Angiogenesis inhibitors derived from thalidomide

Noguchi, Takao; Fujimoto, Haruka; Sano, Hiroko; Miyajima, Atsushi; Miyachi, Hiroyuki; Hashimoto, Yuichi

doi:10.1016/j.bmcl.2005.08.086

Cited by 59 publications

(56 citation statements)

References 25 publications

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“…The results suggested that 5HPP-33 5 does not bind to the site at which colchicine or vinblastine binds. 5HPP-33 5 effectively induces apoptosis of human leukemia cell lines HL-60, THP-1, and human myeloma cells IM9 at 10 lM [30], induces granulocytic cell differentiation of HL-60 at 5 lM [33], and inhibits tube formation (angiogenesis) of human umbilical vein endothelial cells (HUVEC) [29]. Although it remains to be investigated whether these biological effects of 5HPP-33 5 are elicited by tubulin polymerization inhibition, the lack of teratogenicity of the compound, as far as investigated, suggests that it may be useful as a non-teratogenic substitute for thalidomide 1.…”

Section: Mode Of Tubulin Polymerization-inhibition By 5hpp-33mentioning

confidence: 99%

“…These findings suggested that thalidomide 1 is a multi-target drug, and this, in turn, implied the possible usefulness of thalidomide 1 as a template for development of various kinds of medicaments. In fact, various biologically active compounds, such as TNF-a production regulators (including bi-directional ones, pure inhibitors, and pure enhancers) [7,8], androgen antagonists [9 -11], aminopeptidase inhibitors [12 -15], a-glucosidase inhibitors [16 -18], thymidine phosphorylase inhibitors [19], cyclooxygenase (COX) inhibitors [20 -22], nitric oxide synthase (NOS) inhibitors [23,24], histone deacetylase (HDAC) inhibitors [25 -27], anti-angiogenic agents [28,29], tubulin polymerization inhibitors [30 -32], cell differentiation inducers [33], and liver X receptor (LXR) antagonists [34,35] have been developed based on the structure of thalidomide 1 ( Fig. 2 and 3).…”

Section: Introductionmentioning

confidence: 99%

“…3, i.e. TNF-a productionregulating activity [36,37], COX-inhibiting activity [20], NOS-inhibiting activity [23], and anti-angiogenic activity [29]. In addition, thalidomide 1 is a labile compound both metabolically and chemically.…”

Section: Introductionmentioning

confidence: 99%

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

Hashimoto

2008

Archiv der Pharmazie

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Thalidomide is a teratogenic/hypnotic/sedative agent which elicits a wide range of pharmaceutical/biological activities. The diversity of its biological activities suggested that the drug might be useful as a multi-template for development of various kinds of biologically active compounds. We adopted two strategies for the structural development of thalidomide. The first was to develop the structure of the drug based on the target molecules to which thalidomide itself and/ or its metabolites directly bind, or the assay systems in which thalidomide itself and/or its metabolites exhibit activity. Based on this strategy, tumor necrosis factor-a production-regulating agents, cyclooxygenase inhibitors, nitric oxide synthase inhibitors, histone deacetylase inhibitors, anti-angiogenic agents, and tubulin polymerization inhibitors have been created. The second was to develop the structure of thalidomide based on hypothetical target molecule(s)/biological response(s) which might be relevant to the pharmacological effects elicited by thalidomide. Based on this strategy, androgen antagonists, progesterone antagonists, cell differentiation inducers, aminopeptidase inhibitors, thymidine phosphorylase inhibitors, l-calpain inhibitors, a-glucosidase inhibitors and nuclear liver X receptors (LXRs) antagonists have been created. Our structural development studies on thalidomide are reviewed focusing on recent development of tubulin polymerization inhibitors, a-glucosidase inhibitors, and nuclear liver X receptors antagonists.

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Section: Mode Of Tubulin Polymerization-inhibition By 5hpp-33mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hashimoto

2008

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“…[6][7][8][9] Concerning the former two activities, thalidomide (1), 5-OHThal (2a) and N-OH-Thal (2c) all exhibit comparable activity.…”

mentioning

confidence: 99%

“…[7][8][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.…”

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confidence: 99%

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

Nakamura

Noguchi

Kobayashi

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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In‐Depth Look: Anti‐TNF‐α Therapies

Chatterjee

Gaddameedhi

2011

Pharmaceutical Sciences Encyclopedia

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Today, anti ‐tumor necrosis factor‐α (TNF‐α) drugs are being successfully used in the treatment of various inflammatory diseases such as rheumatoid arthritis (RA) and Crohn's disease. In later years, research showed that TNF‐α is involved in the progression of cancer in many other ways besides causing cancer‐associated cachexia. Anti‐TNF‐α therapy aiming to block TNF‐α, directly or indirectly, is now being investigated for treatment as well as for supportive care in cancer patients. Currently, it appears to be one of the promising approaches in resistant and nonresistant tumors as well as for cancer‐associated cachexia. This chapter will review some of the approaches being exploited to block TNF‐α and the anti‐TNF‐α drugs that have made it to clinical trials or have been approved by U.S. Food and Drug Administration (FDA) for anticancer therapy.

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Angiogenesis inhibitors derived from thalidomide

Cited by 59 publications

References 25 publications

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

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

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

In‐Depth Look: Anti‐TNF‐α Therapies

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