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1.
Org Lett ; 23(13): 5218-5222, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34156861

RESUMO

Vibsatin A is a new neurotrophic vibsane-type diterpenoid comprising a bridged bicyclo[4.2.1]nonane skeleton. Inspired by Sawamura's works, we generated the bicyclic backbone through a Conia-ene-derived 7-exo-dig cyclization from an enantiomerically enriched TIPS-based silyl enol ether. The reaction, catalyzed by a sensitive gold(I) complex, was efficiently performed on a large scale by glovebox free techniques. Furthermore, the shape of this system was exploited for subsequent installation of all of the stereogenic centers.

2.
Org Biomol Chem ; 19(5): 1037-1046, 2021 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-33395455

RESUMO

An efficient silver-catalyzed tandem reaction for the formation of 1,2-dihydroisoquinoline derivatives is herein reported. Highly functionalized multiheterocyclic scaffolds are accessible in a straightforward manner using readily accessible starting materials under mild conditions. This methodology offers an attractive route for the synthesis and development of a biologically relevant new heterocyclic pharmacophore, merging the biological activities of isoquinolines with those of various nitrogen-containing heterocycles (indoles, pyrroles) incorporated during the tandem reaction. Mechanistic investigations were also conducted along with a large scope and limitation study, modifying various sites of this pharmacophore.


Assuntos
Isoquinolinas/química , Prata/química , Catálise , Isomerismo , Isoquinolinas/síntese química , Cinética , Temperatura
3.
Chemistry ; 26(72): 17455-17461, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-32978998

RESUMO

A formal [3+2] cyclization mediated by silver(I) oxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is described herein. Through a broad variety of carbonyl compounds, this system can promote cyclization reactions with high yield (up to 85 %) and diastereoselectivity (up to 95:5) for a straightforward access to complex and congested dihydrofuran derivatives in one step under mild conditions. Based on DFT studies, the proposed mechanism would involve an allenyl silver intermediate.

4.
Bioorg Med Chem Lett ; 29(24): 126710, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31699610

RESUMO

We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.


Assuntos
Antineoplásicos/uso terapêutico , Neuropilina-1/uso terapêutico , Antineoplásicos/farmacologia , Humanos , Estrutura Molecular
5.
J Org Chem ; 84(10): 6278-6285, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30990317

RESUMO

Visible light catalysis allows the regioselective synthesis of oxazolines in high yields. The mild photosensitized manifold leverages the intermolecular formation of oxazolines with a wide functional group tolerance on both benzoyl azides and alkenes partners. Mechanistic investigations suggest the sensitization of the azide moiety as the key activation step.

6.
J Org Chem ; 84(9): 5821-5830, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30964681

RESUMO

A novel approach toward the [5-7]fused bicyclic core of thapsigargin, a subnanomolar inhibitor of the endo/sarcoplasmic calcium ATPase (SERCA), is presented. The synthetic route includes an original Ti(II)-mediated hydroxy-directed reductive coupling of an enantiomerically enriched propargylic alcohol and an intramolecular Rh(I)-catalyzed cyclocarbonylation reaction as key steps. Interestingly, through the first experiments of titanocene-mediated reductive cyclization of a 1,8-enyne, a seven-membered cycle was isolated as a unique product with a total diastereoselectivity.

7.
Org Lett ; 18(19): 4814-4817, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27618124

RESUMO

A silver-catalyzed cycloisomerization reaction of a series of o-alkynylbenzohydroxamic acids is reported. Several 5-exo-dig and 6-endo-dig modes of cyclization were observed with the nitrogen or oxygen atoms of the amide group acting as nucleophiles. The selectivity was strongly dependent on the silver salt used and on the presence of triphenylphosphine as an additive. Indeed, while the use of Ag2O at room temperature allowed the isolation of isobenzofuran-1-one oximes (7 compounds, 48-92% yield), [Ag(Im)]n with the concomitant addition of 2 equiv of PPh3 led to a switch in selectivity and to a family of isoindolin-1-ones (10 compounds, 59-87%).

8.
Chem Sci ; 7(8): 5002-5006, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155150

RESUMO

We report the synthesis of various phthalazines via a new cascade reaction, initiated by visible light photocatalysis, involving a radical hydroamination reaction followed by a radical Smiles rearrangement. Phthalazine derivatives are obtained in high yields and from a broad scope readily accessible ortho-alkynylsulfonohydrazone precursors. The mild photoredox conditions ensure an excellent functional group tolerance. Application of this strategy to a one-pot protocol starting from the corresponding carbonyl compounds, and subsequent functionalization allow the rapid synthesis of structurally diverse structures.

