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1.
Parasitol Res ; 119(10): 3503-3515, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772176

RESUMO

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.


Assuntos
Amino Álcoois/farmacologia , Antiprotozoários/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Babesia/efeitos dos fármacos , Babesia/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Modelos Animais de Doenças , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Plasmodium/efeitos dos fármacos , Plasmodium/crescimento & desenvolvimento , Infecções por Protozoários/tratamento farmacológico , Infecções por Protozoários/parasitologia , Resultado do Tratamento , Trypanosoma/efeitos dos fármacos , Trypanosoma/crescimento & desenvolvimento , Células Vero
2.
Med Chem ; 16(3): 385-391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30727909

RESUMO

BACKGROUND: Numerous synthetic bile acid derivatives have been recognized for their various biological activities. Among these, bile acid amides have emerged as an attractive antibacterial agent. We herein illustrate the synthesis and antibacterial evaluation of deoxycholic acidamino alcohols conjugates. OBJECTIVE: Design and Synthesis of novel deoxycholic acid-amino alcohol conjugates to investigate their antibacterial activity against E. coli and S. aureus. METHODS: Novel deoxycholic acid-amino alcohol conjugates were synthesized, from conjugation of deoxycholic acid-NHS ester with amino alcohols. Various amino alcohols moieties were appended to the C24 position of deoxycholic acid to yield deoxycholic acid-amino alcohol conjugates. All the synthesized compounds were characterized by 1H NMR, 13C NMR, IR and massspectroscopy. The entire synthesized deoxycholic acid-amino alcohol conjugates were evaluated for their antibacterial activity against E. coli and S. aureus using the broth dilution method. RESULTS: The outcome illustrated that some of the novel deoxycholic acid-amino alcohol conjugates exhibited enhanced anti-bacterial activities. Amongst them, deoxycholic acid-amino alcohol conjugate containing (-R)-2-aminocyclohexanol (1) demonstrated promising efficacy against both strains S. aureus ATCC 25923 (MIC 15 µg/mL) and E. coli ATCC 25922 (MIC 45 µg/mL) and was identified as a lead molecule. CONCLUSION: Numbers of novel deoxycholic acid-amino alcohol conjugates were synthesized and their antimicrobial activities provided useful information that the potency was strongly depending on the structures of deoxycholic acid-amino alcohol conjugates.


Assuntos
Amino Álcoois/farmacologia , Antibacterianos/farmacologia , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/farmacologia , Amino Álcoois/síntese química , Antibacterianos/síntese química , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
3.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861609

RESUMO

A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The allylic chlorination of (+)-neoisopulegol, derived from natural (-)-isopulegol followed by cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective epoxidation of the key intermediate and subsequent oxirane ring opening with primary amines afforded the required 1,2-aminoalcohols. The ring closure of the secondary amine analogues with formaldehyde provided spiro-oxazolidine ring systems. The dihydroxylation of the methylenetetrahydrofuran moiety with OsO4/NMO (4-methylmorpholine N-oxide) resulted in the formation of a neoisopulegol-based diol in a highly stereoselective reaction. The antimicrobial activity of both the aminoalcohol derivatives and the diol was also explored.


Assuntos
Amino Álcoois/síntese química , Anti-Infecciosos/síntese química , Benzofuranos/química , Monoterpenos Cicloexânicos/química , Amino Álcoois/química , Amino Álcoois/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Benzaldeídos/química , Catálise , Ciclização , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/química
4.
J Mol Model ; 25(8): 229, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321557

