Synthesis and Biological Evaluation of Carbocyclic Analogues  of Pachastrissamine

Kwon, Yongseok; Song, Jaechul; Bae, Hyun Cheol; Kim, Woo-Jung; Lee, Joo‐Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

doi:10.3390/md13020824

Cited by 17 publications

(9 citation statements)

References 35 publications

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“…Studies have also investigated analogues of SKI-II [67,149], RB-005 [150], FTY720 [78,136,143,151,152] and SLR080811 [153]. Additionally, analogues of novel compounds extracted from natural products, like the SK2 inhibitor (2S,3S,4R)-Pachastrissamine [154,155] and the low-potency SK1 inhibitor belanocarpol, a dimer of resveratrol, have been reported [156]. Many of these compounds remain to be validated for their affinity, selectivity and/or effects in cells but may prove to be useful agents after further characterization.…”

Section: Other Sk Inhibitorsmentioning

confidence: 98%

Recent advances in the development of sphingosine kinase inhibitors

Pitman

Costabile

Pitson

2016

Cellular Signalling

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Sphingosine kinase (SK) 1 and 2 are lipid kinases that catalyse the formation of sphingosine 1-phosphate (S1P), a potent signalling molecule with a wide array of cellular effects. SK1 and 2 have been shown to be up-regulated in tumours and their genetic ablation or inhibition has been shown to slow tumour growth as well as sensitise cancer cells to chemotherapeutics. The SKs have been extensively studied, with a plethora of inhibitors developed that target the sphingosine-binding pocket of the enzyme, some with nanomolar affinities. Recently, inhibitors targeting the ATP pocket of SK have also been described. Here we discuss the development of these new small molecule SK inhibitors, summarise the recent discovery of off-targets effects of many current SK inhibitors, and provide an overview of the usefulness of these inhibitors as in vitro tools and therapeutic agents.

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Section: Other Sk Inhibitorsmentioning

confidence: 98%

Recent advances in the development of sphingosine kinase inhibitors

Pitman

Costabile

Pitson

2016

Cellular Signalling

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“…An enyne/diene-ene metathesis reaction was used as the key step of the synthesis. One of the derivatives synthesized exhibits more potent sphingosine kinases inhibitory activity in comparison with the mother, pachastrissamine [ 35 ]. Wu and colleagues from China describe the anticancer activity of the synthetical bis-(2,3-Dibromo-4,5-dihydroxy-phenyl)-methane , initially isolated from marine algae Rhodomelaceae confervoides .…”

Section: Research Articlesmentioning

confidence: 99%

Marine Compounds and Cancer: Where Do We Stand?

Dyshlovoy

Honecker

2015

Marine Drugs

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In Western countries, cancer is among the most frequent causes of death. Despite striking advances in cancer therapy, there is still an urgent need for new drugs in oncology. Current development favors so called “targeted agents” or drugs that target the immune system, i.e., therapeutic antibodies that enhance or facilitate an immune response against tumor cells (also referred to as “checkpoint inhibitors”). However, until recently, roughly 60% of drugs used in hematology and oncology were originally derived from natural sources, and one third of the top-selling agents are either natural agents or derivatives [1]. There is justified hope for the discovery and development of new anticancer agents from the marine environment. Historically, this habitat has proven to be a rich source of potent natural compounds such as alkaloids, steroids, terpenes, macrolides, peptides, and polyketides, among others. Interestingly, marine agents and cancer treatment have had a special relationship from the beginning. One of the first marine-derived compounds, discovered in 1945 that was later developed into a clinically used drug, was spongothymidine [2–4], which was the lead compound for the discovery of cytarabine [5]. Until today, cytarabine remains one of the most widely used agents in the treatment of acute myeloid leukemia and relapsed aggressive lymphomas. [...]