9.
Inorg Chem ; 51(17): 9350-6, 2012 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-22905650

RESUMO

Six Co(III) complexes based on unsubstituted or substituted TPA ligands (where TPA is tris(2-pyridylmethyl)amine) and acetohydroxamic acid (A), N-methyl-acetohydroxamic acid (B), or N-hydroxy-pyridinone (C) were prepared and characterized by mass spectrometry, elemental analysis, and electrochemistry: [Co(III)(TPA)(A-2H)](Cl) (1a), [Co(III)((4-Cl(2))TPA)(A-2H)](Cl) (2a), [Co(III)((6-Piva)TPA)(A-2H)](Cl) (3a), [Co(III)((4-Piva)TPA)(A-2H)](Cl) (4a) and [Co(III)(TPA)(B-H)](Cl)(2) (1b), and [Co(III)(TPA)(C-H)](Cl)(2) (1c). Complexes 1a-c and 3a were analyzed by (1)H NMR, using 2D ((1)H, (1)H) COSY and 2D ((1)H, (13)C) HMBC and HSQC, and shown to exist as a mixture of two geometric isomers based on whether the hydroxamic oxygen was trans to a pyridine nitrogen or to the tertiary amine nitrogen. Complex 3a exists as a single isomer that was crystallized. Its crystal structure revealed the presence of an H-bond between the pivaloylamide and the hydroximate oxygen. Complexes 1a, 2a, and 4a are irreversibly reduced beyond -900 mV versus SCE, while complexes 1b and 1c are reduced at less negative values of -330 and -190 mV, respectively. The H-bond in 3a increased the redox potential up to -720 mV. Reaction of complex 1a with L-cysteine methyl ester CysOMe was monitored by (1)H NMR and UV-vis at 2 mM and 0.2 mM in an aqueous buffered solution at pH 7.5. Complex 1a was successively converted into an intermediate [Co(III)(TPA)(CysOMe-H)](2+), 1d, by exchange of the hydroximate with the cysteinate ligand, and further into Co(III)(CysOMe-H)(3), 5. An authentic sample of 1d was prepared and thoroughly characterized. A detailed (1)H NMR analysis showed there was only one isomer, in which the thiolate was trans to the tertiary amine nitrogen.


Assuntos
Cobalto/química , Cisteína/análogos & derivados , Ácidos Hidroxâmicos/química , Compostos Organometálicos/química , Piridinas/química , Cisteína/química , Ligantes , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/síntese química
10.
Inorg Chem ; 48(13): 5921-7, 2009 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-19514736

RESUMO

The alkyldisulfanido zinc complexes Tp(iPr,iPr)Zn(SSR) and Tp(Ph,Me)Zn(SSR) where Tp(iPr,iPr) is hydridotris-((3,5-isopropyl)pyrazolyl)borate, Tp(Ph,Me) is hydridotris-((3-phenyl,5-methyl)pyrazolyl)borate, and (SSR) is tert-butyldisulfanido or triphenylmethanedisulfanido were synthesized by reaction between the corresponding hydroxo complexes TpZn(OH) and the synthetic persulfide RSSH. All the complexes were characterized by elemental analysis and (1)H NMR spectroscopy, and representative members of the class were also structurally characterized. The reactivity of the alkyldisulfanido TpZn(SSR) complexes with thiols was studied. In the absence of base, a simple exchange reaction between the alkyldisulfanido ligand and the thiol was observed in dichloromethane; when in the presence of base, the corresponding hydrogen(sulfido) complexes TpZn(SH) were obtained. The mechanism of the latter reaction has been studied and does not involve the coordinated alkyldisulfanido group. Reaction of the hydrogen(sulfido) complexes Tp(iPr,iPr)Zn(SH) with the thiosulfonate PhCH(2)S-SO(2)CF(3) did not yield the expected alkyldisulfanido complex but benzyltrisulfide and a new complex tentatively assigned as Tp(iPr,iPr)Zn(O(2)SCF(3)).


Assuntos
Sulfetos/química , Compostos de Zinco/química , Cristalografia por Raios X , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos de Zinco/síntese química
11.
Dalton Trans ; (45): 6415-20, 2008 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-19002328

RESUMO

The reaction of acetohydroxamic (CH3C(O)-NHOH), benzhydroxamic acid (PhC(O)-NHOH) or 1-hydroxypyridin-2(1H)-one (pyrC(O)-NOH) in the presence of tris-(2-pyridylmethyl)amine (TPA), sodium methoxide and an iron(III) salt yields the mononuclear complexes [Fe(TPA)(CH3C(O)-NHO)]2+ (), [Fe(TPA)(PhC(O)-NHO)]2+ () and [Fe(TPA)(pyrC(O)-NO)]2+ (). The hydroxamato complexes and are easily converted to their hydroximato form [Fe(TPA)(CH3C(O)=NO)]+ () and [Fe(TPA)(PhC(O)=NO)]+ () by addition of base. The complexes described were characterized by UV-vis spectroscopy, EPR and cyclic voltammetry, as well as single-crystal X-ray crystallography for and .


