RESUMO
9-Methoxy-2-methylellipticinium acetate (6), along with the 9-methyl and 9-chloro derivatives (7, and 8, respectively) have shown remarkable selectivities in vitro against the NCI human CNS cancer subpanel. In order to target these types of compounds to the CNS in vivo, a series of 1,2-dihydroellipticines was synthesized. 9-Methoxy-2-methyl-1,2-dihydroellipticine (9) retained the potency and selectivity of the parent compound 6 but was unstable toward oxidation to 6. In order to improve the stability of 9, it was converted to the vinylogous amide 33 by introduction of a formyl group in the 4-position. Compound 33 proved to be much more stable than 9, but it was also less potent than 9 by about 1 order of magnitude, and it was less selective for the CNS subpanel than 9. To overcome the limited water solubilities of the ellipticines and dihydroellipticines, several ellipticine analogues incorporating polar groups on the N-2 nitrogen were prepared. The 2-(methoxymethyl)ellipticinium salts 24 and 25, as well as the (methylthio)methyl congener 26, were relatively potent anticancer agents which displayed cytotoxicity selectivity profiles similar to compound 6. The cytotoxic dihydroellipticines 9 and 10 exhibited potencies approaching that of ellipticine itself in facilitating the formation of a "cleavable complex", while the least cytotoxic ellipticine derivatives exhibited no cleavage above background.
Assuntos
Neoplasias Encefálicas/patologia , Elipticinas/síntese química , Neoplasias Encefálicas/tratamento farmacológico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Elipticinas/farmacologia , Humanos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
A series of 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers have been synthesized in an effort to develop a compound that could be used as a maintenance therapy to treat cocaine abuse. Since the effects of cocaine on dopamine (DA) and serotonin (5HT) transporters are important components of its pharmacological activity, the focus was on nonselective inhibitors of monoamine transport. To reduce or eliminate the abuse potential of a DA reuptake blocker, the compounds were designed to be slow-onset, long-duration prodrugs whose N-demethylated metabolites would have increased activity over the parent compound with the ideal being a parent compound that has little or no activity. To achieve this, pairs of compounds with different groups on the amine nitrogen and with and without an additional N-methyl group were synthesized. All of the synthesized compounds were screened for binding and reuptake at the cloned human DA, 5HT, and norepinephrine (NE) transporters. As previously found, trans isomers are nonselective blockers of DA, 5HT, and NE reuptake, cis isomers with small N-alkyl groups are selective blockers of 5HT reuptake, and tertiary amines of the trans compounds are less potent than the corresponding N-demethylated secondary amines as blockers of DA reuptake. Larger N-alkyl groups in both the trans and cis series were found to reduce activity for the 5HT and NE transporters with less effect at DA transporters. Selected trans compounds were also screened for locomotor activity in mice and generalization to a cocaine-like profile in rats. With intraperitoneal administration, all of the trans isomers showed a slow onset of at least 20 min and an extremely long duration of action in the locomotor assays. Several of the trans compounds also fully generalized to a cocaine-like pharmacological profile. An initial lead compound, the N,N-dimethyl analogue trans-1b, was resolved into chirally pure enantiomers. Surprisingly, both enantiomers were found to have significant affinity for the DA transporter and to cause locomotor activation. This is in contrast to the N-methyl compound in which only the (+)-enantiomer had significant activity. The absolute configuration of the more active enantiomer was determined by X-ray crystallography to be 3R,1S.
Assuntos
Indanos/síntese química , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Inibidores da Captação de Neurotransmissores/síntese química , Simportadores , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular , Clonagem Molecular , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cristalografia por Raios X , Aprendizagem por Discriminação/efeitos dos fármacos , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Indanos/química , Indanos/metabolismo , Indanos/farmacologia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An array of novel 2-acyl-1,2-dihydroellipticines was prepared and evaluated for in vitro cytotoxicity in a variety of human cancer cell lines. The ellipticine analogs were also tested for inhibition of topoisomerase II in both decatenation and cleavable complex formation assays. Some of the new ellipticine derivatives were prepared by acylation of ellipticine with acid chlorides in tetrahydrofuran, followed by reduction of the intermediate 2-acylellipticinium ions with sodium cyanoborohydride. Others were synthesized by acylation of ellipticine with p-nitrophenyl chloroformate, reduction of the 2-acylellipticinium ion with sodium cyanoborohydride, and displacement of the p-nitrophenoxide anion with a variety of oxygen and nitrogen nucleophiles. The cytotoxicities of the new 2-acyl-1,2-dihydroellipticines varied widely, and correlated well with their topoisomerase II inhibitory activities.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Elipticinas/síntese química , Elipticinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores da Topoisomerase II , Antineoplásicos Fitogênicos/química , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Elipticinas/química , Inibidores Enzimáticos/química , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Células Tumorais CultivadasRESUMO
An asymmetric synthesis of [beta-(4-pyridyl-1-oxide)-L-alanine4]-angiotensin I (1a), which is a potential suicide substrate (mechanism-based inhibitor) for protein-tyrosine kinases, has been performed. Deprotonation of 6 with n-butyllithium in THF gave the anion 7, which was alkylated with 4-(chloromethyl)pyridine-1-oxide to afford intermediate 9 as a crystalline solid. Hydrolysis of 9 afforded a mixture of 11 and 12 in a ratio of 96:4 as estimated by conversion to the diastereomeric dipeptides 13 and 14 followed by HPLC analysis. The 96:4 mixture of 11 and 12 was used in the solid phase synthesis of the target angiotensin analog 1a and its diastereomer 1b, which were separated and tested for inhibitory activity against two thymocyte protein-tyrosine kinases: p40 and p56lck. Neither peptide displayed significant inhibitory activity toward p40 and both served as weak competitive inhibitors of p56lck.