Calyculins E, F, G, and H, additional inhibitors of protein phosphatases 1 and 2a, from the marine sponge discodermia calyx

Matsunaga, Shigeki; Fujiki, Hirota; Sakata, Daisuke; Fusetani, Nobuhiro

doi:10.1016/s0040-4020(01)96031-4

Cited by 83 publications

(58 citation statements)

References 6 publications

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“…The mixture was stirred for 1 h at À78 C, allowed to warm to 0 C and stirred 1 h at 0 C. The reaction was quenched by addition of saturated aqueous solution of NH 4 Cl (10 mL). After extraction with EtOAc (15 mL) and separation, organic extracts were washed with brine (10 mL), dried over MgSO 4 To a solution of thio-ester 34 (63 mg, 0.092 mmol, 1 equiv) in DMF (0.2 mL) and Et 3 N (0.06 mL) were successively added PdCl 2 (dppf) (7 mg, 0.009 mmol, 0.1 equiv), CuI (34 mg, 0.18 mmol, 1.9 equiv), P(2-furyl) 3 To a solution of ynone 35 (22 mg, 0.023 mmol, 1 equiv) in toluene (1 mL) was added p-TsOH (5 mg, 0.025 mmol, 1.2 equiv) and the mixture was stirred 24 h at rt. The reaction was quenched by addition of a saturated aqueous solution of NaHCO 3 (0.5 mL) and H 2 O (0.5 mL).…”

Section: (2r3s)-s-dodecyl 5-(tert-butyldiphenylsilyloxy)-2-methyl-3-mentioning

confidence: 99%

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Towards the total synthesis of Calyculin C: preparation of the C13–C25 spirocyclic core

2009

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Section: (2r3s)-s-dodecyl 5-(tert-butyldiphenylsilyloxy)-2-methyl-3-mentioning

confidence: 99%

“…[1][2][3] The family is composed of 8 different members, which vary by substitution at C 32 and the olefin geometry of the tetraene moiety (Calyculins A-H, see Fig. 1: Calyculin C).…”

Section: Introductionmentioning

confidence: 99%

Towards the total synthesis of Calyculin C: preparation of the C13–C25 spirocyclic core

2009

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“…Using the experimental data generated in our mutagenesis studies and exploiting PP-1c structure-function information found in the literature (9,11,12,15,30,31), we generated hypothetical models for clavosine binding to PP-1c. Our models of clavosine A, clavosine B, and calyculin A binding are depicted in Fig.…”

Section: Fig 3 Inhibition Of Tyrosine 134 Pp-1c␥ Mutantsmentioning

confidence: 99%

Inhibition of Protein Phosphatase-1 by Clavosines A and B

McCready¹,

Islam²,

Schmitz³

et al. 2000

Journal of Biological Chemistry

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Site-directed mutagenesis was used to investigate the mechanism of interaction between the catalytic subunit of human protein phosphatase-1 (PP-1c␥) and members of the calyculin family of toxins. Clavosines A and B are related to calyculins but are glycosylated with a trimethoxy rhamnose group. We provide experimental evidence implicating Tyr-134 as an important residue in PP-1c␥ that mediates interactions with the calyculins. Mutation of Tyr-134 to Phe, to prevent hydrogen bond formation, resulted in a slight increase in sensitivity of PP-1c␥ to clavosines A and B and calyculin A. In contrast, a Y134A mutant was 10-fold less sensitive to inhibition by all three inhibitors. The greatest effect on inhibition was found by substituting an Asp for Tyr-134 in the phosphatase. Clavosine B inhibited PP-1c␥ Y134D with a 310-fold decrease in potency. Clavosine A and calyculin A were also markedly poorer inhibitors of this mutant. These results suggest that a hydrogen bond between Tyr-134 and the calyculins is unlikely to be essential for inhibitor binding to the phosphatase. Serine/threonine protein phosphatases are highly conserved enzymes, which have been isolated from numerous eukaryotic and prokaryotic organisms (1, 2). Eukaryotic protein phosphatases are inhibited by a structurally diverse array of natural product toxins. These include the polyether okadaic acid from marine dinoflagellates, cyclic peptide microcystins and nodularins from cyanobacteria, and the spiroketal calyculins isolated from marine sponges (3).The first member of the calyculin family of phosphatase inhibitors was identified in 1986 (4). Calyculin A was originally purified from a hydrophobic extract of the marine sponge Discodermia calyx. It was found to be cytotoxic toward P388 and L1210 leukemia cells and to be a strong inhibitor of starfish egg development (4, 5). It was subsequently characterized as a powerful inhibitor of the catalytic subunits of type 1 and 2A protein phosphatases, PP-1c 1 and PP-2Ac, two of the four major eukaryotic serine/threonine protein phosphatases (6). Calyculin A was also shown to have tumor-promoting activity as potent as that of okadaic acid (7). Many additional calyculins (8 -13), and the structurally related calyculinamides (11,14), have since been identified.Recently we reported the isolation of two novel glycosylated members of the calyculin family, clavosines A and B from the marine sponge Myriastra clavosa (15). Clavosines A and B are potent inhibitors of mammalian PP-1c and PP-2Ac and were found to be more cytotoxic overall than the calyculins and the calyculinamides (14, 15) in the National Cancer Institute (NCI) screening panel of tumor cell lines (16). The polyfunctional structure of clavosines A and B and calyculin A is depicted in linear diagrams (Fig. 1a) and space filling models (Fig. 1b). The clavosines (Fig. 1) have many structural features in common with the calyculins but differ markedly from them in having a methyl group at C-32 and an unusual trimethoxy rhamnose group at position C-21. Like the...

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“…2, 3 The different calyculins vary by the substitution at C 32 and the olefin geometry of the tetraene moiety ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Towards the total synthesis of calyculin C: preparation of the C9–C25 spiroketal-dipropionate unit

Habrant

Koskinen

2010

Org. Biomol. Chem.

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An asymmetric synthesis of the C 9 -C 25 spiroketal fragment of calyculin C is described. Key steps include two crotylation reactions using successively Brown's reagent and (Z)-crotyltrifluorosilane for the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the stereoselective construction of the spiroketal framework.

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Calyculins E, F, G, and H, additional inhibitors of protein phosphatases 1 and 2a, from the marine sponge discodermia calyx

Cited by 83 publications

References 6 publications

Towards the total synthesis of Calyculin C: preparation of the C13–C25 spirocyclic core

Towards the total synthesis of Calyculin C: preparation of the C13–C25 spirocyclic core

Inhibition of Protein Phosphatase-1 by Clavosines A and B

Towards the total synthesis of calyculin C: preparation of the C9–C25 spiroketal-dipropionate unit

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