RESUMO
Our research groups recently described a series of small-molecule inducers of ß-cell proliferation that could be used to increase ß-cell mass. To mitigate the risk of nonspecific proliferation of other cell types, we devised a delivery strategy built on the tissue specificity observed in the experimental ß-cell imaging agent (+)-dihydrotetrabenazine (DTBZ). The ß-cell proliferator agent aminopyrazine (AP) was covalently linked with (+)-DTBZ to afford conjugates that retain both the proliferation activity and binding affinity for vesicular monoamine transporter-2 (VMAT2). Inâ vivo mouse tissue distribution studies of a prototypical AP-DTBZ conjugate showed 15-fold pancreas exposure over plasma. Tissue-to-plasma ratios in liver and kidneys were two- and five-fold, respectively. This work is the first demonstration of enhanced delivery of ß-cell-proliferating molecules to the pancreas by leveraging the intrinsic tissue specificity of a ß-cell imaging agent.
Assuntos
Pâncreas/metabolismo , Tetrabenazina/análogos & derivados , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/química , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Rim/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Piridazinas/química , Coelhos , Espectrometria de Massas em Tandem , Tetrabenazina/sangue , Tetrabenazina/química , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia , Distribuição Tecidual , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
A remarkably concise seven- to eight-step total synthesis of a systematic series of key vinblastine derivatives is detailed and used to characterize the importance and probe the role of the C5 ethyl substituent (R = H, Me, Pr, CH=CH(2), C[triple bond]CH, CH(2)OH, and CHO vs Et). The analogues, which bear deep-seated structural changes accessible only by total synthesis, were prepared using a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles ideally suited for use in the assemblage of the vindoline-derived lower subunit followed by their incorporation into the vinblastine analogues through the use of a single-step biomimetic coupling with catharanthine. The evaluation of the series revealed that the tubulin binding site surrounding this C5 substituent is exquisitely sensitive to the presence (Et > H, 10-fold), size (Me < or = Et > Pr, 10-fold), shape (Et > CH=CH(2) and C[triple bond]CH, > 4-fold), and polarity (Et > CHO > CH(2)OH, >10-20-fold) of this substituent and that on selected occasions only a C5 methyl group may provide analogues that approach the activity observed with the naturally occurring C5 ethyl group.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Vimblastina/síntese química , Vimblastina/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Tubulina (Proteína)/metabolismo , Vimblastina/análogos & derivados , Vimblastina/metabolismoRESUMO
Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH(4)/air solution leads to oxidation of the C15'-C20' double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20' alcohols is >60%. Preliminary studies of Fe(III)-NaBH(4)/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O(2) trap at the oxidized carbon, provide a unique entry into C20' functionalized vinblastines, and afford initial insights into the observed C20' diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Delta(19',20')-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.
Assuntos
Vimblastina/análogos & derivados , Vimblastina/síntese química , Vincristina/análogos & derivados , Vincristina/síntese química , Animais , Biomimética , Boroidretos/química , Linhagem Celular Tumoral , Humanos , Ferro/química , Marcação por Isótopo , Camundongos , Oxirredução , Estereoisomerismo , Vimblastina/química , Vimblastina/toxicidade , Alcaloides de Vinca/síntese química , Alcaloides de Vinca/química , Vincristina/toxicidadeRESUMO
A synthesis of 2-epi-amphidinolide E (1) has been accomplished via an unexpected and highly diastereoselective C(2) stereochemical inversion during the modified Yamaguchi esterification of alcohol 4b and Fe(CO)3-complexed dienoic acid 7. [reaction: see text].
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Esterificação , Conformação Molecular , EstereoisomerismoRESUMO
Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and vinylstannane 6. The C19 stereocenters of the C19 epimeric allylsilanes 7 and 8 were introduced via crotylboration reactions early in the synthesis. [3+2]-Annulation reactions of aldehyde 5 with allylsilanes 7 and 8 were employed to set the core tetrahydrofuran units of 1-4. Finally, the C2 stereocenter was installed by esterification using acid 9, without incident, or with acid 10, in which case an unexpected and completely stereoselective inversion of C2 occurs.
RESUMO
A convergent and highly stereocontrolled synthesis of amphidinolide E (1) has been accomplished. The synthesis features a highly diastereoselective (>20:1) BF3.Et2O promoted [3+2] annulation reaction between aldehyde 3 and allylsilane 4 to afford substituted tetrahydrofuran 2.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Aldeídos/síntese química , Aldeídos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Esterificação , Estrutura Molecular , Silanos/síntese química , Silanos/químicaRESUMO
The chiral, nucleophilic catalyst TADMAP [1, 3-(2,2,2-triphenyl-1-acetoxyethyl)-4-(dimethylamino)pyridine] has been prepared from 3-lithio-4-(dimethylamino)pyridine (5) and triphenylacetaldehyde (3), followed by acylation and resolution. TADMAP catalyzes the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselection. The oxazole reactions are especially efficient and are used to prepare chiral lactams (23) and lactones (30) containing a quaternary asymmetric carbon. TADMAP-catalyzed carboxyl migrations in the indole series are relatively slow and proceed with inconsistent enantioselectivity. Modeling studies (B3LYP/6-31G*) have been used in qualitative correlations of catalyst conformation, reactivity, and enantioselectivity.
Assuntos
4-Aminopiridina/análogos & derivados , Aldeídos/química , Ácidos Carboxílicos/química , Lactamas/síntese química , Lactonas/síntese química , 4-Aminopiridina/química , Catálise , Furanos/química , Modelos Moleculares , Conformação Molecular , Oxazóis/química , Estereoisomerismo , TermodinâmicaRESUMO
[reaction: see text] The protiodesilylation of unactivated C(sp3)-SiMe2Ph bonds proceeds efficiently by treatment with tetrabutylammonium fluoride in wet DMF or THF via isolable dimethylsilanol intermediates.