Abstract
Fifteen pyrrole alkaloids were isolated from the Red Sea marine sponge Stylissa carteri and investigated for their biological activities. Four of them were dibrominated [(+) dibromophakelline, Z-3-bromohymenialdisine, (±) ageliferin and 3,4-dibromo-1H-pyrrole-2-carbamide], nine compounds were monobrominated [(−) clathramide C, agelongine, (+) manzacidin A, (−) 3-bromomanzacidin D, Z-spongiacidin D, Z-hymenialdisine, 2-debromostevensine, 2-bromoaldisine and 4-bromo-1H-pyrrole-2-carbamide)] and finally, two compounds were non-brominated derivatives viz., E-debromohymenialdisine and aldisine. The structure elucidations of isolated compounds were based on 1D & 2D NMR spectroscopic and MS studies, as well as by comparison with literature. In-vitro, Z-spongiacidin D exhibited a moderate activity on (ARK5, CDK2-CycA, CDK4/CycD1, VEGF-R2, SAK and PDGFR-beta) protein kinases. Moreover, Z-3-bromohymenialdisine showed nearly similar pattern. Furthermore, Z-hymenialdisine displayed a moderate effect on (ARK5 & VEGF-R2) and (−) clathramide C showed a moderate activity on AURORA-A protein kinases. While, agelongine, (+) manzacidin A, E-debromohymenialdisine and 3,4-dibromo-1H-pyrrole-2-carbamide demonstrated only marginal inhibitory activities. The cytotoxicity study was evaluated in two different cell lines. The most effective secondary metabolites were (+) dibromophakelline and Z-3-bromohymenialdisine on L5178Y. Finally, Z-hymenialdisine, Z-3-bromohymenialdisine and (±) ageliferin exhibited the highest cytotoxic activity on HCT116. No report about inhibition of AURORA-A and B by hymenialdisine/hymenialdisine analogs existed and no reported toxicity of ageliferin existed in literature.
Acknowledgments
We wish to thank Prof. Victor Wray (Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany) for supporting us for the identification of some compounds. Our great appreciation to the Egyptian Government for a scholarship (2006–2008) of Associate Lecturer/Ashraf N. E. Hamed.
Conflict of interest statement: The authors report no declarations of interest.
References
1. Vogel G. The inner lives of sponges. Science 2008;320: 1028–30.10.1126/science.320.5879.1028Search in Google Scholar PubMed
2. Hamed AN, Waetjen W, Edrada-Ebel R, Youssef DT, Wray V, Kamel MS, et al. A new bioactive sesquiterpenoid quinone from the Mediterranean Sea Marine Sponge Dysidea avara. Nat Prod Commun 2013;8:289–92.10.1177/1934578X1300800303Search in Google Scholar PubMed
3. Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR. Marine natural products. Nat Prod Rep 2005;22:15–61.10.1039/b415080pSearch in Google Scholar PubMed
4. Nguyen TN, Tepe JJ. Preparation of hymenialdisine, analogues and their evaluation as kinase inhibitors. Curr Med Chem 2009;16:3122–43.10.2174/092986709788803015Search in Google Scholar PubMed
5. Zhang N, Zhong R, Yan H, Jiang Y. Structural features underlying selective inhibition of GSK3β by dibromocantharelline: implications for rational drug design. Chem Biol Drug Des 2011;77:199–205.10.1111/j.1747-0285.2010.01069.xSearch in Google Scholar PubMed
6. Supriyono A, Schwarz B, Wray V, Witte L, Müller WE, van Soest R, et al. Bioactive alkaloids from the tropical marine sponge Axinella carteri. Z Naturforsch C 1995;50:669–74.10.1515/znc-1995-9-1012Search in Google Scholar PubMed
7. Tasdemir D, Mallon R, Greenstein M, Feldberg LR, Kim SC, Collins K, et al. Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). J Med Chem 2002;45:529–32.10.1021/jm0102856Search in Google Scholar PubMed
8. Meijer L, Thunnissen AM, White AW, Garnier M, Nikolic M, Tsai LH, et al. Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Chem Biol 2000;7:51–63.10.1016/S1074-5521(00)00063-6Search in Google Scholar PubMed
9. Breton JJ, Chabot-Fletcher MC. The natural product hymenialdisine inhibits interleukin-8 production in U937 cells by inhibition of nuclear factor-kappaB. J Pharmacol Exp Ther 1997;282:459–66.Search in Google Scholar PubMed
10. Kobayashi H, Kitamura K, Nagai K, Nakao Y, Fusetani N, van Soest RW, et al. Carteramine A, an inhibitor of neutrophil chemotaxis, from the marine sponge Stylissa carteri. Tetrahedron Lett 2007;48:2127–29.10.1016/j.tetlet.2007.01.113Search in Google Scholar
11. Tasler S, Müller O, Wieber T, Herz T, Krauss R, Totzke F, et al. N-Substituted 2′-(aminoaryl)benzothiazoles as kinase inhibitors: hit identification and scaffold hopping. Bioorg Med Chem Lett 2009;19:1349–56.10.1016/j.bmcl.2009.01.054Search in Google Scholar PubMed
12. Aly AH, Edrada-Ebel R, Indriani ID, Wray V, Müller WE, Totzke F, et al. Cytotoxic metabolites from the fungal endophyte Alternaria sp. and their subsequent detection in its host plant Polygonum senegalense. J Nat Prod 2008;71:972–80.10.1021/np070447mSearch in Google Scholar PubMed
13. Edrada R, Proksch P, Wray V, Witte L, Müller WE, Van Soest RW. Four new bioactive manzamine-type alkaloids from the Philippine marine sponge Xestospongia ashmorica. J Nat Prod 1996;59:1056–60.10.1021/np9604083Search in Google Scholar PubMed
14. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.10.1016/0022-1759(83)90303-4Search in Google Scholar PubMed
15. Limper C, Wang Y, Ruhl S, Wang Z, Lou Y, Totzke F, et al. Compounds isolated from Psoralea corylifolia seeds inhibit protein kinase activity and induce apoptotic cell death in mammalian cells. J Pharm Pharmacol 2013;65:1393–408.10.1111/jphp.12107Search in Google Scholar PubMed
16. Cafieri F, Fattorusso E, Taglialatela-Scafati O. Novel bromopyrrole alkaloids from the sponge Agelas dispar. J Nat Prod 1998;61:122–25.10.1021/np970323hSearch in Google Scholar PubMed
17. Cafieri F, Fattorusso E, Mangoni A, Taglialatela-Scafati O. A novel bromopyrrole alkaloid from the sponge Agelas longissima with antiserotonergic activity. Bioorg Med Chem Lett 1995;5:799–804.10.1016/0960-894X(95)00116-BSearch in Google Scholar
18. Kobayashi J, Kanda F, Ishibashi M, Shigemori H. Manzacidins A-C, Novel tetrahydropyrimidine alkaloids from the Okinawan marine sponge Hymeniacidon sp. J Org Chem 1991;56:4574–6.10.1021/jo00014a052Search in Google Scholar
19. Tsukamoto S, Tane K, Ohta T, Matsunaga S, Fusetani N, van Soest RW. Four new bioactive pyrrole-derived alkaloids from the marine sponge Axinella brevistyla. J Nat Prod 2001;64:1576–8.10.1021/np010280bSearch in Google Scholar PubMed
20. De Nanteuil G, Ahond A, Guilhem J, Poupat C, Tran Huu Dau E, Potier P, et al. Invertebres marins du lagon neo-caledonien-V1: isolement et Identification des metabolites d’une nouvelle espece de spongiaire, Pseudaxinyssa cantharella. Tetrahedron 1985;41:6019–33.10.1016/S0040-4020(01)91443-7Search in Google Scholar
21. Eder C, Proksch P, Wray V, Steube K, Bringmann G, van Soest RW, et al. New alkaloids from the Indopacific sponge Stylissa carteri. J Nat Prod 1999;62:184–7.10.1021/np980315gSearch in Google Scholar PubMed
22. Inaba K, Sato H, Tsuda M, Kobayashi J. Spongiacidins A-D, new bromopyrrole alkaloids from Hymeniacidon sponge. J Nat Prod 1998;61:693–5.10.1021/np970565hSearch in Google Scholar
23. Kobayashi J, Tsuda M, Murayama T, Nakamura H, Ohizumi Y, Ishibashi M, et al. Ageliferins, potent actomyosin ATPase activators from the Okinawan marine sponge Agelas sp. Tetrahedron 1990;46:5579–86.10.1016/S0040-4020(01)87756-5Search in Google Scholar
24. Hassan W, Elkhayat ES, Edrada-Ebel R, Ebel R, Proksch P. New bromopyrrole alkaloids from the marine sponges Axinella damicornis and Stylissa flabelliformis. Nat Prod Commun 2007;2:1149–54.10.1177/1934578X0700201121Search in Google Scholar
25. Schmitz FJ, Gunasekera SP, Lakshmi V, Tillekeratne LM. Marine natural products: pyrrololactams from several sponges. J Nat Prod 1985;48:47–53.10.1021/np50037a008Search in Google Scholar PubMed
26. Iwagawa T, Kaneko M, Okamuro H, Nakatani M, van Soest RW. New alkaloids from the Papua New Guinean sponge Agelas nakamurai. J Nat Prod 1998;61:1310–12.10.1021/np980173qSearch in Google Scholar PubMed
27. Mancini I, Guella G, Amade P, Roussakis C, Pietra F. Hanishin, a semiracemic, bioactive C9 alkaloid of the Axinellid sponge Acanthella carteri from the Hanish Islands. A shunt metabolite? Tetrahedron Lett 1997;38:6271–4.10.1016/S0040-4039(97)01405-6Search in Google Scholar
28. Stierle DB, Faulkner DJ. Metabolites of the marine sponge Laxosuberites species. J Org Chem 1980;45:4980–2.10.1021/jo01312a033Search in Google Scholar
29. Sipkema D, Franssen MC, Osinga R, Tramper J, Wijffels RH. Marine sponges as pharmacy. Mar Biotechnol (NY) 2005;7:142–62.10.1007/s10126-004-0405-5Search in Google Scholar PubMed PubMed Central
30. Jain P, Karthikeyan C, Moorthy NS, Waiker DK, Jain AK, Trivedi P. Human CDC2-like kinase 1 (CLK1): a novel target for Alzheimer’s disease. Curr Drug Targets 2014;15:539–50.10.2174/1389450115666140226112321Search in Google Scholar PubMed
31. Parmentier JG, Portevin B, Golsteyn RM, Pierré A, Hickman J, Gloanec P, et al. Synthesis and CHK1 inhibitory potency of hymenialdisine analogues. Bioorg Med Chem Lett 2009;19:841–4.10.1016/j.bmcl.2008.12.001Search in Google Scholar PubMed
32. Sharma V, Tepe JJ. Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett 2004;14:4319–21.10.1016/j.bmcl.2004.05.079Search in Google Scholar PubMed
33. Wan Y, Hur W, Cho CY, Liu Y, Adrian FJ, Lozach O, et al. Synthesis and target identification of hymenialdisine analogs. Chem Biol 2004;11:247–59.10.1016/j.chembiol.2004.01.015Search in Google Scholar PubMed
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The online version of this article offers supplementary material (https://doi.org/10.1515/znc-2017-0161).
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