2',3'-Didehydro-2',3'-dideoxy-5-hydroxymethyluridine

The conformation of mono- and dimethoxybenzoic acids in solution was determined from their IR spectra and (13)C and (1)H NMR spectra. The main feature is a strong intramolecular hydrogen bond in all 2-methoxy derivatives that persists even in polar aprotic solvents but not in methanol. The methyl groups are mostly coplanar with the ring plane, the two planar conformations are almost equally abundant, and their conformation is not responsible for some enhanced values of the enthalpy of formation. The hydrogen bond (and possibly dimerization) is the reason for differences in the relative acidities (deltapK = pK - pK(H)) measured either in dimethyl sulfoxide or in methanol and also for the differences between deltapK values of methoxybenzoic acids and corresponding methylbenzoic acids. Nevertheless, it was possible to separate with good approximation the polar and steric effects on the acidity. The steric effects in methanol are then parallel for methyl- and methoxybenzoic acids despite variable conformation of the latter. Steric effects in dimethyl sulfoxide are smaller and less regular. The acidity enhancement by ortho substituents is better described as electrostatic induction in the anion rather than a steric hindrance.

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Imidazo[1,5-b]Pyridazine-D4T Conjugates: Synthesis and Anti-Human Immunodeficiency Virus Evaluation

Renoud‐Grappin

Fossey

Fontaine

et al. 1998

Antivir Chem Chemother

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In an attempt to combine the human immunodeficiency virus type 1 (HIV-1)-inhibitory capacity of 2',3'-dideoxy-2',3'-didehydronucleoside analogues [nucleoside reverse transcriptase (RT) inhibitors; NRTI] and non-nucleoside RT inhibitors (NNRTI), we have designed, synthesized and evaluated for their anti-HIV activity several heterodimers of the general formula [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine]. The synthesis of these heterodimers was conducted in three parts. The first part focused on the synthesis of the NRTI. The second part was devoted to the NNRTI and the NNRTI linked to appropriate spacers: [NNRTI]-NH-(CH2)n-NH2. In the third part, the condensation between the NRTI and the [NNRTI]-NH-(CH2)n-NH2 was performed. The in vitro inhibitory activities against HIV-1 of the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers were found to be comparable to that of d4T (stavudine) in HIV-infected cells. Moreover, the heterodimers were endowed with anti-HIV-2 activity and with anti-nevirapine-resistant HIV-1 activity. None of the heterodimers proved markedly cytotoxic to CEM-SS or MT-4 cells. There was not a clear trend toward antiviral potency on lengthening the methylene spacer in the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers.

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2',3'-Didehydro-2',3'-dideoxy-5-hydroxymethyluridine

Cited by 3 publications

References 8 publications

Alternative synthetic routes to 2′,3′-didehydro-2′,3′-dideoxy-5-hydroxymethyluridine

Alternative synthetic routes to 2′,3′-didehydro-2′,3′-dideoxy-5-hydroxymethyluridine

Conformation and Steric Effects in Mono- and Dimethoxybenzoic Acids

Imidazo[1,5-b]Pyridazine-D4T Conjugates: Synthesis and Anti-Human Immunodeficiency Virus Evaluation

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