022 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-35506893

RESUMEN

AQX-1125 is an indane based SHIP1 agonist that has been evaluated in the clinic for the treatment of bladder pain syndrome/interstitial cystitis. To support our own studies on SHIP1 agonists as potential treatments for IBD and Crohn's disease, a new synthetic route to the SHIP1 agonist AQX-1125 has been developed. This sequence utilizes a hydroxy-acid intermediate which allows for ready differentiation of the C6 and C7 positions. The role of the C17 alkene in the biological activity of the system is also investigated, and this functional group is not required for SHIP1 agonist activity. While AQX-1125 shows SHIP1 agonist activity in enzyme assays, it does not show activity in cell based assays similar to other SHIP1 agonists, which limits the utility of this molecule.


Asunto(s)
Ciclohexanoles , Monoéster Fosfórico Hidrolasas , Indanos
6.
Molecules ; 27(23)2022 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-36500543

RESUMEN

Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Monoéster Fosfórico Hidrolasas/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Fosforilación , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Línea Celular
7.
Org Biomol Chem ; 19(28): 6233-6236, 2021 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-34231623

RESUMEN

Tertiary benzylic alcohols react with oxoammonium salts, undergoing a tandem elimination/allylic oxidation to provide an allylic ether product in a single step. This mode of reactivity provides a rapid entry into allylic ethers from certain benzylic tertiary alcohols. The allylic ether may be cleaved under reductive conditions to reveal the allylic alcohol.

8.
J Immunol ; 202(1): 11-19, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30587569

RESUMEN

After decades of intense effort, therapeutics that leverage the immune system to fight cancer have now been conclusively demonstrated to be effective. Immuno-oncology has arrived and will play a key role in the treatment of cancer for the foreseeable future. However, the search for novel methods to improve immune responses to cancer continues unabated. Toward this end, small molecules that can either reduce immune suppression in the tumor milieu or enhance activation of cytotoxic lymphocyte responses to the tumor are actively being pursued. Such novel treatment strategies might be used as monotherapies or combined with other cancer therapies to increase and broaden their efficacy. In this article, we provide an overview of small molecule immunotherapeutic approaches for the treatment of cancer. Over the next decade and beyond, these approaches could further enhance our ability to harness the immune system to combat cancer and thus become additional weapons in the oncologist's armory.


Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Quimioterapia Combinada , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Inmunización , Neoplasias/inmunología , Microambiente Tumoral/efectos de los fármacos
9.
Tetrahedron Lett ; 772021 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-34334833

RESUMEN

Pyrroloindolines and related systems are present in a large number of complex natural products. These core structures have generated considerable synthetic interest, as many of the compounds possess challenging, elaborate structures and interesting biological properties. Recently we have focused on using trichloroacetimidates for the synthesis of these fascinating molecules. Trichloroacetimidates can be used as an electrophilic source of an alkyl group to form the pyrroloindoline directly from tryptamine derivatives. In this manner trichloroacetimidates provide a flexible solution to forming highly functionalized pyrroloindoline core structures, needing only a catalytic amount of a Lewis acid to effect the requisite transformations.

10.
Biochem Soc Trans ; 48(1): 291-300, 2020 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-32049315

RESUMEN

Modulating the activity of the Src Homology 2 (SH2) - containing Inositol 5'-Phosphatase (SHIP) enzyme family with small molecule inhibitors provides a useful and unconventional method of influencing cell signaling in the PI3K pathway. The development of small molecules that selectively target one of the SHIP paralogs (SHIP1 or SHIP2) as well as inhibitors that simultaneously target both enzymes have provided promising data linking the phosphatase activity of the SHIP enzymes to disorders and disease states that are in dire need of new therapeutic targets. These include cancer, immunotherapy, diabetes, obesity, and Alzheimer's disease. In this mini-review, we will provide a brief overview of research in these areas that support targeting SHIP1, SHIP2 or both enzymes for therapeutic purposes.


Asunto(s)
Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Descubrimiento de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/química , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo
11.
J Org Chem ; 84(12): 7871-7882, 2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31117564

RESUMEN

Trichloroacetimidates are useful reagents for the synthesis of esters under mild conditions that do not require an exogenous promoter. These conditions avoid the undesired decomposition of substrates with sensitive functional groups that are often observed with the use of strong Lewis or Brønsted acids. With heating, these reactions have been extended to benzyl esters without electron-donating groups. These inexpensive and convenient methods should find application in the formation of esters in complex substrates.


Asunto(s)
Acetamidas/química , Cloroacetatos/química , Electrones , Ésteres/química , Ácidos Carboxílicos/química
12.
Tetrahedron Lett ; 60(19): 1325-1329, 2019 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-31481819

RESUMEN

Substituted indole scaffolds are often utilized in medicinal chemistry as they regularly possess significant pharmacological activity. Therefore the development of simple, inexpensive and efficient methods for alkylating the indole heterocycle continues to be an active research area. Reported are reactions of trichloroacetimidate electrophiles and indoles to address the challenges of accessing alkyl decorated indole structures. These alkylations perform best when either the indole or the imidate is functionalized with electron withdrawing groups to avoid polyalkylation.

13.
Molecules ; 24(22)2019 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-31731742

RESUMEN

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.


