Mono- and Dihydroxylated Metabolites of Thalidomide: Synthesis and TNF-.ALPHA. Production-Inhibitory Activity

Abstract

Thalidomide (1) was developed in the 1950's as a nontoxic sedative/hypnotic drug, but was withdrawn from the market in the early 1960's because of its serious teratogenicity. [1][2][3][4][5] However, it was subsequently identified as an effective agent for the treatment of multiple myeloma (MM), AIDS, Hansen's disease, and various cancers. [1][2][3][4][5] The US Food and Drug Administration (FDA) approved it for the treatment of erythema nodosum in Hansen's disease in 1998, and (in combination with dexamethasone) for the treatment of MM in 2006. Official approval for the use of thalidomide (1) to treat MM has also been applied for in Japan. Thalidomide (1) has been discovered to have various biological activities, including inhibition of tumor necrosis factor-a (TNF-a) production, and anti-inflammatory, anti-angiogenic, and cyclooxygenase (COX)-inhibitory activities.1-5) The TNF-a production-inhibitory activity was initially considered to be one of the key mechanisms of thalidomide's actions, [1][2][3][4][5] though the precise molecular mechanism(s) involved remain unclear.Recently, we have reported that thalidomide (1) and/or its two hydroxylated metabolites 5-OH-Thal (2a) and N-OHThal (2c) show cell differentiation-enhancing, anti-angiogenic and tubulin polymerization-inhibitory activities. [6][7][8][9] Concerning the former two activities, thalidomide (1), 5-OHThal (2a) and N-OH-Thal (2c) all exhibit comparable activity.7-9) However, tubulin polymerization-inhibitory activity was observed only for the hydroxylated metabolites (2a, 2c), and thalidomide (1) lacks this activity.6) These results prompted us to investigate comprehensively the biological activities of hydroxylated metabolites of thalidomide.Thalidomide (1) is metabolically labile, and many metabolites have been identified or proposed, [10][11][12][13][14][15][16][17] including seven hydroxylated metabolites, 2a-g (Fig. 1). Hydroxylation is reported to occur mainly at the 5-position in the phthaloyl moiety and the 5Ј-position in the glutarimide moiety, 10) although the 4-position of the phthaloyl moiety and the nitrogen atom of the imide ring can also be hydroxylated (Fig. 1).10) 5-OH-Thal (2a), N-OH-Thal (2c) [11][12][13] and cis-5Ј-OHThal (cis-2f) [14][15][16] have been well-characterized and their methods of preparation have been reported in detail. For 4-OH-Thal (2b), trans-5Ј-OH-Thal (trans-2f), and the dihydroxylated metabolites, 5,N-di-OH-Thal (2d), 4,N-di-OHThal (2e), and 5,5Ј-di-OH-Thal (2g), neither spectroscopic data nor any detailed description of their synthesis is available in the literature, to our knowledge. In addition, the reported synthetic method of cis-5Ј-OH-Thal (cis-2f) via free g-hydroxyglutamic acid is unsatisfactory, because some of the intermediates are sticky and intractable, the overall yield is not so high, and the stereochemistry is difficult to control. We therefore sought to establish methods for systematic preparation of all of the proposed metabolites, 2a-g. In this paper, we describe the synthesis of the mono-and...

Development of Tubulin-Polymerization Inhibitors Based on the Thalidomide Skeleton

“…1) exhibited tubulin polymerization-inhibitory activity, though thalidomide (1) itself does not. [11][12][13][14][15] Inhibition of tubulin function, including tubulin polymerization, is considered to be one of the molecular mechanisms of anti-tumor agents such as vinblastine and paclitaxel. Therefore, it was suspected that the efficacy of thalidomide (1) for the treatment of MM might be due to the tubulin polymerization-inhibitory activity of its metabolite, 5-hydroxythalidomide (2), at least in part.…”

Thalidomide as a Multi‐Template for Development of Biologically Active Compounds

“…In addition, thalidomide 1 is unstable both metabolically and chemically [38,39]. Structural development based on active thalidomide metabolites as well as chemical modification to endow stability of the compounds, would be useful to investigate the molecular basis of thalidomidal action.…”

“…Therefore, metabolic activation of thalidomide 1 may occur. On this basis, known and/or possible thalidomide metabolites have been comprehensively prepared [38,39]. Among them, two major thalidomide metabolites, 5-hydroxythalidomide (5-OH-thalidomide 9), and N-hydroxythalidomide (N-OH-thalidomide 10) (Fig.…”

Interaction of a Biological Response Modifier with Proteins

“…These PSA-specific, potent, nonpeptide, small-molecular inhibitors should be useful as probes to investigate in detail the physiological function of PSA and as lead compounds to develop superior antimetastatic agents. Fluorescent probes [e.g., DAMPAQ-22 (57)] that visualize PSA in living cells have also been developed [49].…”