RESUMO
The synthesis of a series of esters of hycanthone (HC) and 7-hydroxyhycanthone, their antitumor activity, and their antischistosomal effects on HC-sensitive and HC-resistant schistosomes are reported. Binding studies using tritium-labeled HC and hycanthone N-methylcarbamate (HNMC) with calf thymus DNA provided evidence that HNMC but not HC alkylated the DNA. Tritiated HNMC also bound to the DNA of intact HeLa cells exposed to the drug while very little tritiated HC bound to DNA under the same conditions. The mechanism proposed previously to account for the antischistosomal action of HC, namely, drug esterification followed by alkylation of DNA, applies also to the antitumor action of the drug as shown in Scheme I.
Assuntos
Antineoplásicos/síntese química , Hicantone/uso terapêutico , Leucemia P388/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/síntese química , Tioxantenos/uso terapêutico , Animais , Hicantone/análogos & derivados , Hicantone/síntese química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Camundongos , Schistosoma mansoni/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
2-Hydroxyquinoline-4-hydrazide was condensed with some aromatic aldehydes and acetophenones to give the hydrazones 1a-h. It was also reacted with HCOOH, PhCOCl and p-CH3O-PhCOCl to afford 2a-c. Cyclization of 2b was completed by using PPA, POCl3 and/or P2S5, which gave compounds 3, 4, and 6 respectively. Reaction of 4 with some amines gave the corresponding derivatives 5a-f. The thiosemicarbazide 7 was cyclized under acid and basic condition to give the thiadiazolyl-8 and triazolyl-10 derivatives.
Assuntos
Antibacterianos/síntese química , Quinolinas/síntese química , Antifúngicos/síntese química , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Química , Quinolinas/farmacologiaRESUMO
Hycanthone analogues (5 and 6) containing 7-substituted hydroxyl groups were prepared and evaluated as antitumor agents. These compounds were significantly more active than the corresponding unsubstituted derivatives. The 7-hydroxylated 4-(hydroxymethyl)-9H-xanthen-9-ones, 11 and 12, were also active antitumor agents. However, the 7-hydroxy-9H-xanthen-9-one counterparts of the 7-hydroxylucanthones were totally devoid of antitumor activity. Results obtained thus far are consistent with the hypothesis that 4-hydroxymethyl substituents in the 9H-xanthen-9-one and 9H-thioxanthen-9-one series are required for antitumor activity.