RESUMO

Alzheimer's disease (AD) is a complex neurodegenerative disorder associated with the aggregation of the amyloid-beta peptide (Aß) into large oligomers and fibrils that damage healthy brain cells. The predominant peptide fragments in the plaques are mainly formed by the Aß1-40 and Aß1-42 peptides, albeit the eleven-residue Aß25-35 segment is largely used in biological studies because it retains the neurotoxic properties of the longer Aß peptides. Recent studies indicate that treatment with therapeutic steroid hormones reduces the progress of the disease in AD models. Particularly, treatment with 17ß-aminoestrogens (AEs) has shown a significant alleviation of the AD development by inhibiting oxidative stress and neuronal death. Yet, the mechanism by which the AE molecules exhibit their beneficial effects remains speculative. To shed light into the molecular mechanism of inhibition of the AD development by AEs, we investigated the possibility of direct interaction with the Aß25-35 peptide. First, we calculate various interacting electronic properties of three AE derivatives as follows: prolame, butolame, and pentolame by performing DFT calculations. To account for the polymorphic nature of the Aß aggregates, we considered four different Aß25-35 systems extracted from AD relevant fibril structures. From the calculation of different electron density properties, specific interacting loci were identified that guided the construction and optimization of various complexes. Interestingly, the results suggest a similar inhibitory mechanism based on the direct interaction between the AEs and the M35 residue that seems to be general and independent of the polymorphic properties of the Aß aggregates. Our analysis of the complex formation provides a structural framework for understanding the AE therapeutic properties in the molecular inhibitory mechanism of Aß aggregation.


Assuntos
Peptídeos beta-Amiloides/química , Estrogênios/farmacologia , Agregados Proteicos , Amino Álcoois/química , Amino Álcoois/farmacologia , Estrenos/química , Estrenos/farmacologia , Estrogênios/química , Modelos Moleculares , Agregados Proteicos/efeitos dos fármacos , Eletricidade Estática
5.
Eur J Med Chem ; 177: 374-385, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158751

RESUMO

To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of l-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03-0.06 µg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1-2 µg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.


Assuntos
Amino Álcoois/farmacologia , Antifúngicos/farmacologia , Células A549 , Amino Álcoois/síntese química , Amino Álcoois/metabolismo , Amino Álcoois/toxicidade , Antifúngicos/síntese química , Antifúngicos/metabolismo , Antifúngicos/toxicidade , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/enzimologia , Candida albicans/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Domínio Catalítico , Cryptococcus neoformans/efeitos dos fármacos , Desenho de Fármacos , Estabilidade de Medicamentos , Ergosterol/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Estereoisomerismo , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade
6.
Chem Biol Drug Des ; 93(5): 737-759, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30663249

RESUMO

Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of mortality are associated with P. falciparum infections. With the identification of disease source and symptoms, many chemical entities were developed naturally and synthetically for administration as a potential antimalarial drug. The major classes of approved antimalarial drugs that are governed as first-line treatment in tropical and subtropical areas include quinolines, naphthoquinones, antifolates, 8-aminoquinolines, and endoperoxides. However, the efficacy of antimalarial drugs has decreased due to ongoing multidrug resistance problem to current drugs. With increasing resistance to the current antimalarial artemisinin and its combination therapies, malaria prophylaxis has declined gradually. New-generation antimalarial and novel drug target are required to check the incidence of malaria resistance. This review summarizes the emergence of multidrug resistance to known antimalarial and the development of new antimalarial to resolve drug resistance condition. Few essential proteins are also discussed that can be considered as novel drug target against malaria in future.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Plasmodium falciparum/efeitos dos fármacos , Amino Álcoois/química , Amino Álcoois/farmacologia , Apicoplastos/efeitos dos fármacos , Apicoplastos/metabolismo , Biologia Computacional/métodos , Resistência a Medicamentos/efeitos dos fármacos , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Peróxidos/química , Peróxidos/farmacologia , Primaquina/química , Primaquina/farmacologia
7.
Acta Pharmacol Sin ; 40(6): 746-754, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30315249

RESUMO

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system. Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain, heart failure, arrhythmias, and epilepsy. One HCN channel inhibitor, ivabradine, has been clinically approved for the treatment of angina pectoris and heart failure. In this study, we designed and synthesized eight alkanol amine derivatives, and assessed their effects on HCN channels expressed in COS7 cells using a whole-cell patch clamp method. Among them, compound 4e displayed the most potent inhibitory activity with an IC50 of 2.9 ± 1.2 µM at - 120 mV on HCN2 channel expressed in COS7 cells. Further analysis revealed that application of compound 4e (10 µM) caused a slowing of activation and a hyperpolarizing shift (ΔV1/2 = - 30.2 ± 2.9 mV, n = 5) in the voltage dependence of HCN2 channel activation. The inhibitory effect of compound 4e on HCN1 and HCN4 channel expressed in COS7 cells was less potent with IC50 of 17.2 ± 1.3 and 7.3 ± 1.2 µM, respectively. Besides, we showed that application of compound 4e (10 µM) inhibited Ih and action potential firing in acutely dissociated mouse small dorsal root ganglion neurons. Our study provides a new strategy for the design and development of potent HCN channel inhibitors.


