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1.
Bioorg Med Chem ; 23(13): 3481-9, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25963825

RESUMO

Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydrobenzo[e]indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (ΔTm=13°C) and cytotoxicity against LNCaP human prostate cancer cells (IC50=18nM).


Assuntos
Antineoplásicos Alquilantes/síntese química , Ciclopropanos/síntese química , DNA de Neoplasias/antagonistas & inibidores , Indóis/síntese química , Pró-Fármacos , Acetamidas , Alquilação , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Óxidos N-Cíclicos/química , Ciclização , Ciclopropanos/farmacologia , DNA de Neoplasias/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fluoracetatos , Humanos , Concentração de Íons de Hidrogênio , Indóis/farmacologia , Modelos Moleculares , Naftalenos/química , Desnaturação de Ácido Nucleico , Relação Estrutura-Atividade
2.
Bioorg Med Chem ; 23(13): 3013-32, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26026769

RESUMO

The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with ß-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50=2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Naftiridinas/síntese química , Pirimidinonas/síntese química , Tanquirases/antagonistas & inibidores , Amônia/química , Antineoplásicos/química , Compostos Aza/química , Benzamidinas/química , Ácidos Carboxílicos/química , Cristalografia por Raios X , Ciclização , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Cetonas/química , Simulação de Acoplamento Molecular , Naftiridinas/química , Nitrilas/química , Pirimidinonas/química , Relação Estrutura-Atividade , Tanquirases/química
3.
Bioorg Med Chem ; 23(17): 5891-908, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26189030

RESUMO

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/ß-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.


Assuntos
Tanquirases/química , Sítios de Ligação , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 21(17): 5218-27, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23849206

RESUMO

Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of ß-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50=0.23µM vs IC50=1.6µM for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.


Assuntos
Inibidores Enzimáticos/síntese química , Isoquinolinas/química , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Sítios de Ligação , Galinhas , Ciclização , Desenho de Fármacos , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Isoquinolinas/síntese química , Simulação de Acoplamento Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Água/química
5.
Biochemistry ; 50(21): 4720-32, 2011 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-21488658

RESUMO

SJG-136 (1) is a sequence-selective DNA-interactive agent that is about to enter phase II clinical trials for the treatment of malignant disease. Previous studies on the pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers, typified by SJG-136 and DSB-120 (2), have shown that these planar ligands react with the exocyclic NH(2) groups of two guanine bases in the base of the minor groove of DNA to form an irreversible interstrand cross-linked sequence-specific adduct. Using high-field NMR, we have characterized and modeled the previously predicted interstrand duplex adduct formed by SJG-136 with the self-complementary 5'-d(CICGATCICG)(2) duplex (4). This first SJG-136 NMR-refined adduct structure has been compared with previous high-field NMR studies of the adducts of the closely related PBD dimer DSB-120 with the same duplex and of the adduct of tomaymycin (3) formed with 5'-d(ATGCAT)(2). Surprisingly, the SJG-136 duplex adduct appears to be more closely related to the tomaymycin adduct than to the DSB-120 adduct with respect of the orientation and depth of insertion of the ligand within the minor groove. The intrastrand duplex adduct formed in the reaction of SJG-136 with the noncomplementary 5'-d(CTCATCAC)·(GTGATGAG) duplex (5) has also been synthesized and modeled. In this duplex adduct, the nature of the cross-link was confirmed, the central guanines were identified as the sites of alkylation, and the stereochemical configuration at C11 at both ends of the SJG-136 molecule was determined to be S. The NMR-refined solution structures produced for the intrastrand adduct confirm the previously proposed structure (which was based solely on mass spectroscopy). Both the inter- and intrastrand SJG-136 duplex adducts form with minimal distortion of the DNA duplex. These observations have an impact on the proposal for the mechanism of action of SJG-136 both in vitro and in vivo, on the repair of its adducts and mechanism of resistance in cells, and, potentially, on the type of pharmacodynamic assay to be used in clinical trials. SGJ-136 is currently in phase II clinical trials with several groups working on both dimeric cross-linking agents and monoalkylating ligands based on the PBD alkylating moiety. This study suggests subtle differences between the DNA binding of SJG-136 and the C2 unsubstituted analogue DSB-120 that are likely to be the origins of the differences in potency. Confirmation of the stereochemical configuration at the C11 position (particularly in the intrastrand adduct) provides confirmation of binding orientation that was previously only speculation in the HPLC MS study. Together, these observations are likely to be of value in the development of third-generation PBD-based cross-linkers and monoalkylating analogues.


