Immunostimulation: Synthetic and Biological Modulators of Immunity

Fudenberg, H. Hugh; Whitten, H. D.

doi:10.1146/annurev.pa.24.040184.001051

Cited by 25 publications

(5 citation statements)

References 52 publications

(45 reference statements)

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“…18 mL ofMeOH. After scratching, a crystalline solid emerged which was filtered and collected (88 mg): mp 275-330 °C dec; IR (KBr) 1697,1643,1548,1494,1444,1378 cm-1; NMR (400-MHz, DMSO-de) 3.42-3.46 (m, 1H), 3.54-3.57 (m, 1H), 3.98 (t, J = 5.5 Hz), 4.30-4.35 (m, 2H), 4.5-5.1 (bs, 2H), 5.3-5.8 (bs, 1H), 6.59 (s, 2H), 6.72-6.74 (d, J = 6.6 Hz), 11.1 (s, 1H). The 1H NMR revealed the presence of a small amount of DMF (ca.…”

Section: Discussionmentioning

confidence: 99%

“…The supernatant was decanted, and the residual oil was triturated in water to cause precipitation of a white solid which was recrystallized from MeOHether. The first crop which emerged was pure by TLC; this sample was dried under vacuum for 1 d at 75 °C to give 360 mg of 90 (mp 215-217 °C): FAB-MS m/e 298 (M + 1, base peak); NMR (DMSOde) 3.43 (m, 2H), 3.63 (t, 2H), 4.61 (t, 1H, exchangeable), 4.89 (d, 2H, exchangeable), 5.03 (d, 1H), 5.15 (d, 1H), 5.46 (s, 2H), 5.92 (m, 1H), 6.78 (s, 2H, exchangeable), 11.08 (s, 1H, exchangeable). Anal.…”

Section: -Amino-7-(2-propenyl)-9-[5'-(#er#-butyldiphenylsilyl)-mentioning

confidence: 99%

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Small-Molecule Immunostimulants. Synthesis and Activity of 7,8-Disubstituted Guanosines and Structurally Related Compounds

Reitz

Goodman²,

Pope³

et al. 1994

J. Med. Chem.

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A series of 7,8-disubstituted guanosine derivatives was designed and prepared as potential B-cell-selective activators of the humoral immune response. These compounds were evaluated for their ability to act as B-cell mitogens and to augment the antibody response of B cells to sheep red blood cell (SRBC) challenge (adjuvanticity). In addition, they were tested for their ability to stimulate the natural killer (NK) cell response in murine in vitro cell assays. Certain of the compounds demonstrated in vivo activity when administered either intravenously, subcutaneously, or orally. Analogues with a medium-length alkyl chain (2-4 carbons, 5-7) on the 7-position of 7-alkyl-8-oxoguanosines were found to be particularly potent. Compounds bearing hydroxyalkyl, aminoalkyl, or substituted aminoalkyl substituents on this 7-position were weakly active. However, benzyl groups, including those substituted with heteroatoms (e.g., p-nitrobenzyl, 14), were active. Oxo, thioxo, and seleno groups on C-8 of the guanosine ring all imparted strong activity, whereas other larger substituents did not (e.g., N = CN). Stereochemical inversion of the 2'-hydroxyl on the ribose ring in this series, giving arabinose analogue 70, lessened activity. However, removal of the 2'-hydroxyl, either with (64) or without (73) removal of the 3'-hydroxyl, resulted in excellent activity and improved solubility; 64 also displayed good oral in vivo activity as well. A series of ketals involving the 2',3'-hydroxyls were prepared; certain of the nonpolar ketals (e.g., 48) were remarkably active, pointing to an ancillary hydrophobic binding region that can augment activity. 5'-Phosphate derivative 57 was fairly active, and acyclovir analogue 90 displayed good NK-selective activity: other N-9 sugar mimetics were also active (97-104), although this activity did not carry over into the human B-cell assay. A total of 80 compounds were prepared and evaluated for their immunostimulating activity. Within this group, compounds could be divided into those that were active in all three assays, those that displayed some measure of selectivity for the adjuvanticity assay, and those that preferentially activated NK responses. Because of its overall biological profile and ease of synthesis, 7-allyl-8-oxoguanosine (6; loxoribine, RWJ-21757) was chosen for further development. It is among the most potent compounds evaluated in the three biological assays.

