Stereoselective Synthesis of (R)-3-Methylthalidomide by Piperidin-2-one Ring Assembly Approach (original) (raw)
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A Novel Green Synthesis of Thalidomide and Analogs
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A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH 3 Methodology 1
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Supporting Information General methods All reagents were obtained from commercial sources and used without further purification. Solvents for chromatography are of technical grade and were distilled before use. 1 H NMR spectra were recorded at 200 MHz and 300 MHz and chemical shifts are given in δ units relative to the tetramethylsilane (TMS) signal as an internal reference in CDCl 3. Coupling constants (J) are reported in hertz (H). Mass spectra were recorded in the form of m/z (intensity relative to base 100) on a VG 7070H Micromass mass spectrometer at 200 0 C, 70eV, with a trop current of 200 µA and 4 KV acceleration. Melting points have been recorded on an Electro thermal melting point apparatus. IR spectra were recorded on a Perkin Elmer 1620-F spectrophotometer. Analytical TLC of all reactions was performed on Merck prepared plates (silica gel 60F-254 on glass). Column chromatography was performed using Acme silica gel (100 ± 200 mesh). Reactions were routinely carried out under an atmosphere of nitrogen. Products in organic solvents were dried over anhydrous magnesium sulfate before concentration in vaccuo. All of the final compounds synthesized were characterized by 1 H NMR, Mass spectrometry, C, H, N elemental analysis, IR, and melting points for solids.
Simple Thalidomide Analogs in Melanoma: Synthesis and Biological Activity
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Thalidomide is an old well-known drug that is still of clinical interest, despite its teratogenic activities, due to its antiangiogenic and immunomodulatory properties. Therefore, efforts to design safer and effective thalidomide analogs are continually ongoing. Research studies on thalidomide analogs have revealed that the phthalimide ring system is an essential pharmacophoric fragment; thus, many phthalimidic compounds have been synthesized and evaluated as anticancer drug candidates. In this study, a panel of selected in vitro assays, performed on a small series of phthalimide derivatives, allowed us to characterize compound 2k as a good anticancer agent, acting on A2058 melanoma cell line, which causes cell death by apoptosis due to its capability to inhibit tubulin polymerization. The obtained data were confirmed by in silico assays. No cytotoxic effects on normal cells have been detected for this compound that proves to be a valid candidate for further investigations to achiev...
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Synthetic thalidomide analogues (compounds 1-35), including phenylphthalimide, pyridylphthalimide, aminobenzylphthalimide, and diphenylazophthalimide, were tested for their cytotoxic effects on human cancer cell lines Hep2 (Human Larynx Carcinoma Cells), HL-60 (Human Myeloid Leukemia Cells), NUGC (Human Gastric Carcinoma Cells), and HONE-1 (Human Nasopharyngeal Carcinoma Cells) because the incidence rate is more prominent in Asian countries than in Western countries. Compounds 17, 27, 28, and 35 were found to have antitumor activity in Hep2 and HL-60 cell lines. Compounds 2, 4, 15, 17, 19, 20, 23, and 27 can inhibit nitric oxide (NO) synthase activity by more than 90%. These thalidomide analogues were found to be potent inducible nitric oxide synthase (iNOS) inhibitors, and the iNOS inhibiting potential of compounds 17 and 27 might be an advantage for anticancer therapy. In conclusion, inhibition of NO synthesis is a new development in cancer therapy for now and in the future. We modified the structures of the thalidomide analogues to have a stronger anticancer effect and a good therapeutic effect.
Acta Crystallographica Section E Crystallographic Communications
The title compound, C13H16N2O4, crystallizes in the monoclinic centrosymmetric space group, P21/c, with four molecules in the asymmetric unit, thus there is no crystallographically imposed symmetry and it is a racemic mixture. The structure consists of a six-membered unsaturated ring bound to a five-membered pyrrolidine-2,5-dione ring N-bound to a six-membered piperidine-2,6-dione ring and thus has the same basic skeleton as thalidomide, except for the six-membered unsaturated ring substituted for the aromatic ring. In the crystal, the molecules are linked into inversion dimers by R 2 2(8) hydrogen bonding involving the N—H group. In addition, there are bifurcated C—H...O interactions involving one of the O atoms on the pyrrolidine-2,5-dione with graph-set notation R 1 2(5). These interactions along with C—H...O interactions involving one of the O atoms on the piperidine-2,6-dione ring link the molecules into a complex three-dimensional array. There is pseudomerohedral twinning pres...
α-Fluoro-substituted thalidomide analogues
Bioorganic & Medicinal Chemistry Letters, 2003
Thalidomide, (1), has made a remarkable comeback from its days of a sedative with teratogenic properties due to its ability to selectively inhibit TNF-a, a key pro-inflammatory cytokine and its clinical benefit in the treatment of cancer. Thalidomide contains one chiral center and is known to be chirally unstable under in vitro and in vivo conditions. It has been hypothesized that different biological properties are associated with each isomer. Thus, chirally stable analogues of thalidomide, a-fluorothalidomide, (3) and a-fluoro-4-aminothalidomide (4) were prepared by electrophilic fluorination. Analogue 3 was found to be cytotoxic and did not inhibit TNF-a production in LPS stimulated hPBMC below toxic concentrations. On the other hand, 4 was non-cytotoxic at the tested concentrations and was found to be 830-fold more potent than thalidomide as TNF-a inhibitor.
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A new method to obtain enantiopure trisubstituted piperidines 1 by reaction of chiral epoxyaziridine 2 with α-amino esters 3 in the presence of a Lewis acid is reported. This synthesis took place through the successive opening of both oxirane and aziridine rings of 2 by the amino group of the corresponding α-amino ester 3 with total chemo-and regioselectivity. The time of reaction depended on the α-amino ester employed. Moreover, lithium and ytterbium salts were tested to catalyze the reaction, obtaining the best results with ytterbium triflate in comparison with lithium perchlorate.