Asunto(s)
Acetamidas/química , Cloroacetatos/química , Indoles/química , Ácidos de Lewis/química , Catálisis , Estereoisomerismo
14.
J Org Chem ; 83(7): 4131-4139, 2018 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-29478311

RESUMEN

Benzylic trichloroacetimidates are readily displaced by trimethylaluminum under Lewis acid promoted conditions to provide the corresponding methyl substitution product. This method is a convenient way to access 1,1'-diarylethanes and related systems, which play a significant role in medicinal chemistry, with a number of systems owing their biological activity to this functionality. Most benzylic substrates undergo ready displacement, with electron deficient systems being the exception. The use of an enantiopure imidate showed significant racemization, implicating the formation of a cationic intermediate.

15.
J Org Chem ; 83(3): 1634-1642, 2018 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-29308898

RESUMEN

N-Substituted 3-amino-4-halopyridines are valuable synthetic intermediates, as they readily provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of N-substituted 3-amino-4-halopyridines is problematic, as reductive aminations and base-promoted alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described, providing access to a wide scope of N-substituted 3-amino-4-halopyridines. This protocol furnishes many reaction products in high purity without chromatography. Similar reductive amination conditions were also established for deactivated anilines.


Asunto(s)
Compuestos de Anilina/química , Ácidos de Lewis/química , Piridinas/síntesis química , Aminación , Estructura Molecular , Oxidación-Reducción , Piridinas/química
16.
Org Biomol Chem ; 16(21): 4008-4012, 2018 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-29766199

RESUMEN

1,1'-Diarylbutyl groups are a common pharmacophore found in many biologically active small molecules. To access these systems under mild conditions, the reaction of diarylmethyl trichloroacetimidates with allyltributylstannanes was explored. Simply heating allyltributylstannane with the trichloroacetimidate resulted in substitution of the imidate with an allyl group. Unlike other methods used to access these systems, no strong base, transition metal catalyst, Brønsted acid or Lewis acid promoter was required to affect the transformation. Conversions are best with electron rich benzylic trichloroacetimidate systems, where excellent yields are achieved just by refluxing the reactants together in nitromethane.


Asunto(s)
Acetamidas/química , Técnicas de Química Sintética/métodos , Cloroacetatos/química , Diseño de Fármacos , Calor , Compuestos de Estaño/química
17.
Biochemistry ; 56(7): 919-931, 2017 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-28134508

RESUMEN

The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small molecule therapeutics for treatment of obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence of the involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine-modifying electrophiles, revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.


Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Aciltransferasas/metabolismo , Inhibidores Enzimáticos/farmacología , Ghrelina/metabolismo , Triterpenos/farmacología , Acilación , Aciltransferasas/química , Animales , Cisteína/química , Cisteína/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Ghrelina/química , Humanos , Proteínas de la Membrana , Ratones , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Triterpenos/química
18.
J Org Chem ; 82(7): 3982-3989, 2017 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-28323428

RESUMEN

The rearrangement of allylic trichloroacetimidates is a well-known transformation, but the corresponding rearrangement of benzylic trichloroacetimidates has not been explored as a method for the synthesis of benzylic amines. Conditions that provide the trichloroacetamide product from a benzylic trichloroacetimidate in high yield have been developed. Methods were also investigated to transform the trichloroacetamide product directly into the corresponding amine, carbamate, and urea. A cationic mechanism for the rearrangement is implicated by the available data.


Asunto(s)
Acetamidas/química , Cloroacetatos/química , Espectroscopía de Resonancia Magnética/métodos
19.
J Org Chem ; 81(17): 8035-42, 2016 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-27487402

RESUMEN

An intermolecular alkylation of sulfonamides with trichloroacetimidates is reported. This transformation does not require an exogenous acid, base, or transition metal catalyst; instead the addition occurs in refluxing toluene without additives. The sulfonamide alkylation partner appears to be only limited by sterics, with unsubstituted sulfonamides providing better yields than more encumbered N-alkyl sulfonamides. The trichloroacetimidate alkylating agent must be a stable cation precursor for the substitution reaction to proceed under these conditions.


Asunto(s)
Acetamidas/química , Cloroacetatos/química , Sulfonamidas/química , Alquilación , Espectroscopía de Resonancia Magnética con Carbono-13 , Cromatografía Líquida de Alta Presión , Espectroscopía de Protones por Resonancia Magnética , Temperatura
20.
Org Biomol Chem ; 14(5): 1623-8, 2016 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-26691695

RESUMEN

Alcohols are effectively converted to their corresponding diphenylmethyl (DPM) ethers by reaction with O-diphenylmethyl trichloroacetimidate in refluxing toluene without the requirement of a catalyst or other additives. A number of acid and base sensitive substrates were protected in excellent yield using this new method without disturbing the pre-existing functionality present in these molecules. This reaction is the first example of the formation of an ether from stoichiometric amounts of a trichloroacetimidate and an alcohol without the addition of a Brønsted or Lewis acid catalyst.


Asunto(s)
Acetamidas/química , Compuestos de Bencidrilo/síntesis química , Compuestos de Bifenilo/química , Éteres/síntesis química , Temperatura , Ácidos/química , Compuestos de Bencidrilo/química , Catálisis , Éteres/química , Estructura Molecular
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA