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1.
J Med Chem ; 63(7): 3737-3755, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196336

RESUMO

The ability of 6-(aryl)methylidene penicillin-based sulfones 1-7 to repurpose ß-lactam antibiotics activity with bacterial species that carry carbapenem-hydrolyzing class D ß-lactamases (OXA-23, OXA-24/40 and OXA-48), as well as with class A (TEM-1, CTX-M-2) and class C (CMY-2, DHA-1) enzymes, is reported. The combinations imipenem/3 and imipenem/4 restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing A. baumannii strains (1 µg mL-1) and also provided good results for OXA-48 carbapenemase-producing K. pneumoniae strains (4 µg mL-1). Compounds 2-6 in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in E. coli strains carrying class C (CMY-2 and DHA-1) and class A (TEM-1 and CTX-M-2) ß-lactamase enzymes, respectively. Kinetic and inhibition studies with the OXA-24/40 enzyme, protein mass spectrometry analysis and docking studies allowed us to gain an insight into the inhibition mechanism and the experimentally observed differences between the ligands.


Assuntos
Antibacterianos/farmacologia , Penicilinas/farmacologia , Sulfonas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Ampicilina/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Domínio Catalítico , Ceftazidima/farmacologia , Reposicionamento de Medicamentos , Escherichia coli/efeitos dos fármacos , Imipenem/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Penicilinas/síntese química , Penicilinas/metabolismo , Ligação Proteica , Sulfonas/síntese química , Sulfonas/metabolismo , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/metabolismo , beta-Lactamases/química , beta-Lactamases/metabolismo
2.
J Am Chem Soc ; 142(7): 3392-3400, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32009391

RESUMO

Targeted covalent modification of surface-exposed lysines is challenging due to their low intrinsic reactivity and high prevalence throughout the proteome. Strategies for optimizing the rate of covalent bond formation by a reversibly bound inhibitor (kinact) typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing kinact of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity (Ki) or the intrinsic electrophilicity. Starting with a noncovalent ligand, we appended a chiral, conformationally constrained linker, which orients an arylsulfonyl fluoride to react rapidly and enantioselectively with Lys58 on the surface of Hsp90. Biochemical experiments and high-resolution crystal structures of covalent and noncovalent ligand/Hsp90 complexes provide mechanistic insights into the role of ligand conformation in the observed enantioselectivity. Finally, we demonstrate selective covalent targeting of cellular Hsp90, which results in a prolonged heat shock response despite concomitant degradation of the covalent ligand/Hsp90 complex. Our work highlights the potential of engineering ligand conformational constraints to dramatically accelerate covalent modification of a distal, poorly nucleophilic lysine on the surface of a protein target.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lisina/química , Sulfonas/farmacologia , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/química , Humanos , Ligantes , Estereoisomerismo , Sulfonas/síntese química , Sulfonas/química
3.
Eur J Med Chem ; 191: 112139, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32109777

RESUMO

Since our study showed that sulfone derivatives' action mode creates a lesser risk of inducing widespread resistance among Candida spp., we continued verifying sulfones' antifungal activity using the following newly synthesized derivatives: bromodichloromethy-4-hydrazinyl-3-nitrophenyl sulfone (S1), difluoroiodomethyl-4-hydrazinyl-3-nitrophenyl sulfone (S2), and chlorodifluoromethyl-4-hydrazinyl-3-nitrophenyl sulfone (S3). As the mechanism by which sulfones gain access to the cytoplasm has not been elucidated yet, in order to track S1-3, we coupled their hydrazine group with BODIPY (final S1-3 BODIPY-labelled were named SB1-3). This approach allowed us to follow the vital internalization and endocytic routing of SB1-3, while BODIPY interacts primarily with fungal surfaces, thus confirming that S1-3 and their counterparts SB1-2 behaved as non-typical agents by damaging the cell membrane and wall after being endocytosed (SB1-3 fluorescence visible inside the unlysed sessile cells). Thus greatly decreasing the likelihood of the appearance of strains resistance. Core sulfones S1-3 are a promising alternative not only to treat planktonic C. albicans but also biofilm-embedded cells. In the flow cytometric analysis, the planktonic cell surface was digested by S1-3, which made the externalized PS accessible to AnnexinV binding and PI input (accidental cell death ACD). The occurrence of ACD as well as apoptosis (crescent-shaped nuclei) and anoikis of sessile cells (regulated cell death by 100%-reduction in attachment to epithelium) was assessed through monitoring the AO/PI/HO342 markers. CLSM revealed the invasion of S1-3 and SB1-3 in C. albicans without inducing cell lysis. This was a novel approach in which QCM-D was used for real-time in situ detection of viscoelastic changes in the C. albicans biofilm, and its interaction with S1 as a representative of the sulfones tested. S1 (not toxic in vivo) is a potent fungicidal agent against C. albicans and could be administered to treat invasive candidiasis as a monotherapy or in combination with antifungal agents of reference to treat C. albicans infections.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Sulfonas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química
4.
J Med Chem ; 63(3): 975-986, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31971801

RESUMO

The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with Kd and IC50 values of 26 nM and 0.891 µM toward MDM2, respectively, is among the most potent unnatural peptidomimetic inhibitors disrupting the p53-MDM2/MDMX interaction. Using fluorescence polarization assays, circular dichroism, nuclear magnetic resonance spectroscopy, and computational simulations, we demonstrate that sulfono-γ-AApeptides adopt helical structures resembling p53 and competitively inhibit the p53-MDM2 interaction by binding to the hydrophobic cleft of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed promising cellular activity by enhancing p53 transcriptional activity and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides exhibited remarkable resistance to proteolysis, augmenting their biological potential. Our results suggest that sulfono-γ-AApeptides are a new class of unnatural helical foldamers that disrupt PPIs.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Peptidomiméticos/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Sulfonas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/química , Linhagem Celular Tumoral , Humanos , Peptidomiméticos/química , Conformação Proteica em alfa-Hélice , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas c-mdm2/química , Sulfonas/síntese química , Proteína Supressora de Tumor p53/química
5.
Med Chem ; 16(2): 244-255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30987574

RESUMO

BACKGROUND: Peptic ulcer and urolithiasis are largely due to infection caused by ureaseproducing bacteria. Therefore, the discovery of urease inhibitors is an important area of medicinal chemistry research. OBJECTIVE: The main aim of the work was to identify novel urease inhibitors with no cytotoxicity. METHODS: During the current study, a series of ß-ketosulfones 1-26 was synthesized in two steps and evaluated for their in vitro urease inhibition potential. RESULTS: Out of twenty-six compounds, seventeen have shown good to significant urease inhibitory activity with IC50 values ranging between 49.93-351.46 µM, in comparison to standard thiourea (IC50 = 21 ± 0.11 µM). Moreover, all compounds found to be non-cytotoxic against normal 3T3 cell line. CONCLUSION: This study has identified ß-ketosulfones as novel and non-cytotoxic urease inhibitors.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Urease/antagonistas & inibidores , Animais , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Conformação Proteica , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/toxicidade , Urease/química , Urease/metabolismo
6.
J Med Chem ; 63(1): 186-204, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820986

RESUMO

Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rigosertib were designed. Among them, compound 29 showed the most potent antitumor activity in vitro with IC50 values at the nanomolar level against the tested tumor cell lines and 1000-fold higher than cisplatin against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP cells), while it showed only moderate cytotoxicity against normal cells (HEUVC cells). Compound 29 could clearly disturb signaling transduction between RAS and CRAF by directly bonding to CRAF and inhibit CRAF activation. Besides, the enhanced intracellular platinum level made 29 more potent than cisplatin in DNA damage, reactive oxygen species accumulation, and mitochondrial membrane potential decrease. Moreover, 29 induced apoptosis by the endogenous pathway and efficiently inhibited tumor growth in the A549 xenograft model without side effects.


Assuntos
Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Dano ao DNA/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos Endogâmicos BALB C , Platina/química , Proteínas Proto-Oncogênicas c-raf/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sulfonas/síntese química , Sulfonas/química , Sulfonas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
7.
Braz J Microbiol ; 51(1): 5-14, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31486049

RESUMO

Candida albicans represents an interesting microorganism to study complex host-pathogen interactions and for the development of effective antifungals. Our goal was to assess the efficacy of 4-chloro-3-nitrophenyldifluoroiodomethyl sulfone (named Sulfone) against the C. albicans infections in the Galleria mellonella host model. We assessed invasiveness of CAI4 parental strain and mutants: kex2Δ/KEX2 and kex2Δ/kex2Δ in G. mellonella treated with Sulfone. We determined that KEX2 expression was altered following Sulfone treatment in G. mellonella-C. albicans infection model. Infection with kex2Δ/kex2Δ induced decreased inflammation and minimal fault in fitness of larvae vs CAI4. Fifty percent of larvae died within 4-5 days (P value < 0.0001) when infected with CAI4 and kex2Δ/KEX2 at 109 CFU/mL; survival reached 100% in those injected with kex2Δ/kex2Δ. Larvae treated with Sulfone at 0.01 mg/kg 30 min before infection with all C. albicans tested survived infection at 90-100% vs C. albicans infected-PBS-treated larvae. Hypersensitive to Sulfone, kex2Δ/kex2Δ reduced virulence in survival. KEX2 was down-regulated when larvae were treated with Sulfone: 30 min before and 2 h post-SC5314-wild-type infection respectively. kex2Δ/kex2Δ was able to infect larvae, but failed to kill host when treated with Sulfone. Sulfone can be used to prevent or treat candidiasis. G. mellonella facilitates studding of host-pathogen interactions, i.e., testing host vs panel of C. albicans mutants when antifungal is dosed.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Mariposas/efeitos dos fármacos , Sulfonas/farmacologia , Animais , Antifúngicos/síntese química , Candida albicans/genética , Candida albicans/patogenicidade , Contagem de Colônia Microbiana , Proteínas Fúngicas/genética , Interações Hospedeiro-Patógeno , Larva/efeitos dos fármacos , Larva/microbiologia , Mariposas/microbiologia , Sulfonas/síntese química , Virulência
8.
Molecules ; 24(23)2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810327

