Anti-HIV Natural Products from the plants Destributed in the Northern Part of Japan

• Project/Area Number: 10672009
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Niigata College of Pharmacy
• Principal Investigator: IKESHIRO Yasumasa Niigata College of Pharmacy, Professor, 薬学部, 教授 (70139731)
• Co-Investigator(Kenkyū-buntansha): KASHIWADA Yoshiki Niigata College of Pharmacy, Associate Professor, 薬学部, 助教授 (30169429)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: Anti-HIV / Chromene / Chroman / Rhododendron dauricum / Betula platyphylla var.japonica / triterpenoids

Research Abstract

During our continuous screening of plant-derived novel anti-HIV agents from natural products, the MeOH extracts of the leaves and twigs of Rhododendrom dauricum (Ericaceae) and the pollen and flowers of Betula platyphylla var.japonica (Betulaceae) were found to display significant anti-HIV activity (EC_<50>【less than or equal】20μg/mL, T.I.>5).
Bioassay-guided fractionation and repeated chromatography of the MeOH extracts of the leaves and twigs of R.dauricum has led to the isolation of novel isomeric chromane derivatives, rhododaurichromanic acids A (1) and B (2), together with known chromene, daurichromenic acid (3), as anti-HIV agents. The structures of 1 and 2 were elucidated by spectroscopic examinations and the absolute stereostrucutre of 1 was established by X-ray crystallographic analysis. The absolute stereostructures of 2 and 3 were also confirmed by photochemical conversion of 3 into 1 and 2. Daurichromenic acid (3) demonstrated potent anti-HIV activity with an EC50 value of 0 .00567 μg/mL, and therapeutic index (TI) of 3,710. Rhododaurichromanic acid A (1) also showed relatively potent anti-HIV activity with EC50 and TI values of 0.37 μg/mL and 91.9, respectively, whereas rhododaurichromanic acid B (2) displayed no anti-HIV activity.
Compounds 1 and 3 represent a new class of anti-HIV natural products and are considered to be potential new leads for development of anti-HIV agents.
On the other hand, bioassay-guided solvent parttion of the MeOH extract of the pollen and flowers of B.platyphylla var. japonica gave anti-HIV active n-hexane- and 90% MeOH-soluble fractions. Repeated chromatography of these fractions has resulted in the isolation of three new triterpenoids, along with 18 known triterpenoids, whose structures has been elucidated by epctroscopic examinations to be 3,4-seco-oleanene- and 3,4-seco-ursene-type triterpenes and 3-O-methylmalonyl 25,26-27-trisnor-20,24-epoxydammaran type triterpenes. Evaluation of the anti-HIV activities for these compounds are underway.

Research Products

• [Publications] Yoshiki Kashiwada: "Isolation of Rhododaurichromanic Acid B and the Anti-HIV Principles Rhododaurichromanic Acid A and Rhododaurichromenic Acid from Rhododendron dauricum"Tetrahedron. 57(8). 1559-1563 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kashiwada, Y., Yamazaki, Y., Ikeshiro, Y., Yamagishi, T., Fujioka, T., Mihashi, K., Mizuki, K., Cosentino, L.M., Fowke, K., Lee, K.H.: "Isolation of Rhododaurichromanic Acid B and the Anti-HIV Principles Rhododaurichromanic Acid A and Rhododaurichromenic Acid from Rhododendron dauricum"Tetrahedron. 57 (8). 1559-1563 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kashiwada, Y., Nagao, T., Hashimoto, A., Ikeshiro, Y., Okabe, H., Cosentino, L.M., Lee, K.H.: "Anti-AIDS Agents 38. Anti-HIV Activities of 3-O-Acyl Ursolic Acid Derivatives"J.Nat.Prod.. 63 (12). 1619-1622 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kashiwada, Y, Chiyo, J., Ikeshiro, Y., Nagao, T., Okabe, H., Cosentino, L.M., Fowke, K., Morris-Natschke, S.M., and Lee, K.H.: "Synthesis and Anti-HIV Activities of 3-Alkylamido-3-Deoxy-Betulinic Acid Derivatives"Chem. Pharm. Bull.. 48 (9). 1387-1390 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kashiwada, Y, Chiyo, J., Ikeshiro, Y., Nagao, T., Okabe, H., Cosentino, L.M., Fowke, K., Morris-Natschke, S.M., and Lee, K.H.: "3, 28-Di-O-(Dimethylsuccinyl)-Betulin Isomers as Anti-HIV Agents"Bioorg. Med. Chem. Lett.. 11 (2). 183-185 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kanamoto, T., Kashiwada, Y., Kanbara, K., Gotoh, K., Yoshimori, M., Goto, T., Sano, K., Nakashima, H.: "Anti-Human Immunodeficiency Virus Activity of YKFH312 (a Betulinic Acid Derivative), a Novel Compound Blocking Viral Maturation"Antimiclob.Agents Chemother.. 45 (4). 1225-1230 (2001)
  • Description: 「研究成果報告書概要(欧文)」より