RESUMO
The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 µM. Moreover, the C7-hydroxy derivative of NEPP11 displayed high cytotoxic selectivity between cancer cell lines and normal human cells. On the other hand, the J-type prostaglandin analogue of NEPP11 and its C13-hydroxy derivatives were much less toxic or nontoxic against the cancer and normal cells at concentrations up to 1 mM.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Prostaglandinas A Sintéticas/química , Prostaglandinas A Sintéticas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Células HL-60 , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Neoplasias/tratamento farmacológico , Prostaglandinas A Sintéticas/síntese química , Relação Estrutura-AtividadeRESUMO
The pseudoenantiomeric 4-O-Boc- and 4-OPMP-cyclopent-2-enones, readily available from hydroxymethylenefurane on multigram scale, are demonstrated to be exceptional building blocks for the synthesis of enantiopure 4-alkyl-5-(1'-hydroxyalkyl) substituted 2-cyclopentenones and derivatives thereof. The 4-OR substituent acts as a traceless stereoinducing element, conferring not only 1,2- but also 1,4-stereocontrol with excellent selectivity. The methodology developed here was applied for the rapid synthesis of natural products and biologically active 2-cyclopentenones such as TEI-9826, guaianes, and pseudoguaianolides.
Assuntos
Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Ciclopentanos/síntese química , Prostaglandinas A Sintéticas/síntese química , Sesquiterpenos de Guaiano/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Catálise , Técnicas de Química Combinatória , Ciclopentanos/química , Modelos Moleculares , Estrutura Molecular , Prostaglandinas A Sintéticas/química , Prostaglandinas A Sintéticas/farmacologia , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , EstereoisomerismoRESUMO
Enantioselective conjugate addition of styrylboronic acid to dienones was effectively catalyzed by an O-monoacyltartaric acid to afford monostyrylated products with good enantioselectivity. The RCM of the monostyrylated products using the Hoveyda-Grubbs II catalyst afforded optically active cyclopentenones, including a synthetic intermediate of the antitumor agent TEI-9826. The study shows that a diene additive such as 1,6-heptadiene or diallyl ether was essential for the RCM.
Assuntos
Antineoplásicos/síntese química , Ácidos Borônicos/química , Ciclopentanos/síntese química , Tartaratos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Catálise , Ciclopentanos/química , Ciclopentanos/farmacologia , Estrutura Molecular , Prostaglandinas A Sintéticas/síntese química , Prostaglandinas A Sintéticas/química , Prostaglandinas A Sintéticas/farmacologia , EstereoisomerismoRESUMO
We report Ir-catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,ß-unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62-94% yield with 90-98% ee and >20:1 branched-to-linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI-9826.
Assuntos
Irídio/química , Cetonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Carbonatos/química , Catálise , Cristalografia por Raios X , Cetonas/síntese química , Conformação Molecular , Prostaglandinas A Sintéticas/síntese química , Prostaglandinas A Sintéticas/química , Silanos/química , EstereoisomerismoRESUMO
A broadly applicable synthesis of chiral 2- or 2,4-substituted cyclopent-2-enones has been developed by combining asymmetric iridium-catalyzed allylic alkylation reactions and ruthenium-catalyzed ring-closing metathesis. Enantiomeric excesses (ee values) in the range of 95-99 % ee have been achieved. This method offers a straightforward access to biologically active prostaglandins of the PGA type. As an example, an enantioselective synthesis of the prostaglandin-analogue 13,14-dihydro-15-deoxy-Delta(7)-prostaglandin-A1-methyl ester (TEI-9826) has been carried out. Furthermore, the carbonucleoside 2'-methylcarbovir has been prepared from O-protected 4-hydroxymethyl-2-methyl-cyclopent-2-enone by Pd-catalyzed allylic amination.
Assuntos
Didesoxinucleosídeos/síntese química , Irídio/química , Prostaglandinas A Sintéticas/síntese química , Alquilação , Catálise , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Prostaglandinas A Sintéticas/química , EstereoisomerismoRESUMO
An enantioselective synthesis of new 12-amino alkylidenecyclopentenone prostaglandins is reported. The key step of the synthesis involved a [3.3] sigmatropic rearrangement of an asymmetric allylic cyanate to elaborate an asymmetric 5-amino-1,6-diene which was further transformed into cyclopentenone by successive ring-closing metathesis reaction catalyzed by the Grubbs reagent and one-pot oxidation. A palladium-catalyzed cross-coupling reaction on a 5-iodo-1,5-diene allowed the synthesis of prostanoids with variable Rw side chains. These new compounds exhibit high cytotoxic activities.