Assuntos
Adutos de DNA/química , Ressonância Magnética Nuclear Biomolecular/métodos , Cromatografia Líquida de Alta Pressão , Modelos Moleculares , Conformação de Ácido Nucleico
6.
Biochemistry ; 50(19): 4143-54, 2011 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-21469674

RESUMO

Previous structural studies of the cyclopropapyrroloindole (CPI) antitumor antibiotics have shown that these ligands bind covalently edge-on into the minor groove of double-stranded DNA. Reversible covalent modification of the DNA via N3 of adenine occurs in a sequence-specific fashion. Early nuclear magnetic resonance and molecular modeling studies with both mono- and bis-alkylating ligands indicated that the ligands fit tightly within the minor groove, causing little distortion of the helix. In this study, we propose a new binding model for several of the CPI-based analogues, in which the aromatic secondary rings form π-stacked complexes within the minor groove. One of the adducts, formed with adozelesin and the d(ATTAAT)(2) sequence, also demonstrates the ability of these ligands to manipulate the DNA of the binding site, resulting in a Hoogsteen base-paired adduct. Although this type of base pairing has been previously observed with the bisfunctional CPI analogue bizelesin, this is the first time that such an observation has been made with a monoalkylating nondimeric analogue. Together, these results provide a new model for the design of CPI-based antitumor antibiotics, which also has a significant bearing on other structurally related and structurally unrelated minor groove-binding ligands. They indicate the dynamic nature of ligand-DNA interactions, demonstrating both DNA conformational flexibility and the ability of two DNA-bound ligands to interact to form stable covalent modified complexes.


Assuntos
Antineoplásicos Alquilantes/química , Pareamento de Bases , Ácidos Cicloexanocarboxílicos/química , Cicloexenos/química , Adutos de DNA/química , Indóis/química , Modelos Moleculares , Ácidos Nucleicos Heteroduplexes/química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antineoplásicos Alquilantes/metabolismo , Sequência de Bases , Benzofuranos , Sítios de Ligação , DNA/química , DNA/metabolismo , Adutos de DNA/metabolismo , Duocarmicinas , Ligantes , Ressonância Magnética Nuclear Biomolecular , Ácidos Nucleicos Heteroduplexes/metabolismo
7.
Org Biomol Chem ; 9(3): 881-91, 2011 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-21127791

RESUMO

The considerable interest in substituted isoquinolin-1-ones related to 5-aminoisoquinolin-1-one (5-AIQ) as drugs points to a need for an efficient and straightforward synthesis of the 4,5-disubstituted bicycles. Bromination of 5-nitroisoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but neither this nor 5-amino-4-bromoisoquinolin-1-one would participate in Pd-catalysed couplings. Protection of the lactam as 1-methoxy- and 1-benzyloxy-4-bromo-5-nitroisoquinolines, however, permitted Stille, Suzuki and Buchwald-Hartwig couplings to take place in high yields, insensitive to electronic demands and severe steric bulk in the arylboronic acids. Lithiation of 4-bromo-1-methoxy-5-nitroisoquinoline and quench with iodomethane gave 1-methoxy-4-methyl-5-nitroisoquinoline in low yield. Demethylation of the 1-methoxy-4-substituted-5-nitroisoquinolines with hydrogen bromide gave 4-substituted-5-nitroisoquinolin-1-ones, whereas hydrogenolytic debenzylation was achieved with simultaneous reduction of the 5-nitro group. 5-Amino-4-(4-trifluoromethylphenyl)isoquinolin-1-one was identified as a new potent and selective inhibitor of poly(ADP-ribose)polymerase-2 (PARP-2).


Assuntos
Aminas/química , Inibidores Enzimáticos/síntese química , Isoquinolinas/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Alquilação , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Isoquinolinas/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
8.
Org Biomol Chem ; 9(17): 6089-99, 2011 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-21750829

RESUMO

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 °C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl)acetals leads to subsequent alkylation at N(3). 3-Substituted anthranilamides give 8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N(3)-alkyl group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving 4-isopropoxyquinazolines, along with N(3)-methylquinazolin-4-ones where the methyl is derived from N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide di(neopentyl)acetal forms a mixture of quinazolin-4-one and N(3)-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.