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Section: Discussionmentioning

confidence: 99%

Section: -Amino-7-(2-propenyl)-9-[5'-(#er#-butyldiphenylsilyl)-mentioning

confidence: 99%

Small-Molecule Immunostimulants. Synthesis and Activity of 7,8-Disubstituted Guanosines and Structurally Related Compounds

Reitz

Goodman²,

Pope³

et al. 1994

J. Med. Chem.

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“…Early in vivo and in vitro studies on the immunomodulating activity of IP, dating roughly back to the first two decades of its use, have been presented in various review papers [1, 8, 29–32]. We here summarize the main findings from these studies together with results from more recent publications which may shed further light on the pharmacological activity of IP (Table 1).…”

Section: Immunomodulating Activitymentioning

confidence: 98%

Inosine Pranobex: A Key Player in the Game Against a Wide Range of Viral Infections and Non-Infectious Diseases

Slíva

Pantzartzi²,

Votava³

2019

Adv Ther

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Inosine pranobex (IP), commonly known as inosine acedoben dimepranol, isoprinosine and methisoprinol, has been proven to positively impact the host's immune system, by enhancing T-cell lymphocyte proliferation and activity of natural killer cells, increasing levels of proinflammatory cytokines, and thereby restoring deficient responses in immunosuppressed patients. At the same time, it has been shown that it can affect viral RNA levels and hence inhibit growth of several viruses. Due to its immunomodulatory and antiviral properties, and its safety profile, it has been widely used since 1971 against viral infections and diseases, among which subacute sclerosis panencephalitis, herpes simplex virus, human papilloma virus, human immunodeficiency virus, influenza and acute respiratory infections, cytomegalovirus and Epstein-Barr virus infections.Following an analysis of almost five decades of scientific literature since its original approval, we here summarize in vivo and in vitro studies manifesting the means in which IP impacts the host's immune system. We also provide a synopsis of therapeutic trials in the majority of which IP was found to have a beneficial effect. Lastly, positive results from limited studies, suggesting the putative future use of IP in new therapeutic indications are briefly described. In order to support use of IP against viral infections apart from those already approved, and to establish its use in clinical practice, further welldesigned and executed trials are warranted. Funding: Ewopharma International.

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“…INF and interferon inducers are currently being studied for their effects in the treatment of chronic inflammatory, malignant, and infectious diseases (Fudenberg & Whitten 1984;Bardana 1985;Mannering & Deloria 1986). It is quite probable that patients who are given INF or interferon inducers will also be receiving other drugs which are eliminated primarily via hepatic metabolism.…”

Section: Poly I:c Interferonmentioning

confidence: 99%

Perturbation of Metabolism and Disposition of Cyclophosphamide by Interferon and Poly I:C, an Interferon Inducer, in Mice

Ishikawa¹,

Sasaki²,

Takayanagi³

et al. 1991

Pharmacology & Toxicology

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The effects of interferon and poly I:C on the metabolism and disposition of cyclophosphamide were investigated in mice. Elimination of cyclophosphamide from the blood was decreased in mice treated 24 hr previously with interferon (2.5 x 10(6) U/kg, intraperitoneally) or poly I:C (10 mg/kg, intraperitoneally). The blood half-life of cyclophosphamide in interferon or poly I:C-pretreated mice was prolonged to a first order of disappearance of 29.3 and 41.6 min., respectively, compared to 19.0 min. in control mice. Also, the rate of formation of activated cyclophosphamide was delayed and the peak blood level of activated cyclophosphamide was not as high in poly I:C-pretreated and interferon-pretreated mice as in control mice. The decreased elimination and elevated blood levels of activated cyclophosphamide were reflected by changes in its antitumour activity and toxicity in the mice. In 9,000 x g supernatants prepared from the liver homogenate of mice treated with interferon or poly I:C, the oxidation of cyclophosphamide in vitro has decreased by 29 and 37%, respectively. However, the addition of these agents to normal 9,000 x g supernatant suspensions had no effect on cyclophosphamide oxidation. Modulation of the metabolism and disposition resulted from depressed levels of cytochrome P-450 in the hepatic microsomes of the mice administered interferon or poly I:C.

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Immunostimulation: Synthetic and Biological Modulators of Immunity

Cited by 25 publications

References 52 publications

Small-Molecule Immunostimulants. Synthesis and Activity of 7,8-Disubstituted Guanosines and Structurally Related Compounds

Small-Molecule Immunostimulants. Synthesis and Activity of 7,8-Disubstituted Guanosines and Structurally Related Compounds

Inosine Pranobex: A Key Player in the Game Against a Wide Range of Viral Infections and Non-Infectious Diseases

Perturbation of Metabolism and Disposition of Cyclophosphamide by Interferon and Poly I:C, an Interferon Inducer, in Mice

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