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“…In addition, several analogues of 1 have been synthesized and their biological activities have been investigated. 7,[42][43][44][45][46][47] Kim and colleagues reported the synthesis of the sulfur analogue 4 from D-ribo-phytosphingosine and 4 exhibited higher cytotoxicity against several cancer cell lines than 1. 46) Because sulfur-containing heterocycles such as thiosugars often exhibit various interesting biological activities 48) and a sulfur atom can exist in multiple oxidized forms, replacement of the oxygen atom in the ring of 1 by a sulfur atom serves as a potential way to produce new drug candidates.…”

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confidence: 99%

Synthetic Studies on a Pachastrissamine Sulfur Analogue: Synthesis of a 4-<i>epi</i>-Sulfur Analogue

Liu

Hashimoto

Nambu

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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A versatile synthetic procedure for a sulfur analogue of pachastrissamine (jaspine B), which involves the tandem thiolation-cyclization of a 1,4-ditosylate to construct a tetrahydrothiophene ring, was developed. Nucleophilic amino substitution of a tetrahydrothiophene-4-sulfonate with unexpected retention of the configuration afforded the sulfur analogue of 4-epi-pachastrissamine.Key words pachastrissamine; analogue; tetrahydrothiophene; thiolation; cyclization; neighboring group participation Pachastrissamine (1, jaspine B) is a natural anhydrophytosphingosine derivative that has an all-cis-2,3,4-trisubstituted tetrahydrofuran structural framework and was isolated from the marine sponges Pachastrissa sp.1) and Jaspis sp.2) in 2002 and 2003, respectively (Fig. 1). It exhibits cytotoxic activity against various cancer cell lines [1][2][3][4][5][6][7][8][9] and induces programmed cell death, such as autophagy 6) and apoptosis 7-10) in some cancer cells. Owing to its interesting structural features and significant biological properties, many researchers have reported the total synthesis of 1 [3][4][5][6][7] and its stereoisomers 5,6,[20][21][22][23][24][25][26][27][28][29][31][32][33][34][35][36][37][38][39][40][41] to date. In addition, several analogues of 1 have been synthesized and their biological activities have been investigated. 7,[42][43][44][45][46][47] Kim and colleagues reported the synthesis of the sulfur analogue 4 from D-ribo-phytosphingosine and 4 exhibited higher cytotoxicity against several cancer cell lines than 1.46) Because sulfur-containing heterocycles such as thiosugars often exhibit various interesting biological activities 48) and a sulfur atom can exist in multiple oxidized forms, replacement of the oxygen atom in the ring of 1 by a sulfur atom serves as a potential way to produce new drug candidates. Very recently, we succeeded in the synthesis of 1, 2-epi-pachastrissamine 2, and the 2-epi-aza analogue 3. 31) Our synthetic route to 1-3 would be useful for the synthesis of their derivatives bearing various alkyl side chains, because inexpensive diethyl D-tartrate is employed as a starting material and the alkyl side chain is introduced at a later stage. Here, we report studies on the synthesis of a sulfur analogue of pachastrissamine, which is based on the synthetic strategy for 1-3, and the synthesis of the 4-epi-sulfur analogue 5.Our strategy to synthesize 4 is outlined retrosynthetically in Chart 1. On the basis of our previous syntheses of 1-3, 31) the desired analogue 4 would be derived from the tetrahydrothiophene 6 via S N 2-type amination at the 4-position. Because olefin cross-metathesis of sulfur-containing compounds is often problematic, [49][50][51][52] we planned to extend the alkyl side chain before the introduction of a sulfur atom. The thiophene ring system would be created by stepwise thiolation-cyclization via the 4-mercapto-1,2-diol 7 from 8, which would be converted from the 3,4-anti-homoallylic alcohol 9 using olefin cross-metathesis. Compound 9 has already been prepa...

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Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

Cited by 17 publications

References 35 publications

Recent advances in the development of sphingosine kinase inhibitors

Recent advances in the development of sphingosine kinase inhibitors

Marine Compounds and Cancer: Where Do We Stand?

Synthetic Studies on a Pachastrissamine Sulfur Analogue: Synthesis of a 4-<i>epi</i>-Sulfur Analogue

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