Assuntos
Compostos Férricos/química , Compostos Férricos/síntese química , Ácidos Hidroxâmicos/síntese química , Cristalografia por Raios X , Eletroquímica , Espectroscopia de Ressonância de Spin Eletrônica , Ligantes , Conformação Molecular , Solventes , Espectrofotometria Ultravioleta
12.
Org Lett ; 8(20): 4493-6, 2006 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-16986933

RESUMO

The first example of the formation of a seven-membered ring by way of intramolecular-catalyzed amination of saturated C-H bonds is reported (Du Bois reaction). The influence of various structural parameters was studied, and it was shown that the unexpected regioselectivity observed in nitrogen-containing systems could be rationalized by conformational factors. These results open the way to innovative strategies for the general synthesis of polyfunctionalized piperidines.


Assuntos
Nitrogênio/química , Aminação , Carbono/química , Catálise , Hidrogênio/química , Modelos Moleculares
13.
Acta Crystallogr D Biol Crystallogr ; 59(Pt 7): 1200-5, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12832763

RESUMO

A new alpha-aminophosphinic compound able to inhibit both zinc-containing exopeptidases and endopeptidases has been crystallized with TLN as a model in order to investigate the mode of zinc recognition by the phosphinic moiety and to evaluate the potential role of the free alpha-amino group in the formation of enzyme-inhibitor complexes. In addition to the main interactions between the backbone of the inhibitor and the enzyme active site, it is observed that the phosphinic group acts as a distorted bidentate ligand for the zinc ion, while the free alpha-amino function does not directly participate in interactions within the active site. Association of the present data and the K(i) values of various analogues of the inhibitor towards TLN and neprilysin suggests differences in the hydrophobicity of the S(1)-S(2) domains of the enzymes. This could be taken into account in the design of selective inhibitors.


Assuntos
Metaloendopeptidases/antagonistas & inibidores , Compostos Organofosforados/química , Termolisina/química , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Inibidores Enzimáticos/química , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Zinco
14.
Acta Crystallogr D Biol Crystallogr ; 58(Pt 12): 2198-200, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12454500

RESUMO

A new crystallization protocol for thermolysin (EC 3.4.24.27) from Bacillus thermoproteolyticus is presented. After dissolving the protein in the presence of KSCN, which avoids the use of DMSO and CsCl, crystals were obtained following the salting-in method. Crystal cell parameters are isomorphous with those previously reported from DMSO/CsCl mixtures. The new SCN(-) crystal structure has been analyzed. It shows the presence of one thiocyanate ion in the catalytic site and several rearrangements in the S(1) and S(2) subsites. These results are in agreement with the measurements of Inouye et al. [(1998), J. Biochem. (Tokyo), 123, 847-852], who observed in solution that the solubility of TLN, which is particularly poor in low ionic strength solutions, increases dramatically in the presence of several neutral salts. The results reported here suggest possible explanations for the solubility increase and for the inhibitory effects of high SCN(-) concentrations on thermolysin activity.


Assuntos
Termolisina/química , Tiocianatos/química , Bacillus/enzimologia , Cristalização , Cristalografia por Raios X , Modelos Moleculares , Conformação Proteica
15.
Bioorg Med Chem Lett ; 12(15): 2001-5, 2002 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-12113828

RESUMO

We have previously reported the design of a lead compound 1a for the joint inhibition of neprilysin (NEP, EC 3.4.24.11), angiotensin converting enzyme (ACE, EC 3.4.15.1) and endothelin converting enzyme (ECE-1, EC 3.4.24.71), three metallopeptidases which are implicated in the regulation of fluid homeostasis and vascular tone. We report here the synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes. Compounds 8b and 15c are the most potent triple inhibitors described to date.


Assuntos
Aminoácidos/química , Aminoácidos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/síntese química , Indanos/química , Indanos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Enzimas Conversoras de Endotelina , Injeções Intravenosas , Neprilisina/antagonistas & inibidores , Ressonância Magnética Nuclear Biomolecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Fatores de Tempo
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