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1.
ACS Chem Neurosci ; 10(9): 4076-4101, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31441641

RESUMO

Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).

2.
J Med Chem ; 61(15): 6546-6573, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29890830

RESUMO

Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, molecules bearing a 4-aminoquinoline scaffold were reported as dual inhibitors of these targets and showed a significant in vivo efficacy in animal models of hematological malignancies. Here, we report a detailed exploration around three growing vectors born by this chemotype. Exploring this chemical space led to the identification of features to navigate G9a and DNMT1 biological spaces: not only their corresponding exclusive areas, selective compounds, but also common spaces. Thus, we identified from selective G9a and first-in-class DNMT1 inhibitors, >1 log unit between their IC50 values, with IC50 < 25 nM (e.g., 43 and 26, respectively) to equipotent inhibitors with IC50 < 50 nM for both targets (e.g., 13). Their ADME/Tox profiling and antiproliferative efficacies, versus some cancer cell lines, are also reported.


Assuntos
Aminoquinolinas/química , Aminoquinolinas/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Drogas , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Aminoquinolinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/metabolismo , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Conformação Proteica
3.
J Med Chem ; 61(15): 6518-6545, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29953809

RESUMO

Using knowledge- and structure-based approaches, we designed and synthesized reversible chemical probes that simultaneously inhibit the activity of two epigenetic targets, histone 3 lysine 9 methyltransferase (G9a) and DNA methyltransferases (DNMT), at nanomolar ranges. Enzymatic competition assays confirmed our design strategy: substrate competitive inhibitors. Next, an initial exploration around our hit 11 was pursued to identify an adequate tool compound for in vivo testing. In vitro treatment of different hematological neoplasia cell lines led to the identification of molecules with clear antiproliferative efficacies (GI50 values in the nanomolar range). On the basis of epigenetic functional cellular responses (levels of lysine 9 methylation and 5-methylcytosine), an acceptable therapeutic window (around 1 log unit) and a suitable pharmacokinetic profile, 12 was selected for in vivo proof-of-concept ( Nat. Commun. 2017 , 8 , 15424 ). Herein, 12 achieved a significant in vivo efficacy: 70% overall tumor growth inhibition of a human acute myeloid leukemia (AML) xenograft in a mouse model.


Assuntos
Antineoplásicos/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Ensaios Antitumorais Modelo de Xenoenxerto
4.
ACS Med Chem Lett ; 9(5): 428-433, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795754

RESUMO

In an effort to find novel chemical series as antifibrinolytic agents, we explore α-phenylsulfonyl-α-spiropiperidines bearing different zinc-binding groups (ZBGs) to target those metalloproteinases involved in the fibrinolytic process: MMP3 and MMP10. Surprisingly, all these new chemical series were inactive against these metalloproteinases; however, several new molecules retained the antifibrinolytic activity in a phenotypic functional assay using thromboelastometry and human whole blood. Further optimization led to compound 38 as a potent antifibrinolytic agent in vivo, three times more efficacious than the current standard-of-care (tranexamic acid, TXA) at 300 times lower dose. Finally, in order to decipher the underlying mode-of-action leading to this phenotypic response, an affinity-based probe 39 was successfully designed to identify the target involved in this response: a potentially unknown mechanism-of-action in the fibrinolytic process.

5.
Bioorg Med Chem Lett ; 28(1): 6-10, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29169674

RESUMO

Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.


Assuntos
Antiprotozoários/síntese química , Compostos de Boro/síntese química , Tripanossomíase Africana/tratamento farmacológico , Valina/análogos & derivados , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Bovinos , Camundongos , Relação Estrutura-Atividade , Trypanosoma congolense/efeitos dos fármacos , Trypanosoma vivax/efeitos dos fármacos , Tripanossomíase Africana/patologia , Tripanossomíase Africana/veterinária , Valina/síntese química , Valina/farmacologia , Valina/uso terapêutico
6.
J Med Chem ; 58(5): 2465-88, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25686153

RESUMO

Growing evidence suggests that matrix metalloproteinases (MMP) are involved in thrombus dissolution; then, considering that new therapeutic strategies are required for controlling hemorrhage, we hypothesized that MMP inhibition may reduce bleeding by delaying fibrinolysis. Thus, we designed and synthesized a novel series of MMP inhibitors to identify potential candidates for acute treatment of bleeding. Structure-based and knowledge-based strategies were utilized to design this novel chemical series, α-spiropiperidine hydroxamates, of potent and soluble (>75 µg/mL) pan-MMP inhibitors. The initial hit, 12, was progressed to an optimal lead 19d. Racemic 19d showed a remarkable in vitro phenotypic response and outstanding in vivo efficacy; in fact, the mouse bleeding time at 1 mg/kg was 0.85 min compared to 29.28 min using saline. In addition, 19d displayed an optimal ADME and safety profile (e.g., no thrombus formation). Its corresponding enantiomers were separated, leading to the preclinical candidate 5 (described in Drug Annotations series, J. Med. Chem. 2015, ).


Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Desenho de Drogas , Hemorragia/tratamento farmacológico , Ácidos Hidroxâmicos/química , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Metaloproteinases da Matriz/química , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 23(4): 963-6, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23312945

RESUMO

We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype. The design concept involved the replacement of the 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group. The synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple functional groups. The antibacterial activity of the newly synthesized compounds has been evaluated.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ciprofloxacino/química , Ciprofloxacino/farmacologia , Relação Estrutura-Atividade
8.
Photochem Photobiol ; 82(1): 50-6, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-15934790

RESUMO

The photosolvolysis of several biphenyl methanols (Ph-PhCH[Ph]OH) substituted with hydroxy or methoxy groups on the benzene ring not containing the -CH(Ph)OH moiety has been studied in aqueous solution. This work is a continuation of our studies of photosolvolysis of hydroxy-substituted arylmethanols that generate quinone methide intermediates, some of which are known to be relevant intermediates in toxicology and in biological and organic chemistry in general. In this study, we further probe the ability of the biphenyl ring system to transmit charge from the ring substituted with a potential electron-donating group (hydroxy and methoxy) to the adjacent benzene ring that contains a labile benzyl alcohol moiety. We show that in systems with a hydroxy substituent, biphenyl quinone methides (BQM) are the first formed intermediates that are detectable by nanosecond laser flash photolysis, and are responsible for the observed overall photosolvolysis reaction of these compounds. The highly conjugated BQM are found to absorb at long wavelengths (lambda(max) 580 and approximately 750 nm for the p,p' and o,p'-isomers, respectively) with relatively long lifetimes in neutral aqueous solution (500 and 30 micros, respectively). The BQM from the o,p'-isomer was found to undergo a competing intramolecular Friedel-Crafts alkylation, to give a fluorene derivative.

9.
Chem Commun (Camb) ; (33): 4231-3, 2005 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-16100613

RESUMO

Photodecarboxylation of p-benzoylphenylacetic acid in aqueous solution produces the elongated enol 5, whose strength as an oxygen acid (pQ(E/a)= 7.67) makes it more acidic than simple enol analogs by several orders of magnitude.

10.
J Am Chem Soc ; 125(42): 12961-70, 2003 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-14558845

RESUMO

Evidence is presented for the photochemical generation of novel biphenyl quinone methide (BQM)-type intermediates on photolysis of hydroxybiphenyl alkenes 7 and 8 and hydroxybiphenyl alcohols 9 and 10. Mechanistic investigations utilizing product, fluorescence, and nanosecond laser flash photolysis (LFP) studies indicate two distinct pathways for the formation of these BQMs depending upon the functional groups of the progenitor. Formal excited-state intramolecular proton transfer (ESIPT) between the phenol and the alkene led to BQMs upon irradiation of the hydroxybiphenyl alkenes 7 and 8, while excited-state proton transfer (ESPT) to solvent followed by dehydroxylation was responsible for BQM formation from the hydroxybiphenyl alcohols 9 and 10. Photolysis of 7 and 8 in aqueous CH(3)CN gave photohydration products via attack of water on the respective BQMs, while photolysis of the analogous methyl ethers (of the phenolic moiety) gave only carbocation intermediates. Hydroxybiphenyl alcohols 9 and 10 yielded the corresponding photomethanolysis products in aqueous methanol, through attack of CH(3)OH on the respective BQMs. Although no evidence was found for BQM formation in LFP studies of 8 and 10, due to its suspected short lifetime, the respective diaryl carbocation (lambda(max) 420 nm, tau = 8.5 micros) has been observed upon irradiation of 8 in 2,2,2-trifluoroethanol. A BQM (lambda(max) 580 nm) was observed for 9 but not for 10, the latter having more complex chemistry on laser excitation, resulting in a transient that appears to mask any BQM absorption. Significant quenching of fluorescence from the hydroxybiphenyl alkenes at low water content implies that H(2)O is directly involved in reaction from the singlet excited state. The decrease in fluorescence intensity of 8 was found to depend on [H(2)O](3); however, the distance required for ESIPT in these systems is too large to be bridged by a water trimer. The nonlinear quenching has been attributed to deprotonation of the phenol by two water molecules, with concerted protonation at the alkene by another molecule of water. Fluorescence quenching of the hydroxybiphenyl alcohols required much higher water content, implying a different mechanism of reaction, consistent with the proposal of ESPT (to solvent water) followed by dehydroxylation.

11.
Chem Commun (Camb) ; (2): 136-7, 2002 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-12120340

RESUMO

The title compound undergoes a novel excited state intramolecular redox reaction in which the 'distal' side chain benzylic alcohol is oxidized to the aldehyde and the carbonyl moieties of anthraquinone reduced, with evidence suggesting that the primary photochemical process is a deprotonation of the benzylic C-H proton (by water) mediated by the solvent.

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