Assuntos
Amidas/química , Quinazolinas/síntese química , ortoaminobenzoatos/química , Alquilação , Quinazolinas/química
9.
Artigo em Inglês | MEDLINE | ID: mdl-21505241

RESUMO

Human sirtuin 1 is a member of the histone deacetylase family and is involved in cellular aging, tumourigenesis and cellular metabolism. Recombinant sirtuin 1 comprising residues 140-747 was crystallized using the hanging-drop vapour-diffusion method. The crystal diffracted to 3.4 Šresolution and belonged to space group P622, with unit-cell parameters a = b = 203.1, c = 625.3 Å, and is estimated to contain between six and 12 molecules per asymmetric unit.


Assuntos
Sirtuína 1/química , Clonagem Molecular , Cristalização , Cristalografia por Raios X , Humanos , Sirtuína 1/genética , Sirtuína 1/isolamento & purificação
10.
J Am Chem Soc ; 131(38): 13756-66, 2009 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-19725510

RESUMO

SJG-136 (1) is a sequence-selective DNA-interactive agent that is about to enter phase II clinical trials. Using a HPLC/MS-based methodology developed to evaluate the binding of DNA-interactive agents to oligonucleotides of varying length and sequence, we have demonstrated that, in addition to the previously known interstrand cross-link at Pu-GATC-Py sequences, 1 can form a longer interstrand cross-link at Pu-GAATC-Py sequences, an intrastrand cross-link at both shorter Pu-GATG-Py and longer Pu-GAATG-Py sequences, and, in addition, monoalkylated adducts at suitable PBD binding sites where neither intra- or interstrand cross-links are feasible because of the unavailability of two appropriately positioned guanines. Crucially, we have demonstrated a preference for the extended intrastrand cross-link with Pu-GAATG-Py, which forms more rapidly than the other cross-links (rank order: Pu-GAATG-Py > Pu-GATC-Py >> Pu-GATG-Py and Pu-GAATC-Py). However, thermal denaturation studies suggest that the originally reported Pu-GATC-Py interstrand cross-link is more stable, consistent with the covalent joining of both strands of the duplex and a lower overall distortion of the helix according to modeling studies. These observations impact on the proposed mechanism of action of SJG-136 (1) both in vitro and in vivo, the repair of its adducts and mechanism of resistance in cells, and potentially on the type of pharmacodynamic assay used in clinical trials.


Assuntos
Benzodiazepinonas/química , Reagentes de Ligações Cruzadas/química , Adutos de DNA/química , Pirróis/química , Sequência de Bases , Dimerização , Conformação de Ácido Nucleico
11.
Eur J Med Chem ; 118: 316-27, 2016 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-27163581

RESUMO

Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4'-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD(+)-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Tanquirases/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Tanquirases/química , Via de Sinalização Wnt/efeitos dos fármacos
12.
Chem Commun (Camb) ; (23): 2876-7, 2002 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-12478791

RESUMO

The structure of the 2:1 complex between beta-cyclodextrin and 1-phenyl-1,2-dicarba-closo-dodecaborane(12) is demonstrated by NOE and NOESY spectroscopy; this complex is remarkably refractory.


Assuntos
Boranos/química , Ciclodextrinas/química , Terapia por Captura de Nêutron de Boro/métodos , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular
13.
J Org Chem ; 61(23): 8141-8147, 1996 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11667802

RESUMO

An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The "amino thioacetal" cyclization procedure was used to produce the electrophilic DNA-interactive N10-C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a-d), a versatile convergent approach has been developed to join two units of vanillic acid with alpha,omega-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.

14.
J Org Chem ; 64(6): 1859-1867, 1999 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-11674275

RESUMO

L-733,725, a new immunosuppressant drug candidate, was prepared by a highly chemoselective alkylation of the macrolide ascomycin at the C32 hydroxy position with the imidazolyl trichloroacetimidate 16. The trichloroacetimidate-activated side chain 16 was prepared by an efficient four-step sequence in 42% overall yield. The high chemoselectivity in the alkylation of the C32 hydroxy group of the unprotected ascomycin was the result of the synergetic effects of the electron-donating protecting group on the imidazole 16, the polar, moderately basic solvent, and the strong acid catalyst. N,N-Dimethylpivalamide mixed with acetonitrile was found to be the best solvent and trifluromethanesulfonic acid the best catalyst. This synthesis coupled with a resin column purification of L-733,725 followed by crystallization of its tartrate salt has been used to make multi-kilogram quantities of the bulk drug with consistent and high purity.

15.
ACS Med Chem Lett ; 4(12): 1173-7, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900625

RESUMO

Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC50 = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4'-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.

