Synthesis and Structure−Activity-Relationships of 1H-Imidazo[4,5-c]quinolines That Induce Interferon Production

Abstract

1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.

TLR7 and TLR8 as targets in cancer therapy

“…In most experimental studies in vitro, imiquimod concentrations of up to 5 mg ml À1 elicited a robust proinflammatory response by dendritic cells. A number of additional imidazoquinolines (some have been mentioned above) have been tested in vitro for their capacity to induce cytokine and chemokine production, and for some species effective concentrations of as low as 0.05 mg ml À1 have been described (Gerster et al, 2005). In addition, it has been shown in vivo that topically applied imiquimod induces functional maturation of epidermal Langerhans cells and stimulates migration of these antigen-presenting cells to regional lymph nodes where they presumably promote a specific T-cell response (Stanley, 2002).…”

“…Although these substances did not exert direct antiviral activities, some of them showed considerable indirect efficacy against virally induced lesions through TLR7/8-mediated induction of cytokines (Chen et al, 1988;Harrison et al, 1988;Gerster et al, 2005). Following the demonstration of profound antitumoral activities in preclinical models (Sidky et al, 1992), imidazoquinolines, the lead compound imiquimod in particular, have moved into the limelight of clinical and experimental oncology.…”

Synthesis and characterization of novel imidazoquinoline based 2-azetidinones as potent antimicrobial and anticancer agents

“…Compound (4-chloro-1-isobutyl-1H-imidazo [4,5-c] quinoline (6) was synthesized from 2,4 dihydroxyquinoline (1) according to a previously reported procedure [24]. The compound 4-hydrazino-1-isobutyl-1H-imidazo[4,5-c]quinoline (7) was prepared by the reaction of hydrazine hydrate with 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline (6).…”

Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis–Hillman adduct of o-nitrobenzaldehyde

“…Similar structures, in which a methyl group is used to protect pyrrole ring, have been synthesized to afford very potent antiviral, antibacterial and anticancer agents. 33,34 Directly used without any purification, methyl-protected pyrrole 8 was hydrogenated at room temperature in methanol using Pd/C under H 2 atmosphere, 35 yielding a very polar compound, which was identified as the stable hitherto unknown 4-ethyl-1-methyl-1H-pyrrolo- [3,2-c]quinoline N-oxide 9 36 with the nitrone function confined to a ring structure in good yield, after purification by column chromatography. The conversion was not quantitative and 16% of the starting material was still present in the mixture, as determined by 1 H NMR of the crude.…”