α-Fluoro-substituted thalidomide analogues (original) (raw)
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Selection of novel analogs of thalidomide with enhanced tumor necrosis factor α inhibitory activity
Molecular Medicine
Tumor necrosis factor alpha (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was shown to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, however, be necessary to rescue the host from more acute and extensive toxicities of TNF alpha-mediated inflammation. Three structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality. The new compounds (two esters and one amide) showed increased inhibiti...
Thalidomide Analogs from Diamines: Synthesis and Evaluation as Inhibitors of TNF-.ALPHA. Production
Chemical and Pharmaceutical Bulletin, 2007
Fourteen thalidomide analogs bearing two phthalimido units were prepared in high yields (83-94%) by condensation of different diamines with phthalic or 3-nitrophthalic anhydride. An in vitro investigation of the compounds as inhibitors of the TNF-a a production was performed. The inhibition was higher for compounds bearing amino and nitro groups and was modulated by increasing the size of the spacers between the phthalimide groups.
Thalidomide Analogs from Diamines: Synthesis and Evaluation as Inhibitors of TNF-α Production
CHEMICAL & PHARMACEUTICAL BULLETIN, 2007
Fourteen thalidomide analogs bearing two phthalimido units were prepared in high yields (83-94%) by condensation of different diamines with phthalic or 3-nitrophthalic anhydride. An in vitro investigation of the compounds as inhibitors of the TNF-a a production was performed. The inhibition was higher for compounds bearing amino and nitro groups and was modulated by increasing the size of the spacers between the phthalimide groups.
Recent Developments of Thalidomide Derivatives Possessing Anti-Inflammatory Activity
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2010
Thalidomide (-N-phthalimidoglutarimide) was a widely used drug in the late 1950s as a hypnotic/ sedative agent. Thalidomide was subsequently withdrawn from the market due to teratogenicity in the early 1960s. Surprisingly, even after the initial impact of the thalidomide disaster, the drug was still used in the therapy of many diseases, and research studies in the field of thalidomide derivatives have significantly increased because of its tumor necrosis factor (TNF-) production regulating effect. Recently, novel thalidomide derivatives have been synthesized as anti-inflammatory lead-candidates. This review will summarize the recent development of thalidomide derivatives which possess antiinflammatory activity.
Thalidomide Analogues as Anticancer Drugs
Recent Patents on Anti-Cancer Drug Discovery, 2007
The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein.
Chemical and Pharmaceutical Bulletin, 2006
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. 1-5) However, it was subsequently identified as an effective agent for the treatment of multiple myeloma (MM), AIDS, Hansen's disease, and various cancers. 1-5) 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, 1-5) 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-OH-Thal (2c) show cell differentiation-enhancing, anti-angiogenic and tubulin polymerization-inhibitory activities. 6-9) Concerning the former two activities, thalidomide (1), 5-OH-Thal (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, 10-17) 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) 11-13) and cis-5Ј-OH-Thal (cis-2f) 14-16) 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-OH-Thal (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 dihydroxylated metabolites of thalidomide (2a-g), as well as the results of chemical/physical characterization and evaluation of their TNF-a production-inhibitory activity. Chemistry Hydroxylated metabolites 2a-e were synthesized as shown in Chart 1. Boc-glutamine 3 was treated with 1,1Ј-carbonyldiimidazole (CDI) in the presence of a catalytic amount of 4-dimethylaminopyridine (DMAP) to afford the cyclic imide 4. 18) The Boc group of 4 was removed with 30% HBr/AcOH to afford 5 as the HBr salt. Boc-glutamic acid 6 was treated with O-benzylhydroxylamine in the presence of N-ethyl-NЈ-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt), 13) to afford the cyclic imide 7. The Boc group was removed with trifluoroacetic acid (TFA) to afford 8 as the TFA salt. The hydroxyl groups of 4-hydroxyphthalic acid (9a) and 3-hydroxyphthalic acid (9b) were protected as the benzyl ether, and the protected compounds were
Antiangiogenic activity of N-substituted and tetrafluorinated thalidomide analogues
Cancer research, 2003
Inhibition of angiogenesis is currently perceived as one of the promising strategies in the treatment of cancer. The antiangiogenic property of thalidomide has inspired a second wave of research on this teratogenic drug. Previous studies from our group and others demonstrated that metabolites of thalidomide are responsible for the drug's pharmacological actions. On the basis of the structures of these metabolites, we synthesized 118 thalidomide analogues. Preliminary screening selected 7 of these 118 analogues for more extensive testing in the current study. In the rat aortic ring assay, all 4 analogues in the N-substituted class and 2 of the 3 analogues in the tetrafluorinated class significantly inhibited microvessel outgrowth at 12.5-200 microM. Thalidomide failed to block angiogenesis at similar concentrations. Subsequently, the effects of these analogues on human umbilical vein endothelial cell proliferation and tube formation were determined. Those analogues showing antian...