Planta Med 2008; 74(3): 258-263
DOI: 10.1055/s-2008-1034315
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Separation and SAR Study of HIF-1α Inhibitory Tubulosines from Alangium cf. longiflorum

Paul Klausmeyer1 , Thomas G. McCloud1 , Badarch Uranchimeg2 , Giovanni Melillo2 , Dominic A. Scudiero3 , John H. Cardellina4  II , Robert H. Shoemaker4
  • 1Natural Products Support Group, NCI-Frederick, Frederick, Maryland, USA
  • 2DTP Tumor Hypoxia Laboratory, NCI-Frederick, Frederick, Maryland, USA
  • 3Molecular Target Screening Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA
  • 4Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI-Frederick, Frederick, Maryland, USA
Further Information

Publication History

Received: October 18, 2007 Revised: January 15, 2008

Accepted: January 16, 2008

Publication Date:
26 February 2008 (online)


A crude organic solvent extract of Alangium cf. longiflorum exhibited potent inhibition of hypoxia-induced HIF-1 transcriptional activity in human U251 glioma cells. Dereplication and bioactivity-guided fractionation, including Sephadex LH-20 and chiral HPLC chromatographies, led to the isolation of tubulosine (1), 9-desmethyltubulosine (2), and isotubulosine (3). Structures were verified by complete 1H and 13C assignments using 1D- and 2D-NMR techniques. Tubulosine strongly inhibited HIF-1 transcriptional activity, isotubulosine was devoid of activity, and 9-desmethyltubulosine possessed 6-fold less potency than tubulosine.


  • 1 Rapisarda A, Uranchimeg B, Scudiero D A, Selby M, Sausville E A, Shoemaker R H. et al . Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway.  Cancer Res. 2002;  62 4316-24
  • 2 Klausmeyer P, McCloud T G, Scudiero D A, Cardellina JH I I, Shoemaker R H. Identification of a new natural camptothecin analogue in targeted screening for HIF-1α inhibitors.  Planta Med. 2007;  73 49-52
  • 3 Sakurai N, Nakagawa-Goto K, Ito J, Sakurai Y, Nakanishi Y, Bastow K F. et al . Cytotoxic Alangium alkaloids from Alangium longiflorum. .  Phytochemistry. 2006;  67 894-7
  • 4 Chau N -M, Rogers P, Aherne W, Carroll V, Collins I, McDonald E. et al . Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1α induction in response to hypoxic stress and growth factors.  Cancer Res. 2005;  65 4918-28
  • 5 Popelak A, Haack E, Spingler H. Isolierung von isotubulosin aus Alangium lamarckii Thw.  Tetrahedron Lett. 1966;  41 5077-80
  • 6 Troconis M, Ma W, Nichols D E, McLaughlin J. Molecular modeling study of tubulosine and other related ipecac alkaloids.  J Comput Aided Mol Des. 1998;  12 411-8
  • 7 Zhou Y - D, Kim Y - P, Mohammed K A, Jones D K, Muhammad I, Dunbar D C. et al . Terpenoid tetrahydroisoquinoline alkaloids emetine, klugine, and isocephaeline inhibit the activation of hypoxia-inducible factor-1 in breast tumor cells.  J Nat Prod. 2005;  68 947-50
  • 8 Gupta R S, Siminovitch L. Mutants of CHO cells resistant to the protein synthesis inhibitors, cryptopleurine and tylocrebrine: genetic and biochemical evidence for common site of action of emetine, cryptopleurine, tylocrebine, and tubulosine.  Biochemistry. 1977;  16 3209-14
  • 9 Hsiang Y H, Hertzberg R, Hecht S, Liu L F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I.  J Biol Chem. 1985;  260 14 873-8
  • 10 Chan J, Khan S N, Harvey I, Merrick W, Pelletier J. Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles.  RNA. 2004;  10 528-43
  • 11 Ron D, Hinnebusch A G. Targeting translation in hypoxic tumors.  ACS Chem Biol. 2006;  1 145-8

Thomas G. McCloud

Natural Products Support Group

SAIC-Frederick, Inc.

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