121288-39-9Relevant articles and documents
Guanosine derivatives as immunostimulants. Discovery of loxoribine
Chen,Goodman,Argentieri,Bell,Burr,Come,Goodman,Klaubert,Maryanoff,Pope,Rampulla,Schott,Reitz
, p. 551 - 562 (1994)
7-Allyl-8-oxoguanosine (loxoribine, 5) was selected from a series of guanosine derivatives for further evaluation as an immunostimulant. Numerous related analogs were also synthesized and evaluated: 2',3'-ketals of 5 are particularly interesting because they are active, apparently without being cleaved to the free nucleoside.
Small-molecule immunostimulants. Synthesis and activity of 7,8- disubstituted guanosines and structurally related compounds
Reitz,Goodman,Pope,Argentieri,Bell,Burr,Chourmouzis,Come,Goodman,Klaubert,Maryanoff,McDonnell,Rampulla,Schott,Chen
, p. 3561 - 3578 (2007/10/02)
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.
A CONVINIENT SYNTHESIS OF 7-ALLYL-8-SUBSTITUTED GUANOSINES
Come, J.,Burr, L.,Chen, R.
, p. 4823 - 4826 (2007/10/02)
An efficient and useful synthesis of 7-allyl-8-substituted guanosine derivatives has been achieved using a Claisen rearrangement as the key step.
