RESUMO
Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.
Assuntos
Inibidores Enzimáticos/farmacologia , Tiamina/análogos & derivados , Transcetolase/antagonistas & inibidores , Animais , Catálise , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Camundongos , Conformação Proteica , Relação Estrutura-Atividade , Tiamina/química , Tiamina/farmacologiaRESUMO
Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiamina/análogos & derivados , Tiamina/antagonistas & inibidores , Transcetolase/antagonistas & inibidores , Animais , Neoplasias do Colo/enzimologia , Cristalografia por Raios X , Glucosefosfato Desidrogenase/metabolismo , Humanos , Técnicas In Vitro , Complexo Cetoglutarato Desidrogenase/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Estrutura Molecular , Oxitiamina/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/enzimologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The microbiological hydroxylation of some 3 alpha,5-cycloandrostanes by the fungus, Cephalosporium aphidicola has been shown to take place at C-2 alpha and C-14 alpha and a 6 beta-alcohol was oxidized to the 6-ketone.
Assuntos
Acremonium/metabolismo , Androstanos/metabolismo , Androstanos/química , Hidroxilação , Conformação Molecular , Estrutura Molecular , OxirreduçãoRESUMO
Samarium(II) iodide was used to access eight-, nine-, and ten-membered carbocycles via a domino reaction composed of a cyclization/fragmentation process. 2-(Iodoalkyl)-, 2-(iodomethyl)allyl-, and 2-(2-iodomethyl)benzyl-2-methyl-3-(methanesulfonyloxy)cycloalkanones were subjected to Barbier-type reductive coupling conditions. Intermediate cycloalkanedione derivatives were also treated under similar conditions, providing bicyclic hydroxy ketones with complete diastereoselectivity and high yields. This method represents a general and efficient approach to a variety of highly functionalized, stereodefined carbocycles.
Assuntos
Alcanos/química , Iodetos/química , Samário/química , Alquilação , Ciclização , Cetonas/química , OxirreduçãoRESUMO
A series of new acetogenin analogues incorporating a central catechol moiety instead of the tetrahydrofuran ring(s) have been prepared and tested against L1210 leukemia cells. Although less potent than bullatacinone, which has the same terminal lactone, these compounds display interesting cell cycle effects.
Assuntos
4-Butirolactona/análogos & derivados , Annonaceae/química , Antineoplásicos Fitogênicos/farmacologia , Álcoois Graxos/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Catecóis/química , Ciclo Celular/efeitos dos fármacos , Álcoois Graxos/síntese química , Citometria de Fluxo , Indicadores e Reagentes , Leucemia L1210/tratamento farmacológico , Leucemia L1210/patologia , Camundongos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A set of 16 new simplified analogues of acetogenins has been designed based on: (i) the replacement of the bis THF moiety of these natural products by an ethylene glycol bis ether unit; (ii) the introduction of different lipophilic side chains (alkyl, aryl, dialkylamino, O-cholesteryl); (iii) the presence of the same terminal isolactone. In vitro cytotoxic activity against L1210 leukemia is reported.