Assuntos
Amino Álcoois/farmacologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Moduladores de Transporte de Membrana/farmacologia , Potenciais de Ação/efeitos dos fármacos , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Células COS , Chlorocebus aethiops , Humanos , Masculino , Moduladores de Transporte de Membrana/síntese química , Moduladores de Transporte de Membrana/química , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Canais de Potássio
8.
Antiviral Res ; 158: 171-177, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30125617

RESUMO

Influenza continues to pose a threat to public health by causing illness and mortality in humans. Discovering host factors that regulate influenza virus propagation is vital for the development of novel drugs. We have previously reported that sphingosine kinase (SphK) 1 promotes influenza A virus (IAV) replication in vitro. Here we demonstrate that the other isoform of SphK, SphK2 promotes the replication of influenza A virus (IAV) in cultured cells, and temporary inhibition of SphK1 or SphK2 enhances the host defense against influenza in mice. IAV infection led to an increased expression and phosphorylation of SphK2 in host cells. Furthermore, pharmacologic inhibition or siRNA-based knockdown of SphK2 attenuated IAV replication in vitro. Notably, oral administration of an SphK2-specific inhibitor substantially improved the viability of mice following IAV infection. In addition, the local instillation of an SphK1-specific inhibitor or an inhibitor that globally blocks SphK1 and SphK2 provided protection to IAV-infected mice. Collectively, our results indicate that both SphK1 and SphK2 function as proviral factors during IAV infection in vivo. Therefore, SphK1 and SphK2 represent potential host targets for therapeutics against influenza.


Assuntos
Vírus da Influenza A/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Células A549 , Adamantano/análogos & derivados , Adamantano/farmacologia , Administração Oral , Amino Álcoois/farmacologia , Aminofenóis/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Vírus da Influenza A/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Isoformas de Proteínas , Piridinas/farmacologia , RNA Interferente Pequeno , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Tiazóis/farmacologia , Replicação Viral
9.
Eur J Med Chem ; 157: 657-664, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30125724

RESUMO

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, ß-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation.


Assuntos
Amino Álcoois/farmacologia , Antineoplásicos/farmacologia , Aziridinas/farmacologia , DNA/efeitos dos fármacos , Alquilação/efeitos dos fármacos , Amino Álcoois/química , Antineoplásicos/química , Aziridinas/química , Linhagem Celular , Cisplatino/química , Cisplatino/farmacologia , DNA/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
10.
Chembiochem ; 19(21): 2293-2299, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30136342

RESUMO

A chiral amino alcohol based ligand was found to promote the highly enantioselective addition of terminal conjugated diynes to aromatic and aliphatic aldehydes. The combination of easily available C2 -symmetric (R)- and (S)-BINOL with Ti(OiPr)4 , Zn powder, and EtI was also found to catalyze the asymmetric addition of 1,3-diynes to aldehydes under mild reaction conditions, and thus, both enantiomers of the chiral conjugated diynols could be prepared with high enantioselectivities. The resulting optically active conjugated diynols were found to have potential anticancer activities with significant differences against HepG2 and HeLa cancer cells, and remarkable enantioselective cytotoxicity was observed for the first time.


