Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox). Both TRYP and TRYP-Ox inhibited matrix metalloproteinase (MMP)-3 gene expression in interleukin (IL)-1b-stimulated primary human FLS, as well as IL-1b-induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, human umbilical vein endothelial cells (HUVECs), and monocytic THP-1 cells, although TRYP-Ox was generally more effective and had no cytotoxicity in vitro. Evaluation of the therapeutic potential of TRYP and TRYP-Ox in vivo in murine arthritis models showed that both compounds significantly attenuated the development of collagen-induced arthritis (CIA) and collagen-antibody-induced arthritis (CAIA), with comparable efficacy. Collagen II (CII)specific antibody levels were similarly reduced in TRYP-and TRYP-Ox-treated CIA mice. TRYP and TRYP-Ox also suppressed proinflammatory cytokine production by lymph node cells from CIA mice, with TRYP-Ox being more effective in inhibiting IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-kB ligand (RANKL). Thus, even though TRYP-Ox generally had a better in vitro profile, possibly due to its ability to inhibit c-Jun N-terminal kinase (JNK), both TRYP and TRYP-Ox were equally effective in inhibiting the clinical symptoms and damage associated with RA. Overall, TRYP and/or TRYP-Ox may represent potential new directions for the pursuit of novel treatments for RA.

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

“…A number of JNK inhibitors with anti-inflammatory properties have been developed [ 158 ], yet few have been developed for the treatment of rheumatoid arthritis. Recently, we reported that 11 H -indeno[1,2- b ]quinoxalin-11-one oxime (compound 30 ), its sodium salt IQ-1S , and tryptanthrin-6-oxime (compound 31 ) were JNK inhibitors [ 41 , 116 ]. We found that the side chain oxime substituent was critical for JNK binding and biological activity of these compounds [ 38 , 41 ].…”

“…Finally, 31 was anchored in the JNK3 cavity via H-bonding of the oxime group with Asp207 [ 38 ]. Compound 31 demonstrated high binding activity toward all three JNK isoforms (JNK 1-3) [ 38 ], inhibited MMP-3 gene expression in IL-1β-stimulated human FLS, and inhibited IL-1β-induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, HUVECs, and monocytic THP-1 cells [ 116 ]. Evaluation of the therapeutic potential of compound 31 in vivo in murine arthritis models showed that it attenuated the development of CIA and collagen-antibody-induced arthritis (CAIA).…”

“…Collagen II-specific antibody levels were reduced in compound 31 -treated CIA mice. This compound also suppressed the production of proinflammatory cytokines IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-κB ligand (RANKL) by lymph node cells from CIA mice [ 116 ].…”

Degradation Products of Tryptophan in Cell Culture Media: Contribution to Color and Toxicity

“…Pityriacitrin (32) and pityriacitrin B (31) have demonstrated toxicity against some cancer cell lines [33], and while eudistomin U (34) displayed some toxicity in human cancer cell lines, it was most potent as an antibacterial agent [34]. Tryptanthrin ( 39) is known to exhibit low micromolar toxicity against a wide range of both cancerous and non-cancerous human cell lines [29,35,36]. As we have demonstrated that these compounds are generated from degraded Trp, it was of interest to investigate the toxicity of these and the other established Trp degradants in CHO cells, the most prevalent cell type used in the biomanufacturing industry.…”

Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold

“…Previously, we identified a new class of JNK inhibitors based on the 11 H -indeno[1,2- b ]quinoxalin-11-one and indolo[2,1- b ]quinazoline-6,12-dione scaffolds [ 35 , 36 ]. Specifically, compound IQ-1 (11 H -indeno[1,2- b ]quinoxalin-11-one oxime) and its analogs inhibited JNK activity and, consequently, proinflammatory cytokine production by human myeloid cells [ 35 , 36 , 37 , 38 , 39 ]. These JNK inhibitors required the presence of an oxime group ( Table 1 ), and compound C containing a Cl atom at position R 3 had greater selectivity for JNK1/3 compared to JNK2 [ 36 ].…”