A new class of HIV-1 specific 6-substituted acyclouridine derivatives: synthesis and anti-HIV-1 activity of 5- or 6-substituted analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Abstract

A series of novel acyclouridine derivatives substituted at both the C-5 and C-6 positions were synthesized for the purpose of improving the activity of a recently reported HIV-1-specific lead, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). Preparation of C-6 substituted derivatives was carried out based on the following three methods: (1) LDA (lithium diisopropylamide) lithiation of a thymine derivative (4) and subsequent reaction with electrophiles, (2) an addition-elimination reaction of HEPT or its 6-(phenylsulfinyl) derivative (10), or (3) palladium-catalyzed cross-coupling between a 6-iodo derivative (16) and terminal alkynes. Following the methods, 21 C-6 substituted analogues were synthesized. Among these, 6-(cyclohexylthio) (8), 6-phenoxy (13), and 6-benzyl (27) derivatives showed anti-HIV-1 (HTLV-IIIB) activity with EC50 values of 8.2, 85, and 23 microM, respectively. Preparation of C-5 substituted derivatives was based on either LTMP (lithium 2,2,6,6-tetramethylpiperidide) lithiation of 6-(phenylthio)uracil derivative 37 or the above mentioned palladium-catalyzed cross-coupling of a 5-iodo-6-(phenylthio)uracil derivative (38). Following these methods, 11 C-5 substituted analogues were synthesized. Some 5-substituted derivatives (5-I, 44; 5-CH = CPh2, 49; 5-CH = CHPh (Z), 54; and 5-CH = CH2, 55) were more active than HEPT, but their selectivity indices (SI = CC50/EC50) were lower than that of HEPT. Compound 8 was also evaluated against another HIV-1 strain (HTLV-IIIRF) and HIV-2 strains (LAV-2ROD and LAV-2EHO). Only HTLV-IIIRF was as sensitive as HTLV-IIIB.

[2',5'-Bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives of purine and pyrimidinenucleosides as potent and selective inhibitors of human immunodeficiency virus type 1

“…The Pa values for AZT and compound 2 were 1.12 and 0.117, respectively. Compounds 3,4,6,7,9,12,13,14,18,24,27, and 33 were found to be present for more than 95% in the n-octanol phase. Consequently, the Pa values could not be accurately determined.…”

“…These highly specific HIV-1 inhibitors include the 6-substituted acyclouridine derivatives {i.e., 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT)} (1-4, 27), benzodiazepinone and benzodiazepinthione (TIBO) derivatives [i.e., tetrahydroimidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-one and tetrahydroimidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-thione] (17,21), dipyridodiazepinones (i.e., BI-RG-587) (16,19), pyridinones (i.e., L-697,639 and L-697,661) (14), and bis(hetero)arylpiperazine (BHAP) (24). All these classes of compounds seem to be targeted at the HIV-1 reverse transcriptase (RT) (2,9,11,13,14,19,21,27,28). We have now identified a novel class of compounds, i.e., [2',5'-bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) (TSAO) derivatives of pyrimidine and purine nucleosides, that selectively inhibit the replication of HIV-1 but not that of HIV-2, SIV, or other retroviruses.…”

Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3'-azido-3'-deoxythymidine or 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro

“…In contrast, nucleoside analog inhibitors, such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine, and 2',3'-dideoxycytidine (ddC), mimic the normal deoxynucleotide triphosphate substrate for RT and thus act as chain terminators during proviral synthesis (31). Other nonnucleoside RT inhibitors include dipyridodiazepinones (nevirapine) (18,23), pyridinones (L-697,661) (12), thiobenzimidazolone compounds (TIBO Ro82150) (25), and the more recently reported TSAO [2',5' -bis-O-(tert-butyl-dimethylsilyl)-3' -spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide)pyrimidine] and HEPT {1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine} compounds (2,32).…”

Antiretroviral therapy: reverse transcriptase inhibition

“…There are numerous other candidate nucleoside analogs which are under investigation, with chemical modifications designed to maximize activity against the viral RT, improve the pharmacokinetic profile, and minimize toxicity. Among these are halogenated nucleosides (85), nucleotide dimers (83), and a series of acyclic and carbocyclic nucleoside analogs, such as carbovir (carbocyclic 2',3'-didehydro-2,3-dideoxyguanosine) (10) and HEPT {1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine} (93). HEPT derivatives are nucleoside analogs that do not require anabolic phosphorylation for their activity and are HIV-1 specific (2); thus, they possess the characteristics of some of the nonnucleoside RT inhibitors (see below).…”