Abasic analogues of TSAO-T as the first sugar derivatives that specifically inhibit HIV-1 reverse transcriptase.
With the aim of assessing the role that the thymine base of TSAO-T may play in the interaction of TSAO compounds with HIV-1 reverse transcriptase (RT), we have designed, synthesized, and evaluated for their anti-HIV-1 activity a series of 3-spiro sugar derivatives substituted at the anomeric position with nonaromatic rings or with amine, amide, urea, or thiourea moieties that mimic parts or the whole thymine base of TSAO-T. Also, a dihydrouracil TSAO analogue and O-glycosyl 3-spiro sugar derivatives substituted at the anomeric position with methyloxy or benzyloxy groups have been prepared. Compounds substituted at the anomeric position with an azido, amino, or methoxy group, respectively, were devoid of marked antiviral activity (EC50: 10-200 microM). However, the substituted urea sugar derivatives led to an increase in antiviral potency (EC50: 0.35-4 microM), among them those urea derivatives that mimic most closely the intact TSAO-T molecule retained the highest antiviral activity. Also, the dihydrouracil TSAO derivative retained pronounced anti-HIV-1 activity. None of the compounds showed any anti-HIV-2 activity. The results described herein represent the first examples of sugar derivatives that interact in a specific manner with HIV-1 RT. Molecular modeling studies carried out with a prototype urea derivative indicate that a heteroaromatic ring is not an absolute requirement for a favorable interaction between TSAO-T and HIV-1 RT. Urea derivatives, which can mimic to a large extent both the shape and the electrostatic potential of a thymine ring, can effectively replace this nucleic acid base when incorporated into a TSAO molecular framework with only moderate loss of activity.
Velázquez
S
S
Instituto de Química Médica, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain.
Chamorro
C
C
Pérez-Pérez
M J
MJ
Alvarez
R
R
Jimeno
M L
ML
Martín-Domenech
A
A
Pérez
C
C
Gago
F
F
De Clercq
E
E
Balzarini
J
J
San-Félix
A
A
Camarasa
M J
MJ
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D002241:Carbohydrates; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D014508:Urea; D054303:HIV Reverse Transcriptase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine