A new class of HIV-1-specific 6-substituted acyclouridine derivatives: synthesis and anti-HIV-1 activity of 5- or 6-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
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.
Tanaka
H
H
School of Pharmaceutical Science, Showa University, Tokyo, Japan.
Baba
M
M
Hayakawa
H
H
Sakamaki
T
T
Miyasaka
T
T
Ubasawa
M
M
Takashima
H
H
Sekiya
K
K
Nitta
I
I
Shigeta
S
S
D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D007202:Indicators and Reagents; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D013941:Thymine