Rigidin E, a New Pyrrolopyrimidine Alkaloid from a Papua New Guinea Tunicate Eudistoma Species

Davis, Rohan A.; Christensen, Lane V.; Richardson, Adam D.; Rocha, Rosana M.; Ireland, Chris M.

doi:10.3390/md101027

Cited by 37 publications

(30 citation statements)

References 15 publications

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“…When the two agents were compared as inhibitors of the binding of [3H]colchicine to tubulin,12 however, combretastatin A-4 was more potent than compound 7. In reaction mixtures containing 1.0 μM tubulin and 5.0 μM inhibitor and colchicine, combretastatin A-4 inhibited colchicine binding by 98 ± 0.5 (SD) %, while the result obtained with 7 was 76 ± 0.2%.…”

Section: Resultsmentioning

confidence: 99%

“…rigida found near Okinawa and New Guinea. 3 Recently, we reported a general total synthesis of rigidins A, B, C, and D, which involved only four steps from commercially available starting materials and was amenable to the production of synthetic rigidin analogues. 4 Subsequently, extensive structure–activity relationship studies revealed that the replacement of the 7-deazaxanthine scaffold associated with the rigidins by the 7-deazahypoxanthine variant through the removal of the carbonyl at C2 (Figure 1A) led to compounds possessing significant antiproliferative activities by targeting the microtubule network in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities

et al. 2015

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Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC50 values and showed statistically significant tumor size reduction in a colon cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities

et al. 2015

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“…rigida found near Okinawa and New Guinea and has remained scantly explored despite initial reports of promising biological activities. 10-12 The first general total synthesis of rigidins A, B, C and D, which involved only four steps from commercially available materials, was reported by the authors in 2011 13 and allowed for a thorough investigation of their biological properties. However, despite the earlier reports of promising antiproliferative activity against murine leukemia L1210 cells, 11 the rigidins were found to have very little, if any, activity against cultured human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Synthetic and Biological Studies of Tubulin Targeting C2‐Substituted 7‐Deazahypoxanthines Derived from Marine Alkaloid Rigidins

et al. 2014

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C2-aryl- and C2-alkyl-7-deazahypoxanthines as analogues of marine alkaloid rigidins were prepared utilizing novel synthetic methods developed for the construction of the pyrrolo[2,3-d]pyrimidine ring system. The new compounds exhibited submicromolar to nanomolar antiproliferative potencies against a panel of cell lines including in vitro models for drug resistant tumors, such as glioblastoma, melanoma and non-small-cell lung cancer. A selected representative C2-methyl-7-deazahypoxanthine was found to inhibit microtubule dynamics in cancer cells, lending evidence for tubulin targeting as a mode of action for these compounds in cancer cells. The results of the docking studies utilizing the colchicine site on β-tubulin were consistent with the observed SAR data, including an important finding that derivatization at C2 with long alkyl groups leads to the retention of activity, thus permitting the attachment of a biotin-containing linker for the subsequent proteomics assays. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, the reported antitubulin rigidin analogues have significant potential as new anticancer agents.

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“…badium [42]. (IC 50 of 100 μg/mL against HCT 116 human colon carcinoma cell lines) [44]. However, the IC 50 of column fraction PI-8 was potent when compared to the lamellarin b from ascidian Didemnum sp.…”

Section: Fig (8) Change In Morphological Features Of the Hela Cellsmentioning

confidence: 98%

Anticancer Activity of the Ascidian Polyclinum Indicum against Cervical Cancer Cells (HeLa) Mediated through Apoptosis Induction

Rajesh

Ramasamy²,

Annappan³

2010

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The cytotoxicity-based chemotherapy treatment for cancer has significant side effects. Therefore, anticancer research is concentrated on identifying an effective drug with minimal side effects. The methanol extract of ascidian Polyclinum indicum and its column fraction PI-8 showed cytotoxicity against cervical cancer cells (HeLa) with an IC₅₀ of 77.5 µg/mL and 1.12 µg/mL. Hoechst staining with PI-8 treated cells portrayed the apoptotic events in drug-induced apoptosis. The PI-8 markedly arrested G₂/M and S phases in cell cycle. The occurrence of a second population of apoptotic cells in the range of lower Forward Scatter (FSC) and higher Side Scatter (SSC) compared to control cells indicated the characteristic feature of the cells dying of apoptosis. DNA fragmentation has established the apoptotic event. The study emphasized the fraction PI-8 of P. indicum as a potential lead compound for apoptosis targeted anticancer drugs. The molecular mechanism and chemotherapeutic potential of the fraction PI-8 needs further investigation.

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Rigidin E, a New Pyrrolopyrimidine Alkaloid from a Papua New Guinea Tunicate Eudistoma Species

Abstract: A new pyrrolopyrimidine alkaloid, rigidin E (1) and the known metabolites rigidin (2) and 1-methylherbipoline (3) have been isolated from a Papua New Guinea tunicate Eudistoma sp. A combination of spectroscopic data were used to determine the structures of these metabolites

Cited by 37 publications

References 15 publications

Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities

Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities

Synthetic and Biological Studies of Tubulin Targeting C2‐Substituted 7‐Deazahypoxanthines Derived from Marine Alkaloid Rigidins

Anticancer Activity of the Ascidian Polyclinum Indicum against Cervical Cancer Cells (HeLa) Mediated through Apoptosis Induction

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