Synthesis of the pyrrolo[3,2-d]pyrimidine C-nucleoside isostere of inosine

Lim, Mu-Ill; Klein, Robert S.; Fox, Jack J.

doi:10.1016/s0040-4039(00)78826-5

Cited by 45 publications

(10 citation statements)

References 10 publications

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“…Amantadine (Symmetrel) was purchased from Du Pont Pharmaceuticals, Garden City, N.Y. Dideoxyinosine (DDI) and Isoprinosine were obtained from Barbara Laughon, Developmental Therapeutics Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases. 9-Deazainosine (9D1) was synthesized by previously described methods (25,26); additional amounts of 9DI were provided by Barbara Laughon.…”

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Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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The efficacy of antifolate, antiviral, and other drugs was compared in an experimental model of pneumocystosis. Sulfamethoxazole (SMX) administered alone in doses of .60 mg/kg/day was highly effective in treatment and prophylaxis. Low (c15 mg/kg/day) doses of SMX showed limited, dose-related antiPneumocystis carinii activity in therapy but were more effective in prophylaxis. The dihydrofolate reductase (DHFR) inhibitors trimethoprim (TMP), pyrimethamine, and trimetrexate exhibited little anti-P. carinii activity when administered alone and did not enhance the efficacy of SMX; the effects of the DHFR inhibitors could not be related to the dose or the concentration in serum. These data suggested that the rat model is an excellent system for studying the anti-P. carinii activity of sulfonamides but is of limited value in studying DHFR inhibitors. The antiviral drugs azidothymidine, dideoxyinosine, inosine pranobex (Isoprinosine), amantadine, and acyclovir displayed little or no activity against P. carinii; however, azidothymidine did not impair the efficacy of SMX or TMP-SMX. These results supported the clinical practice of giving antiviral agents together with antifolate drugs to patients infected with human immunodeficiency virus and suggested that the beneficial effects of antiviral agents on the occurrence of pneumocystosis are due mainly to their effects on the virus or the host immune response. In contrast to the antiviral drugs, 9-deazainosine, a nucleoside analog with antiprotozoal properties, deinonstrated marked activity against P. carinii which was related to dose and route of administration. These data raised the possibility that anti-P. carinii activity is a general property of purine nucleosides Experimental studies of anti-P. carinii drugs have usually been performed in an immunosuppressed rat model of pneumocystosis, which is a reliable predictor of activity against the human form of the disease (10,13,20). In a previous study of antifolate drugs in this model (34), we found that anti-P. carinii activity was a general property of sulfonamides; these compounds were so effective that a doseresponse curve could not be established at the doses used. By contrast, DHFR inhibitors exhibited little anti-P. carinii activity and did not improve the efficacy of the sulfonamides * Corresponding author.or the sulfone dapsone. This lack of synergism differed from the results of previous workers (10,14,15) and raised questions about the value of using the rat model to screen antifolate drugs.In the present study, we have extended these observations by exploring the effect of lower doses of the sulfonamide sulfamethoxazole (SMX) in the therapy of experimental pneumocystosis. We

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Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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“…Following initial attempts to synthesise the target TS analogue of nucleoside hydrolases, the "sketch" of which bore similarities to the PNP TS blueprint, in his own laboratories Schramm approached Richard Furneaux's carbohydrate chemistry group in New Zealand where he and Peter Tyler had extensive experience synthesising iminosugars and in particular derivatives of castanospermine [72][73][74][75][76] and deoxymannojirimycin. 77 Tyler adapted the C-nucleoside synthesis of the deazapurines: deazainosine, 78 deazaadenosine, 79 and deazaguanosine (Fig. 6).…”

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confidence: 99%

The transition to magic bullets – transition state analogue drug design

2018

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“…The resulting C-nucleosides show interesting biological activity and they are also endowed with stability towards chemical or enzymatic cleavage. 6 C-Nucleoside analogues of cytidine (1-deazacytidine), 7 guanosine (9-deazaguanosine), 8 adenosine (9-deazaadenosine, Figure 1) 9 and inosine (9-deazainosine, Figure 1) 10 have been synthesized and studied. In fact, 9deazainosine is active against Trypanosoma brucei subsp.…”

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confidence: 99%