RESUMEN
Hydrolysis of phosphatidylnucleosides, 5'-(rac-1-hexadecyl-2-palmitoyl-sn-glycero-3-phosphoryl)-3'-azido- 3'-deoxythymidine and -2',3'-didehydro-3'-deoxythymidine, effected by phospholipases (PL) A2, C, and D was studied to reveal the metabolism of these derivatives. It was shown that PLA2 deacetylates the glycerol residue at position 2, PLC is inactive, and PLD hydrolyzes the phosphatidylnucleosides to give free nucleosides.
Asunto(s)
Didesoxinucleósidos/química , Ácidos Fosfatidicos/química , Fármacos Anti-VIH/química , Hidrólisis , Fosfolipasa D/química , Fosfolipasas/química , Fosfolipasas A/química , Fosfolipasas A2 , Especificidad por Sustrato , Fosfolipasas de Tipo C/químicaRESUMEN
An effective synthesis of thymogen was developed. Conjugates of 2',3'-didehydro-3'-deoxythymidine (nucleoside d4T) with thymogen were prepared in which the nucleoside hydroxyl group was linked to the thymogen carboxyl group of either tryprophan or glutamic acid residues. It was shown that the anti-HIV activity of the d4T-thymogene conjugate with the tryptophan linkage was comparable to that of d4T, whereas its cytotoxicity was nil. The d4T-tryptophan conjugate also displayed high anti-HIV activity.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Dipéptidos , VIH-1/efectos de los fármacos , Péptidos/síntesis química , Péptidos/farmacología , Estavudina/química , Estavudina/farmacología , Humanos , Péptidos/químicaRESUMEN
New nucleoside-phospholipid conjugates were synthesized based on 1,2-disubstituted glycerides and nucleosides. These contain rac-1-hexadecyl-2-palmitoyl(or 2-methylcarbamoyl)-sn-glycero-3-phosphate as the phospholipid component and 2',3'-didehydro-3'-deoxythymidine, 1-(Z-5-hydroxypentene-2-yl)thymine, or 2',3'-isopropylideneuridine as a nucleoside component. The conjugates were synthesized by three different ways: from rac-1-hexadecyl-2-acyl-sn-glycero-3-phospodichlorides, -3-phosphatidic acids, or -3-H-phosphonates. When subjected to mild alkaline hydrolysis, conjugates containing a 2-palmitoyl group formed conjugates with the lysophospholipid component that had not yet been described. All the conjugates obtained were amorphous compounds stable at room temperature. Their hemolytic and anti-HIV activities were determined. Some conjugates were found to completely inhibit in vitro HIV-1 reproduction in lower doses than the corresponding nucleosides.