Practical synthesis of fingolimod from diethyl acetamidomalonate

Kandagatla, Bhaskar; Raju, Vetukuri Venkata Naga Kali Vara Prasada; Kumar, Narayana Sravan; Reddy, Ganta Madhusudhan; Srinivas, K.; Iqbal, Javed; Bandichhor, Rakeshwar; Oruganti, Srinivas

doi:10.1039/c3ra40894a

Cited by 9 publications

(6 citation statements)

References 10 publications

(6 reference statements)

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“…In conclusion, we have reported on the anticancer activity of a series of novel constrained analogues of FTY720, including a stereochemically distinct isomer ( 6 ) with enhanced activity. A subset of these compounds, and particularly those lacking the hydroxymethyl group, may lack the dose-limiting toxicities of the parent compound yet kill leukemia cells with similar potency …”

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confidence: 99%

Design, Synthesis, and Antileukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)

Fransson

McCracken

Chen

et al. 2013

ACS Med. Chem. Lett.

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FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has anti-neoplastic actions. Our published work suggests that at least some of FTY720’s anti-cancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720’s S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective anti-tumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for anti-leukemic activity.

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confidence: 99%

Design, Synthesis, and Antileukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)

Fransson

McCracken

Chen

et al. 2013

ACS Med. Chem. Lett.

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“…The four to six-step synthesis of all derivatives is presented in Schemes – . A crucial step in the synthesis was the nucleophilic substitution of halide or mesylate with diethyl acetamidomalonate in the presence of cesium carbonate to obtain para -bromo N-acetylated diester intermediates 2 , 36 – 37 , 51 , 58 , and 70 – 73 , or N-acetylated diester phenol intermediate 20 . Bromo intermediates were later used for microwave-assisted Suzuki coupling with an appropriate boronic acid and palladium catalyst (Schemes and ), while a phenol intermediate was used for O-alkylation with appropriate alkyl bromide in the presence of potassium carbonate (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Fingolimod Derivatives as Antibacterial Agents

et al. 2021

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We recently identified fingolimod as a potent antibiofilm compound by screening FDA-approved drugs. To study if the antibacterial activity of fingolimod could be further improved and to explore in-depth structure−activity relationships, we synthesized 28 novel fingolimod derivatives and evaluated their efficacy against Staphylococcus aureus grown in planktonic/single cell and biofilms. The most effective derivatives were tested on preformed S. aureus biofilms and against Gram-negative bacteria Acinetobacter baumannii and Pseudomonas aeruginosa, using fingolimod as the reference compound. Seven derivatives were more effective against S. aureus, while five other derivatives showed improved activity against P. aeruginosa and/or A. baumannii, with no apparent change in cytotoxicity on human cells. The most interesting derivatives, compounds 43 and 55, displayed a broader spectrum of antibacterial activity, possibly exerted by the change of the para-hydrocarbon chain to a meta position for 43 and by an additional hydroxyl group for 55.

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“…To date, several synthetic routes for Fingolimod have been reported [ 5 - 15 ]. However, these synthetic methods were unsuitable to industrial scale-up mainly due to the involvement of multiple steps and dangerous chemicals such as lithium aluminium hydride (LAH).…”

Section: Resultsmentioning

confidence: 99%

A concise synthesis of Fingolimod: an orally available drug for treating multiple sclerosis

Yan

Chen

Bai

et al. 2015

Chemistry Central Journal

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A concise route for the synthesis of Fingolimod is reported. Starting from n-octylbenzene and 3-nitropropionic acid, a sequence of reactions consisting of Friedel-Crafts acylation, reduction, and double Henry reaction, followed by hydrogenation were applied to prepare Fingolimod with a yield of 31%, and an overall atom economy of 82.7%.Graphical AbstractStarting from 3-nitropropanyl chloride, Fingolimod was obtained in 4 steps with an overall yield of 31%.

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Practical synthesis of fingolimod from diethyl acetamidomalonate

Cited by 9 publications

References 10 publications

Design, Synthesis, and Antileukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)

Design, Synthesis, and Antileukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)

Synthesis and Biological Evaluation of Fingolimod Derivatives as Antibacterial Agents

A concise synthesis of Fingolimod: an orally available drug for treating multiple sclerosis

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