Assuntos
Aldeídos/química , Amino Álcoois/química , Antineoplásicos/química , Di-Inos/química , Aldeídos/síntese química , Aldeídos/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Catálise , Di-Inos/síntese química , Di-Inos/farmacologia , Células HeLa , Células Hep G2 , Humanos , Ligantes , Naftóis/síntese química , Naftóis/química , Naftóis/farmacologia , Neoplasias/tratamento farmacológico , Estereoisomerismo , Titânio/química , Zinco/química
11.
J Org Chem ; 83(10): 5650-5664, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29696970

RESUMO

A strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes is described. Employment of chiral ß- and γ-amino alkoxides allowed for highly diastereoselective assembly of a small series of enantiopure cyclopropane-fused oxazepanones. It was shown that the chiral center at C-4 plays a crucial role in controlling desymmetrization of the cyclopropenyl moiety, instigated by a profound potassium-templated effect. The preliminary biological activities of the new cyclopropane-fused medium heterocycles against Gram-positive bacteria, Gram-negative bacteria, mycobacteria, cancer cells, and fungus were evaluated.


Assuntos
Amino Álcoois/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Ciclopropanos/farmacologia , Neoplasias/tratamento farmacológico , Amino Álcoois/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Reação de Cicloadição , Ciclopropanos/síntese química , Ciclopropanos/química , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neoplasias/patologia , Potássio/química , Estereoisomerismo
12.
Bioorg Chem ; 78: 298-306, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29625269

RESUMO

A series of pterostilbene ß-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC50 = 24.04 µM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. Moreover, 5f also showed self-induced Aß1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amino Álcoois/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Amino Álcoois/síntese química , Amino Álcoois/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
13.
Bioorg Chem ; 77: 25-37, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29324250

RESUMO

A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with KIs in the range of 8.5-2679.1 nM, hCA II with KIs in the range of 4.8-380.5 nM and hCA IX with KIs in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX.


Assuntos
Amino Álcoois/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Piperazina/farmacologia , Sulfonamidas/farmacologia , Triazinas/farmacologia , Amino Álcoois/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperazina/química , Relação Estrutura-Atividade , Sulfonamidas/química , Triazinas/química
14.
Autophagy ; 14(6): 942-957, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29368980

RESUMO

The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the enzyme that produces it, SPHK1 (sphingosine kinase 1), regulate many processes important for the etiology of cancer. It has been suggested that SPHK1 levels are regulated by the tumor suppressor protein TP53, a key regulator of cell cycle arrest, apoptosis, and macroautophagy/autophagy. However, little is still known of the relationship between TP53 and SPHK1 activity in the regulation of these processes. To explore this link, we examined the effects of inhibiting SPHK1 in wild-type and TP53 null cancer cell lines. SK1-I, an analog of sphingosine and isozyme-specific SPHK1 inhibitor, suppressed cancer cell growth and clonogenic survival in a TP53-dependent manner. It also more strongly enhanced intrinsic apoptosis in wild-type TP53 cells than in isogenic TP53 null cells. Intriguingly, SK1-I induced phosphorylation of TP53 on Ser15, which increases its transcriptional activity. Consequently, levels of TP53 downstream targets such as pro-apoptotic members of the BCL2 family, including BAX, BAK1, and BID were increased in wild-type but not in TP53 null cells. Inhibition of SPHK1 also increased the formation of autophagic and multivesicular bodies, and increased processing of LC3 and its localization within acidic compartments in a TP53-dependent manner. SK1-I also induced massive accumulation of vacuoles, enhanced autophagy, and increased cell death in an SPHK1-dependent manner that also required TP53 expression. Importantly, downregulation of the key regulators of autophagic flux, BECN1 and ATG5, dramatically decreased the cytotoxicity of SK1-I only in cells with TP53 expression. Hence, our results reveal that TP53 plays an important role in vacuole-associated cell death induced by SPHK1 inhibition in cancer cells.


