5-Halo-6-phenyl pyrimidinones and 8-substituted guanosines: biological response modifiers with similar effects on B cells.
5-Halo-6-phenyl pyrimidinones, represented by 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and 2-amino-5-iodo-6-phenyl-4(3H)-pyrimidinone (AIPP), and 8-substituted guanosines, represented by 8-bromoguanosine (8-BrGuo) and 8-mercaptoguanosine (8-MGuo), are well-documented biological response modifiers. We have found that these substituted pyrimidinones and guanosines are very similar in their abilities to activate B cells. ABPP, AIPP, 8-BrGuo, and 8-MGuo induced murine B cells to polyclonally proliferate and differentiate in vitro. The maximal B-cell response levels and the kinetics of the responses elicited with both classes of compounds were comparable; however, ABPP and AIPP were approximately 10-fold more potent than 8-BrGuo and 8-MGuo. An additional similarity observed between the two classes was that polyclonal activation of B cells by ABPP, AIPP, 8-BrGuo, and 8-MGuo was limited to large B cells which had probably been activated previously in vivo. This is in contrast to lipopolysaccharide which is capable of inducing both large, activated B cells and small, resting B cells to proliferate and differentiate. Although substituted pyrimidinones and guanosines were not able to induce new DNA synthesis or antibody production in small B cells, both classes of compounds increased the expression of Ia antigens on the surface of both small and large B cells. These data, together with the recent observations that 8-BrGuo, like ABPP and AIPP, can stimulate NK and cytotoxic macrophage activity via the induction of interferon, strongly suggest that 5-halo-6-phenyl pyrimidinones and 8-substituted guanosines belong to the same structural class of biological response modifiers. Thus, the residues held in common by these two classes of stimulators may interact with the same cellular constituent in the target cells.
Wicker
L S
LS
Department of Immunology Research, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Ashton
W T
WT
Boltz
R C
RC
Meurer
L C
LC
Miller
B J
BJ
Nichols
E A
EA
Sigal
N H
NH
Tolman
R L
RL
Peterson
L B
LB
D000818:Animals; D001402:B-Lymphocytes / Q000145:classification / Q000166:cytology / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007399:Interphase / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D013872:Thionucleosides / Q000494:pharmacology*
D000949:Histocompatibility Antigens Class II; D013872:Thionucleosides; D006151:Guanosine; C035169:8-bromoguanosine; C033561:2-amino-5-iodo-6-phenyl-4-pyrimidinone; D003596:Cytosine; C037031:8-thioguanosine; C033560:bropirimine