RESUMO

Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron-dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect.


Assuntos
Compostos de Boro/química , Técnicas de Química Sintética , Pirrolidinas/química , Pirrolidinas/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirrolidinas/síntese química , Análise Espectral , Relação Estrutura-Atividade , Sulfonas/síntese química
9.
Eur J Med Chem ; 182: 111619, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434039

RESUMO

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.0043 µM to 4.42 µM. Notably, compound 27 (EC50 = 4.7 nM, SI = 5183) and 33 (EC50 = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC50 = 0.094 µM), and also showed exceptional activity against E138K (EC50 = 0.014 µM), L100I (EC50 = 0.011 µM) and K103 N (EC50 = 0.025 µM). Additionally, most compounds showed markedly reduced cytotoxicity (CC50) compared to lead compounds, especially 36 (CC50 > 234.91 µM, SI > 18727) and 37 (CC50 > 252.49 µM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Sulfonas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , Humanos , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química
10.
Bioorg Med Chem ; 27(19): 115045, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31427145

RESUMO

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10-12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.


Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Pirróis/uso terapêutico , Sulfetos/uso terapêutico , Sulfonas/uso terapêutico , Sulfóxidos/uso terapêutico , Analgésicos/síntese química , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Carragenina , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/metabolismo , Sulfonas/síntese química , Sulfonas/metabolismo , Sulfóxidos/síntese química , Sulfóxidos/metabolismo
11.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
12.
J Med Chem ; 62(15): 6876-6893, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31282155

RESUMO

The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.


Assuntos
Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Indanos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Sulfonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Cães , Relação Dose-Resposta a Droga , Feminino , Haplorrinos , Humanos , Indanos/síntese química , Indanos/farmacologia , Neoplasias Renais/metabolismo , Camundongos , Camundongos SCID , Ratos , Sulfonas/síntese química , Sulfonas/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Chem Pharm Bull (Tokyo) ; 67(6): 599-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155566

RESUMO

The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.


Assuntos
Antineoplásicos/síntese química , Pirrolidinas/química , Sulfonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
14.
Mol Inform ; 38(10): e1900014, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31166649

RESUMO

We report the building, validation and release of QSPR (Quantitative Structure Property Relationship) models aiming to guide the design of new solvents for the next generation of Li-ion batteries. The dataset compiled from the literature included oxidation potentials (Eox ), specific ionic conductivities (κ), melting points (Tm ) and boiling points (Tb ) for 103 electrolytes. Each of the resulting consensus models assembled 9-19 individual Support Vector Machine models built on different sets of ISIDA fragment descriptors.(1) They were implemented in the ISIDA/Predictor software. Developed models were used to screen a virtual library of 9965 esters and sulfones. The most promising compounds prioritized according to theoretically estimated properties were synthesized and experimentally tested.


Assuntos
Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Eletrólitos/química , Eletrólitos/síntese química , Solventes/química , Solventes/síntese química , Condutividade Elétrica , Fontes de Energia Elétrica , Técnicas Eletroquímicas , Eletrólitos/análise , Ésteres/síntese química , Ésteres/química , Lítio/química , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Software , Solventes/análise , Sulfonas/síntese química , Sulfonas/química , Máquina de Vetores de Suporte
15.
16.
Mater Sci Eng C Mater Biol Appl ; 99: 491-504, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889724

RESUMO

Polyurethane (PU) with three different functional groups: carboxyl, hydroxyl and sulphonyl group on its molecular structure were synthesised in this work. The synthesised material suppresses blood clotting and exhibits anticoagulant characteristics due to the presence of the important anionic groups. The synthesised PU was blended with polyethersulphone (PES) and fabricated into flat-sheet membrane to study the physico-chemical and biocompatibility properties of the PES membrane for blood purification application. PES-PU flat-sheet membranes were fabricated via the dry-wet phase separation technique. Different loading of PU (0, 1, 2, 3, 4, and 5%) blended with PES was studied and compared. Based on the in-vitro biocompatibility analysis of the membrane, it can be suggested that the membrane incorporated with PU has better anticoagulant properties compared to the pristine PES membrane. PU incorporation prolonged the clotting time, decreased the formation of thrombin, decreased soluble complement component 3a (C3a) generation and suppressed platelet adhesion and aggregation. The anionic groups on the membrane surface might bind to coagulation factors (antithrombin) and the calcium ions, Ca2+ and thus improve anticoagulant ability. Based on both physico-chemical and in-vitro studied, 4% loading of PU is the optimum loading for incorporation with PES membrane. These results suggested that the blended PES-PU membranes with good haemocompatibility allowed practical application in the field of blood purification.