Assuntos
Apoptose , Proteína Beclina-1/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Amino Álcoois/farmacologia , Apoptose/efeitos dos fármacos , Autofagia , Proteína 5 Relacionada à Autofagia/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Vacúolos/ultraestrutura
15.
Xenobiotica ; 48(3): 258-268, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28287856

RESUMO

1. CS-0777, a candidate compound for autoimmune diseases, becomes phosphorylated active metabolite, M1, by fructosamine 3-kinase (FN3K), FN3K-related protein (FN3K-RP); and M1 is reverted back to CS-0777 by alkaline phosphatase (ALP) in the body. We performed enzyme kinetic analysis of phosphorylation of CS-0777 by FN3K, FN3K-RP, human erythrocytes and human platelets; and dephosphorylation of M1 by various ALP isozymes and human liver, kidney, lung and small intestine microsomes. 2. The Michaelis constants of human FN3K, FN3K-RP and erythrocytes for CS-0777 phosphorylation were in the range from 498 µM to 1060 µM. FN3K inhibitor, 1-deoxy-1-morpholinofructose, suppressed only about 20% of CS-0777 phosphorylation activity in human erythrocyte lysate. Immunodepletion of FN3K and FN3K-RP decreased M1 formation activity by about 25% and 50%, respectively, in human erythrocyte lysate. 3. The Michaelis constants of four human ALPs and microsomes were in the range from 10.9 µM to 32.1 µM. The ALP inhibitor, levamisole, suppressed over 50% of M1 dephosphorylation activity in liver, kidney and lung microsomes. 4. FN3K-RP is expected to take a prominent role in the phosphorylation of CS-0777 in human erythrocytes; dephosphorylation of M1 was observed in all ALPs and human tissue microsomes examined, with a similar affinity towards M1 among them.


Assuntos
Amino Álcoois/farmacologia , Pirróis/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Amino Álcoois/metabolismo , Amino Álcoois/farmacocinética , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Frutose/análogos & derivados , Frutose/farmacologia , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Cinética , Levamisol/farmacologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Morfolinas/farmacologia , Fosforilação/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirróis/metabolismo , Pirróis/farmacocinética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
16.
Acta Trop ; 182: 285-290, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28859963

RESUMO

Cystic echinococcosis is a globally distributed zoonotic disease, which is caused by the larval stage of Echinococcosus granulosus sensu lato. The chemotherapy of the disease is limited to the use of benzimidazoles. Recently, mefloquine and its analogues, aminoalcohol-carbazole, and some amino alcohol derivatives were reported to display inhibitory effects on parasites. Here, the activities of 130 amino alcohol compounds against E. granulosus were tested on protoscoleces and germinal cells at a concentration of 20 µg/ml over a period of three days. As a result, sixteen compounds totally were effective against both protoscoleces and germinal cells, and their IC50 and LC50 were also calculated respectively. Then effects of the most active compounds were observed on metacestodes over 14 days in vitro. Although the structure of active compounds were variable, hydroxyl and amino groups connected by two carbon atoms are held in common as the key feature of these compounds. The further investigation on metacestodes incubated with these active compounds revealed that the effects of JF16 and BTB4 were comparable to that of mefloquine and mebendazole. In addition, the ultrastructure alternations induced by these compounds on E. granulosus were confirmed by scanning electron microscopy and transmission electron microscopy observations. In conclusion, amino alcohols were a class of compounds with efficacy against E. granulosus. The most effective compounds JF16 and BTB4 indicated that their basic structure would be useful in the synthesis of new compound for the treatment of echinococcosis. However, their in vivo efficacy and toxicity need to be carefully evaluated in the future.


Assuntos
Amino Álcoois/farmacologia , Antiparasitários/farmacologia , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Animais , Equinococose/parasitologia , Mebendazol/farmacologia , Mefloquina/farmacologia , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão
17.
Eur J Med Chem ; 143: 780-791, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29220798

RESUMO

Excess adiposity is a hallmark of obesity, which is caused due to an imbalance between energy intake and energy consumed. Obesity is often associated with several metabolic disorders like dyslipidemia, cardiovascular diseases and type 2 diabetes. Earlier, our group had reported natural product Aegeline (amino-alcohol) isolated from the plant Aegle marmelos as an anti-diabetic and anti-dyslipidemic compound. With this background, we synthesized a series of novel amino alcohol and thiazolidinedione hybrid molecules and studied their antiadipogenic activity. As a result, we have identified a potent hybrid compound 12c as an inhibitor of adipocyte differentiation. The compound 12c inhibits lipid accumulation and adipogenesis in 3T3-L1 preadipocyte cell line. Exposure of compound 12c blocks mitotic clonal expansion and arrests cells in S-phase of cell cycle. Detailed analysis showed that compound 12c decreases expression of two major transcription factors that are involved in adipocyte differentiation, PPARγ, C/EBPα, and other adipogenesis associated genes like aP2 and FAS. Thus, we concluded that compound 12c shows potential ability to inhibit adipocyte differentiation which can be used therapeutically for the treatment of obesity and its associated metabolic disorders.