16.
Biochem Pharmacol ; 86(11): 1621-5, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24041740

RESUMO

Ibuprofen and related 2-arylpropanoic acid (2-APA) drugs are often given as a racemic mixture and the R-enantiomers undergo activation in vivo by metabolic chiral inversion. The chiral inversion pathway consists of conversion of the drug to the coenzyme A ester (by an acyl-CoA synthetase) followed by chiral inversion by α-methylacyl-CoA racemase (AMACR; P504S). The enzymes responsible for hydrolysis of the product S-2-APA-CoA ester to the active S-2-APA drug have not been identified. In this study, conversion of a variety of 2-APA-CoA esters by human acyl-CoA thioesterase-1 and -2 (ACOT-1 and -2) was investigated. Human recombinant ACOT-1 and -2 (ACOT-1 and -2) were both able to efficiently hydrolyse a variety of 2-APA-CoA substrates. Studies with the model substrates R- and S-2-methylmyristoyl-CoA showed that both enzymes were able to efficiently hydrolyse both of the epimeric substrates with (2R)- and (2S)- methyl groups. ACOT-1 is located in the cytosol and is able to hydrolyse 2-APA-CoA esters exported from the mitochondria and peroxisomes for inhibition of cyclo-oxygenase-1 and -2 in the endoplasmic reticulum. It is a prime candidate to be the enzyme responsible for the pharmacological action of chiral inverted drugs. ACOT-2 activity may be important in 2-APA toxicity effects and for the regulation of mitochondrial free coenzyme A levels. These results support the idea that 2-APA drugs undergo chiral inversion via a common pathway.


Assuntos
Acil Coenzima A/química , Ibuprofeno/química , Palmitoil-CoA Hidrolase/química , Tioléster Hidrolases/química , Acil Coenzima A/metabolismo , Cristalografia por Raios X , Escherichia coli/genética , Ésteres , Humanos , Hidrólise , Ibuprofeno/metabolismo , Cinética , Modelos Moleculares , Estrutura Molecular , Palmitoil-CoA Hidrolase/genética , Palmitoil-CoA Hidrolase/metabolismo , Conformação Proteica , Estereoisomerismo , Especificidade por Substrato , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo
17.
Chem Commun (Camb) ; 47(26): 7332-4, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21614403

RESUMO

Metabolic chiral inversion of 2-arylpropanoic acids (2-APAs;'profens'), such as ibuprofen, is important for pharmacological activity. Several 2-APA-CoA esters were good racemisation substrates for human AMACR 1A, suggesting a common chiral inversion pathway for all 2-APAs and an additional mechanism for their anti-cancer properties.


Assuntos
Antineoplásicos/química , Antineoplásicos/metabolismo , Ibuprofeno/química , Ibuprofeno/metabolismo , Racemases e Epimerases/metabolismo , Antineoplásicos/farmacologia , Domínio Catalítico , Ésteres , Humanos , Ibuprofeno/farmacologia , Modelos Moleculares , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Racemases e Epimerases/química , Estereoisomerismo
18.
J Med Chem ; 54(7): 2049-59, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21417348

RESUMO

PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH═CHCO(2)H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC(50(PARP-1))/IC(50(PARP-2)) = 9.3) to date, in a comparative study.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Linhagem Celular Tumoral , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoquinolinas/síntese química , Lactamas/química , Camundongos , Modelos Moleculares , Oxigênio/química , Poli(ADP-Ribose) Polimerases/química , Conformação Proteica , Especificidade por Substrato
19.
J Org Chem ; 73(6): 2302-10, 2008 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-18278942

RESUMO

An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.


Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Naftiridinas/síntese química , Quinolinas/síntese química , Receptores de Vitronectina/antagonistas & inibidores , Naftiridinas/química , Naftiridinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Estereoisomerismo , Difração de Raios X
20.
J Org Chem ; 72(19): 7409-12, 2007 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-17715975

RESUMO

Treatment of 5-nitroisocoumarin with aromatic acyl chlorides under Friedel-Crafts conditions gives 3-aryl-5-nitroisocoumarins, rather than the expected 4-acyl-5-nitroisocoumarins. This procedure was optimized for reaction temperature (150 degrees C), solvent (nitrobenzene), and Lewis acid (SnCl4). Reaction of 5-nitroisocoumarin with [13C]-carbonyl benzoyl chloride under the optimum conditions gave 5-nitro-3-phenylisocoumarin in which the 13C is located at the 3-C of the heterocycle, indicating that the benzoyl carbon framework is incorporated intact.


Assuntos
Cumarínicos/síntese química , Cumarínicos/química , Nitrocompostos/síntese química , Nitrocompostos/química , Ressonância Magnética Nuclear Biomolecular
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