Alkaloids from the antarctic sponge Kirkpatrickia varialosa. Part 2: Variolin A and N(3′)-methyl tetrahydrovariolin B

Golakoti, Trimurtulu; Faulkner, D. John; Perry, Nigel B.; Ettouati, Laurent; Litaudon, Marc; Blunt, John W.; Munro, Murray H. G.; Jameson, Geoffrey B.

doi:10.1016/s0040-4020(01)89674-5

Cited by 121 publications

(72 citation statements)

References 8 publications

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“…Both meridianins (11) and variolins (17,22,23) show distinct antiproliferative and proapoptotic activities. These effects may be correlated with their inhibitory activities toward CDKs and other protein kinases (11,23).…”

Section: Resultsmentioning

confidence: 99%

“…Meridianins share some structural similarity with variolins, another family of marine natural compounds containing a central pyrido [3 ¶,2 ¶:4,5]pyrrolo [1,2-c] pyrimidine core substituted with a 2-aminopyrimidine ring. Variolins were initially extracted from Kirkpatrickia variolosa, a rare Antarctic sponge (16,17). Total synthesis by Morris (18,19) and others (20,21) allowed easy access to the variolins.…”

Section: Introductionmentioning

confidence: 99%

“…Total synthesis by Morris (18,19) and others (20,21) allowed easy access to the variolins. Variolin B and deoxyvariolin B (PM01218) display potent cytotoxicity against several human cancer cell lines (17,22,23); as a result, PM01218 is being investigated by PharmaMar as a potential antitumor drug. Recently, as this work was in progress, variolin B and deoxyvariolin B were reported to inhibit CDKs (23).…”

Section: Introductionmentioning

confidence: 99%

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Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

et al. 2007

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Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1A, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms. [Cancer Res 2007;67(17):8325-34]

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

et al. 2007

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“…Variolins constitute a new family of inhibitors of CDKs. They are marine alkaloids possessing an uncommon pyrido [3',2':4,5]pyrrolo [1,2-c]pyrimidine skeleton, which were first isolated in 1994 from Kirkpatrickia variolosa, a rare Antarctic sponge [1,2]. Five variolins have been isolated: variolin A (1), variolin B (2), deoxyvariolin B (3), N(3')-methyl tetrahydrovariolin B (4), and variolin D (5) (Figure 1).…”

Section: β-Pyridopyrrolopyrimidine Alkaloids: Variolins a New Familymentioning

confidence: 99%

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

et al. 2014

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Abstract:The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery.

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“…[2][3][4] Nevertheless, this class of heterocycles has attracted considerable interest due to their physicochemical and pharmacological properties. In this way, luminescence properties of 7-azaindole derivatives and complexes have been studied and recently reviewed.…”

Section: Introductionmentioning

confidence: 99%

Gold catalysis in the synthesis of azaindoles: pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrazines

Gala¹,

Córdoba²,

Izquierdo³

et al. 2014

Arkivoc

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Alkaloids from the antarctic sponge Kirkpatrickia varialosa. Part 2: Variolin A and N(3′)-methyl tetrahydrovariolin B

Cited by 121 publications

References 8 publications

Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

Gold catalysis in the synthesis of azaindoles: pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrazines

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