Assuntos
Células Sanguíneas/citologia , Separação Celular/métodos , Membranas Artificiais , Polímeros/síntese química , Poliuretanos/síntese química , Sulfonas/síntese química , Coagulação Sanguínea , Ativação do Complemento , Complemento C3a/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Microscopia de Força Atômica , Adesividade Plaquetária , Polímeros/química , Poliuretanos/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectroscopia de Infravermelho com Transformada de Fourier , Sulfonas/química , Propriedades de Superfície , Temperatura , Trombose/patologia
17.
J Am Chem Soc ; 141(7): 3006-3013, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30735362

RESUMO

In this Article, we expand upon the catalytic hydrothiolation of 1,3-dienes to afford either allylic or homoallylic sulfides with high regiocontrol. Mechanistic studies support a pathway in which regioselectivity is dictated by the choice of counterion associated with the Rh center. Non-coordinating counterions, such as SbF6-, allow for η4-diene coordination to Rh complexes and result in allylic sulfides. In contrast, coordinating counterions, such as Cl-, favor neutral Rh complexes in which the diene binds η2 to afford homoallylic sulfides. We propose mechanisms that rationalize a fractional dependence on thiol for the 1,2-Markovnikov hydrothiolation while accounting for an inverse dependence on thiol in the 3,4- anti-Markovnikov pathway. Through the hydrothiolation of an essential oil (ß-farnesene), we achieve the first enantioselective synthesis of (-)-agelasidine A.


Assuntos
Alcadienos/química , Sulfetos/síntese química , Catálise , Complexos de Coordenação/química , Guanidinas/síntese química , Isomerismo , Cinética , Modelos Químicos , Ródio/química , Sesquiterpenos/química , Sulfonas/síntese química
18.
Bioorg Med Chem ; 27(5): 769-776, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30679133

RESUMO

Anthranilic diamide insecticide could control lepidopteran pests by selectively binding and activating insect ryanodine receptors (RyRs), and the unique mode of action is different from other conventional insecticides. In order to discover new anthranilic diamide insecticide as ryanodine receptors activators, a series of 11 novel anthranilic diamides derivatives (Ia-k) were synthesized and confirmed by melting point, 1H NMR, 13C NMR and elemental analyses. The preliminary bioactivity revealed that most title compounds showed moderate to remarkable activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Especially, compounds Ia and If, which exhibited 100% larvicidal activity against oriental armyworm at 1.0 mg L-1, and comparable to that of chlorantraniliprole (100% at 1 mg L-1). If displayed 60% insecticidal activity against diamondback moth at 0.01 mg L-1, better than chlorantraniliprole (45% at 0.01 mg L-1). The preliminary structure activity relationships were discussed. In addition, the calcium imaging experiment indicated that the insect ryanodine receptor is the potential target of If.


Assuntos
Amidas/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Inseticidas/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ortoaminobenzoatos/farmacologia , Amidas/síntese química , Amidas/química , Animais , Cálcio/metabolismo , Agonistas dos Canais de Cálcio/síntese química , Agonistas dos Canais de Cálcio/química , Inseticidas/síntese química , Inseticidas/química , Larva/efeitos dos fármacos , Estrutura Molecular , Mariposas/efeitos dos fármacos , Periplaneta/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Sulfonas/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
19.
Bioorg Chem ; 85: 49-59, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30599412

RESUMO

Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2-7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Sulfonas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Compostos de Vinila/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Simulação de Acoplamento Molecular , Sulfonas/síntese química , Sulfonas/farmacocinética , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacocinética , Compostos de Vinila/síntese química , Compostos de Vinila/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Chem Biol Drug Des ; 93(3): 254-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30264436

RESUMO

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond.


Assuntos
Antimaláricos/síntese química , Cromanos/química , Desenho de Fármacos , Safrol/análogos & derivados , Sulfonas/química , Alquilação , Antimaláricos/química , Antimaláricos/farmacologia , Carboidratos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/farmacologia , Células HeLa , Humanos , Plasmodium falciparum/efeitos dos fármacos , Safrol/síntese química , Safrol/química , Safrol/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
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