Synthesis and Enantiomeric Separation of 2-Phthalimidino-glutaric Acid Analogues:  Potent Inhibitors of Tumor Metastasis

Shah, Jignesh; Swartz, Glenn M.; Papathanassiu, Adonia E.; Treston, Anthony M.; Fogler, William E.; Madsen, John W.; Green, Shawn J.

doi:10.1021/jm990083y

Cited by 27 publications

(24 citation statements)

References 17 publications

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“…The synthesis of thalidomide metabolites was accomplished using reported synthetic procedures 46,47) and confirmed by NMR and MS. (This part has already mentioned in chemical section. )…”

Section: Synthesis Of Thalidomide Metabolitesmentioning

confidence: 99%

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

Marks

Shi

Fry

et al. 2002

Biological & Pharmaceutical Bulletin

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Angiogenesis, the process of blood vessel formation from pre-formed vessels, has recently become a primary target of anticancer therapy. This is due in part to the finding that removing the blood supply to a tumor can not only prevent further growth but can also starve the existing cells to death.2) In the past several years there have been many potential anti-angiogenic agents developed acting by many mechanisms including interruption of growth factor receptor phosphorylation, [3][4][5] growth factor-receptor binding, 6,7) cell adhesion molecule expression and signaling 8,9) and alterations in endothelial cell apoptosis. 10,11) In addition, several agents such as thalidomide have been shown to inhibit angiogenesis by an as yet not fully understood mechanism.12-18) Furthermore, thalidomide has been shown to reduce tumor growth both in model systems [19][20][21] and in patients. [22][23][24][25][26][27][28] Clinically, however, thalidomide has a fairly weak effect as a monotherapy in patients with solid tumors [22][23][24] but is showing tremendous promise against multiple myeloma.25-28) It has been shown that activation of thalidomide by human or rabbit liver enzymes, but not by rat liver enzymes, significantly enhances the anti-angiogenic effect of the drug in rat aortic sections or isolated endothelial cells.29) This is very interesting because thalidomide is virtually non-toxic to rats when given orally (PO). Intraperitoneal (IP), administration however, commonly associated with "first-pass" hepatic metabolism, 30) recapitulates the teratogenic effect of thalidomide in rats. 31)Kenyon et al. 19) also showed that thalidomide given IP was effective as an anti-angiogenic agent in the mouse corneal model, whereas thalidomide given PO was inactive. In addition, thalidomide teratogenesis was only found to occur after activation of the drug by liver enzymes. 13,[32][33][34][35] Furthermore, in a Xenopus oocyte assay of teratogenesis, activation of thalidomide by a single cytochrome P450 enzyme, CYP2E1, lead to a teratogenic compound whereas unactivated thalidomide was non-teratogenic.35) Thus metabolism of thalidomide is critical to its anti-angiogenic and teratogenic activity. However, the identity of the active anti-angiogenic and teratogenic moiety or moieties of thalidomide are still unknown.The goal of this work was to explore the effect of putative hydroxylated thalidomide metabolites on blood vessel density and target cell proliferation. Since the anti-angiogenic activity of thalidomide was first reported, 36) only a limited number of thalidomide metabolites have been tested for antiangiogenic activity. Figure 1 shows known and hypothesized metabolites of thalidomide (structures M1-M8) based on extensive literature review. [37][38][39][40][41][42][43][44][45] Thalidomide can be metabolized through hydrolysis at the glutarimide and/or phthalimide ring to yield metabolites such as M6-M8. Its hydroxylation can occur on glutarimide or phthalimide ring to yield metabolites M1-M5. Interestingly, only metabolites M5...

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“…The synthesis of thalidomide metabolites was accomplished using reported synthetic procedures 46,47) and confirmed by NMR and MS. (This part has already mentioned in chemical section. )…”

Section: Synthesis Of Thalidomide Metabolitesmentioning

confidence: 99%

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

Marks

Shi

Fry

et al. 2002

Biological & Pharmaceutical Bulletin

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“…Direct treatment of hydroxylactam 8 with thiophenol and p-toluenesulfonic acid in dichloromethane resulted in quantitative phenylthiation, thereby furnishing the phenylthiolactam 9. Reductive desulfurization of the sensitive phenylthiolactam 9 utilized Raney nickel in ethanol over 5 h at room temperature and provided the N-(4-methoxybenzyl)-protected glutarimide (10) in 80% yield after purification by column chromatography. The age of the Raney nickel and the reaction time have a profound effect on the outcome of the desulfurization.…”

Section: Resultsmentioning

confidence: 99%

Thalidomide Metabolites and Analogues. 3. Synthesis and Antiangiogenic Activity of the Teratogenic and TNFα-Modulatory Thalidomide Analogue 2-(2,6-Dioxopiperidine-3-yl)phthalimidine

Luzzio

Mayorov

et al. 2003

J. Med. Chem.

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Versatile synthesis of the teratogenic, TNFalpha-modulatory, and antiangiogenic thalidomide analogue 2-(2,6-dioxopiperidine-3-yl)phthalimidine (1) and its direct antiangiogenic properties are described. With thalidomide or thalidomide derivatives as precursors, the synthesis involved either carbonyl reduction/thiation-desulfurization or carbonyl reduction/acyliminium ion reduction protocols. Compared to earlier studies with thalidomide, which was only active with microsomal treatment, 1 exhibited marginal inhibitory activity in the rat aortic ring assay, thereby demonstrating the requirement for metabolic activation.

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“…Solvents used are pyridine, toluene/triethylamine, 18 or acetic acid at reflux temperature. 19 The ring-closure step is usually unreliable, and purification of products is required.…”

Section: Resultsmentioning

confidence: 99%

Solid-Phase Synthesis of Thalidomide and Its Analogues

et al. 2002

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A novel solid-phase synthesis of thalidomide and its metabolites and analogues is described. The synthetic strategy involves the coupling of hydroxymethyl polystyrene with phthalic anhydride to form the resin-linked acid. The acid is then reacted with primary amines followed by acid or base treatment to form thalidomide and its analogues with either open or closed phthalimide rings. Most of the analogues are synthesized with high yields (40.3-98.1% in three steps) and purities (92.3-98.9%).

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Synthesis and Enantiomeric Separation of 2-Phthalimidino-glutaric Acid Analogues: Potent Inhibitors of Tumor Metastasis

Cited by 27 publications

References 17 publications

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

Thalidomide Metabolites and Analogues. 3. Synthesis and Antiangiogenic Activity of the Teratogenic and TNFα-Modulatory Thalidomide Analogue 2-(2,6-Dioxopiperidine-3-yl)phthalimidine

Solid-Phase Synthesis of Thalidomide and Its Analogues

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