A Novel Green Synthesis of Thalidomide and Analogs (original) (raw)
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A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH 3 Methodology 1
Organic Process Research & Development, 2005
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.
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.
Simple Thalidomide Analogs in Melanoma: Synthesis and Biological Activity
Applied Sciences
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...
Medicinal Chemistry Research, 2012
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.
Green Chemistry and Synthesis of Anticancer Molecule
InTech eBooks, 2018
Green chemistry is a modern area of chemistry merged with chemical engineering methods. It highlighted the synthesis of molecules in a manner of using environment-friendly chemical reagents with low waste material for enhancing environmental performance which reduce the formation of hazard substances. Modern researches are trying to reduce the risk of human kind health and the environment of our world by doing magnificent work in the field of green chemistry. In the pharmaceutical field, green chemistry works very well with the formation of many drugs and it utilizes non-hazards, reproducible and environment-friendly solvents with low time and money costs by using catalyst, microwave, ultrasonic, solid phase and solvent-free synthesis. Until now, scientist has synthesized many anticancer molecules by using these modern green chemistry techniques. These compounds showed significant anticancer activities against many human cancer cell lines. In this chapter, we will cover different views and the recently published literature to summarize the role of green chemistry in the synthesis of anticancer compounds.
International Journal of Molecular Sciences
Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antiproliferative activities against three human cancer cell lines, namely hepatocellular carcinoma (HepG-2), prostate cancer (PC3), and breast cancer (MCF-7). It was found that compounds XII, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, and XIVc showed IC50 values ranging from 2.03 to 13.39 µg/mL, exhibiting higher activities than thalidomide against all tested cancer cell lines. Compound XIIIa was the most potent candidate, with an IC50 of 2.03 ± 0.11, 2.51 ± 0.2, and 0.82 ± 0.02 µg/mL compared to 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 µg/mL for thalidomide against HepG-2, PC3, and MCF-7 cells, respectively. Furthermore, compound XIVc reduced the expression of NFκB P65 levels in HepG-2 cells from 278.1 pg/mL to 63.1 pg/mL compared to 110.5 pg/mL for thalidomide. Moreover, compound XIVc induced an eightfold increase in caspase-8 levels with a simultaneous decrease in TNF-α and VEGF levels in...
Current Research in Green and Sustainable Chemistry, 2020
Thiazolidin-4-one has been known as a powerful moiety present in various approved medications. Thiazolidin-4ones are amongst the most effective and actively explored fields of current antimicrobial and antiviral chemotherapy that portray broad spectrum and potent activity. The wide range of medicinal properties of thiazolidin-4one related drugs encourages the medicinal chemists to synthesize a significant variety of new medicinal substances. Microwave induced organic reactions earned substantial coverages in recent years due to many advantages such as ease of work, cost-effectiveness, short reaction time and excellent yield. Microwave radiations provide a substitute for traditional heating by incorporating energy to the reactions. The usage of microwave irradiation has contributed to the emergence of innovative ideas in chemistry, as energy absorption and propagation in microwave irradiation is entirely dissimilar to the traditional heating method. In synthetic chemistry, microwave heating is a rapidly growing area of research. This review cover organic synthesis of thiazolidin-4-one analogues via the use of microwave irradiation as an effective technique and the antiviral and antimicrobial action of thiazolidin-4-one based compounds.
Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives
Chemico-Biological Interactions, 2015
The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50 lg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30 ± 4.9, 64.6 ± 1.8 and 46.5 ± 19.5%, respectively) (p < 0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9 ± 2.3 and 14.8 ± 3.3%), neovascularization area (13.1 ± 1.7 and 14.3 ± 1.7%) and total length of vessels (9.2 ± 1.5 and 9.9 ± 1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.
Thalidomide and Its Analogs as Anticancer Agents
Thalidomide has reemerged as a promising anticancer and anti-inflammatory drug despite its devastating congenital birth defects. Many thalidomide derivatives with enhanced antiangiogenic and immunomodulatory effects or greater cytokine inhibition accompanied by less adverse toxicities than the parent drug have been developed. The mechanisms of action of thalidomide and its analogs are complex and not yet fully understood, but studies indicate that their antiangiogenic and immunomodulatory effects play important roles. Thalidomide and lenalidomide have been approved for the treatment of multiple myeloma and myelodysplastic syndrome. The powerful antiangiogenic, anti-inflammatory, and apoptotic effects mean that thalidomide and its immunomodulatory derivatives will continue to be explored in the treatment of a variety of cancers and inflammatory diseases. [Tzu Chi Med J 2008;20(3):188-195] Article Info