Antiviral and Interferon-Inducing Properties of 1,5-Diamino Anthraquinones

Abstract

A series of anthraquinones with amino substituents at the 1,5 positions were found to induce interferon in mice. A prototype compound, 1,5-bis [(3-morpholi- Interferon, a broad-spectrum antiviral protein produced by virus-infected cells, appears to be an important component of the host's antiviral defense system. Several high-molecular-weight substances other than viruses can also cause cellular production of interferon and consequently protect animals against a variety of viral infections (6, 16). In addition, several relatively low-molecular-weight compounds also stimulate production of interferon in vivo (1,4,5,(9)(10)(11)(12)(13). In an effort to broaden our understanding of molecular structural requirements necessary for in vivo or in vitro interferon stimulation, we initiated a search for molecules that possess the ability to induce interferon in mice and consequently protect them from lethal virus infection. During these studies several compounds were found to be active inducers. One of the most interesting of these agents was 1,5-bis[(3-morpholinopropyl)amino]-anthraquinone (Ia). This report summarizes our findings with Ia and three closely related structural analogs (Fig. 1).Studies were initiated to determine the kinetics of the serum interferon response, what cells produce interferon in vivo, the minimum dose needed to protect mice against virus infection, and the maximum tolerated dose when compounds were given by any of several routes.Particular attention was given to the development of a reduced ability of animals to respond to inducers when given in consecutive daily doses. It is well documented that animals and cells progressively lose their ability to respond to daily doses of the same interferon inducer (2,3,7,8,14,15,17). Such a reduced response could limit the use of inducers as effective antiviral agents, and studies were therefore undertaken to determine if such a situation could be controlled or avoided. How quickly hyporeactivity developed in response to each inducer, how long it persisted, and whether its onset could be avoided by alternating between injection of different inducers were explored.

Immunoenhancing properties and antiviral activity of 7-deazaguanosine in mice

“…This phenomenon applies to other interferon inducers (22). Also, hyporeactivity to interferon inducers occurs by repeated administration of compounds (20) and as a result of certain virus infections (19). It is highly probable that repeated treatments with 7-dzGuo will lead to hyporesponsiveness, although this has yet to be investigated.…”

Treatment of murine cytomegalovirus infections in severe combined immunodeficient mice with ganciclovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, interferon, and bropirimine

“…The evaluation of a once-weekly treatment regimen with HPMPC was based on a report indicating the prolonged effects of the nucleotide against herpes simplex virus in mice (31). Bropirimine was administered infrequently to avoid the hyporesponsive phenomenon that occurs with interferon inducers (28). The parameters used to assess antiviral activity included increased numbers of survivors and mean survival time and decreased tissue virus titers.…”

Chemotherapy of Viral Infections

“…Anthraquinones induced the highest interferon levels when given orally (STRINGFELLOW et al 1979). Maximal titers (1,000-10,000 U/ml serum) were reached 12-24 h after administration.…”

“…Maximal titers (1,000-10,000 U/ml serum) were reached 12-24 h after administration. It thus appears that nonlymphoid radiation-sensitive cells in the thymus and spleen, such as reticulocytes, may be involved in the interferon response (STRINGFELLOW et al 1979). Examination of organ levels revealed high interferon levels in spleen and thymus tissue collected from animals injected with each of the anthraquinone derivatives used.…”