Assuntos
Adipogenia/efeitos dos fármacos , Amidas/farmacologia , Amino Álcoois/farmacologia , Tiazolidinedionas/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Amidas/química , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
18.
Br J Pharmacol ; 175(21): 4083-4094, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29127708

RESUMO

The calcium-sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss-of-function and gain-of-function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G-protein subunit α11 (Gα11 ) and adaptor-related protein complex-2 σ-subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Gα11 or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient-based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.


Assuntos
Amino Álcoois/farmacologia , Calcimiméticos/farmacologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Amino Álcoois/química , Animais , Calcimiméticos/química , Humanos , Receptores de Detecção de Cálcio/metabolismo
19.
Med Chem ; 14(3): 293-303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28745231

RESUMO

BACKGROUND: We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[ 1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain. OBJECTIVES: To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity. METHOD: Four enantiopure aminoalcoholpyrrolo[1,2-a]quinoxalines 2 were synthetized via Sharpless asymmetric dihydroxylation reaction in eight steps. Their antimalarial activity was evaluated on two Plasmodium falciparum strains 3D7 and W2 with a SYBR Green I fluorescence-based method and their cytotoxicity was measured on four cell lines HepG2, THP-1, CHO and HFF. RESULTS: IC50 values of the four compounds 2 were close to the micromolar against the two P. falciparum strains. They were more active against P. falciparum strain W2 vs. P. falciparum strain 3D7. (R)- enantiomers were always more active than their (S)-counterpart whatever the strain. Selectivity indexes of compounds 2 were lower than 100. CONCLUSION: A novel series of enantiopure aminoalcohols with pyrrolo[1,2-a]quinoxaline core were synthesized in eight steps. They displayed IC50 values close to the micromolar against two P. falciparum strains 3D7 and W2. Although, In this series, 2,8-bistrifluoromethylquinoline was a best core than pyrrolo[1,2-a]quinoxaline for an optimal antimalarial activity, the pyrroloquinoxaline 2b showed an interesting antimalarial activity.


Assuntos
Amino Álcoois/farmacologia , Antimaláricos/farmacologia , Mefloquina/análogos & derivados , Mefloquina/farmacologia , Pirróis/farmacologia , Quinoxalinas/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Amino Álcoois/toxicidade , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/toxicidade , Células CHO , Linhagem Celular Tumoral , Cloroquina/farmacologia , Cricetulus , Humanos , Mefloquina/química , Mefloquina/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Pirróis/toxicidade , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/toxicidade , Estereoisomerismo
20.
ChemMedChem ; 12(23): 1977-1984, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-28975712

RESUMO

Analogues of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal ß-glucosidase 2 (GBA2) and the lysosomal ß-glucosidase 1 (GBA1). Compounds 5 a-6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB-DGJ (N-butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N-(n-butyl)- and N-(n-nonyl)-DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N-(n-butyl)- (35 a), N-(n-nonyl)-4-amino-5-(hydroxymethyl)cyclopentane- (35 b), and N-(1-(pentyloxy)methyl)adamantan-1-yl)-1,2,3-triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N-butyl analogue 35 a was 100-fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 µm for GBA1 and GBA2, respectively). The N-nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N-(1-(pentyloxy)methyl)adamantan-1-yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N-bis-substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono-substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.


Assuntos
1-Desoxinojirimicina/farmacologia , Amino Álcoois/farmacologia , Ciclopentanos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , beta-Glucosidase/antagonistas & inibidores , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/química , Amino Álcoois/química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Conformação Molecular , Relação Estrutura-Atividade , beta-Glucosidase/metabolismo
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