臨床検査53巻8号

2009年08月発行

今月の主題 漢方薬・生薬と臨床検査 各論 〈活性成分探索・解析〉

生薬の抗腫瘍活性を持つ成分の解析

著者： 竹谷孝一¹

所属機関： ¹東京薬科大学薬学部医療薬物薬学科天然医薬品化学

ページ範囲：P.899 - P.907

　伝承薬的に使用されている抗癌生薬，抗腫瘍活性ランダムスクリーニングで選別された高等植物より活性成分が単離・構造決定され，抗腫瘍性，抗癌性が報告されている化合物を紹介するとともに，筆者らの研究室で見いだされた茜草根(Rubia akane, R. cordifoliaの根)からの抗腫瘍活性環状ヘキサペプチド類の最近の研究状況についても紹介する．

参考文献

1) Suffness M, Douros J：Current status of the NCI plant and animal product program. J Nat Prod　45：1-14, 1982

2) 糸川秀治，竹谷孝一，一柳幸生，他：高等植物より得られる抗腫瘍活性物質の研究，薬学雑誌　119：529-583, 1999

3) Sawada S, Okajima S, Aiyama R, et al：Synthesis and Antitumor Activity of 20(S), Camptothecin Derivatives：Carbamate-Linked, Water-Soluble, Derivatives of 7-Ethyl-10-hydroxycamptothecin. Chem Pharm Bull　39：1446-1454, 1991

", CRC Press, Boca Raton, 1995

5) 竹谷孝一：漢方薬・生薬薬剤師講座テキスト第2版，生薬からのガン治療薬の開発，pp152-169, 2005

6) Boyd RW, Shoemaker RH, Cragg GM, et al：New Avenues of Investigation of Marine Biologicals in the Anticancer Drug Discovery Program of the National Cancer Institute. In：Pharmaceuticals and the Sea(Jefford CW, Rinehart KL, Shield LS, eds), Technomic Publishing Co., Lancaster, Penssylvania, pp27-43, 1988

7) Suffness M：New Approaches to the Discovery of Antitumor Agents. In：Biologically Active Natural Products(Hostettmann K, Lea PJ, ed), Clarendon Press, Oxford, pp85-104, 1987

8) Suffness M：Development of Antitumor Natural Products at the National Cancer Institute. In：Gann Monograph on Cancer Research(Takeuchi T, Nitta K, Tanaka N, ed)Japan Scientific Societies Press, Tokyo, No.36, pp21-44, 1989

9) Goldin A, Schepartz SA, Venditti JM, et al：Historical Development and Current Strategy of the National Cancer Institute Drug Development Program. In：Methods in Cancer Research(DeVita VT Jr, Buseh H, ed), Academic Press, New York, Vol.16A, pp165-245, 1979

：results of tumor panel screening, 1976-1982, and future directions. Adv Pharmacol Chemother　20：1-20, 1984

　68：63-76, 1984

12) Cassady JM, Baird WM, Chang CJ：Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents. J Nat Prod　53：23-41, 1990

13) Cassady JM, Douros JD, ed：Anticancer Agents Based on Natural Product Models, Academic Press, New York, 1980

14) Aszalos A, ed：Antitumor Compounds of Natural Origin, CRC Press, Boca Raton, Florida, 1981

15) Pettit GR, Cragg GM, Herald CL, ed：Biosynthetic Products for Cancer Chemotherapy, Elsevier, New York, 1985

16) Alley MC, Scudiero DA, Monks A, et al：Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res　48：589-601, 1988

17) Scudiero DA, Shoemaker RH, Paull KD, et al：Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res　48：4827-4833, 1988

18) Oldham RK：Biological response modifiers program. J Biol Resp Modif　1：81-100, 1982

19) Talmadge JE, Fidler IJ, Oldham RK, ed：Screening for Biological Response Modifiers, Kluwer Academic Publishers, Boston, 1985

20) Suffness M：The Discovery and Development of Antitumor Drugs from Natural Products. In：Advances in Medicinal Plant Research(Vlietinck AJ, Dommisse RA, ed), Wissenschat liche Verlagsgeselschaft mbH, Stuttgart, pp101-133, 1985

21) Suffness M, Douros J：Drugs of Plant Origin. In：Methods in Cancer Research(DeVita VT, Bush H, ed)Vol16, Part A, Academic Press, New York, pp73-126, 1979

22) Tsukagoshi S：Antitumor Natural Products Other Than Antibiotics under Development in Japan. In：Gann Monograph on Cancer Research(Takeuchi T, Nitta K, Tanaka N, ed)No.36, Japan Scientific Societies Press, Tokyo, pp45-55, 1989

23) Pettit GR, Smith CR, Singh SB：Recent Advances in the Chemistry of Plant Antineoplastic Constituents. In：Biologically Active Natural Products(Hostettmann K, Lea PJ, ed)Clarendon Press, Oxford, pp105-116, 1987

24) Takeuchi T, Nitta K：Novel Antitumor Antibiotics Developed in Japan. In：Gann Monograph on Cancer Research(Takeuchi T, Nitta K, Tanaka N, ed)No.36, Japan Scientific Societies Press, Tokyo, pp3-19, 1989

25) Douros JD：Recent Results Cancer Res　63：33-48, 1978

31：1424-1427, 1983 b)Itokawa H, Takeya K, Mori N, et al：Isolation and antitumor activity of cyclic hexapeptides isolated from Rubiae radix. Chem Pharm Bull　32：284-290, 1984

(Cordell, GA, ed), Academic Press, NY, Vol.49, pp301-387, 1997

28) Hitotsuyanagi Y, Aihara T, Takeya K：RA-dimer A, a novel dimeric antitumor bicyclic hexapeptide from Rubia cordifolia L. Tetrahedron Lett　41：6127-6130, 2000

29) Hitotsuyanagi Y, Ishikawa H, Hasuda T, et al：Isolation, structural elucidation, and synthesis of RA-XVII, a novel bicyclichexapeptide fromRubia cordifolia, and the effect of side chain at residue 1 upon theconformation and cytotoxic activity. Tetrahedron Lett　45：935-938, 2004

30) Lee J, Hitotuyanagi Y, Takeya K：Structures of cytotoxic bicyclic hexapeptides, RA-XIX, -XX, -XXI, and -XXII, from Rubia cordifolia L. Tetrahedron　64：4117-4125, 2008

31) Jolad SD, Hoffmann JJ, Torrance SJ, et al：Bouvardin and deoxybouvardin, antitumor cyclic hexapeptides from Bouvardia ternifolia(Rubiaceae). J Am Chem Soc　99：8040-8044, 1977

148：95-97, 1982 b)Sirdeshpande BV, Toogood PL：Inhibition of Protein Synthesis by RA-Ⅶ. Bioorg Chem　23：460-470, 1995

　209：223-229, 2004

34) a)Majima H, Tsukagoshi S, Furue H, et al：Jpn J Cancer Chemother　20：67-78, 1993 b)Yoshida F, Asai R, Majima H, et al：Jpn J Cancer Chemother　21：199-207, 1994

35) Itokawa H, Takeya K, Mori N, et al：Studies on antitumor cyclic hexapeptides RA obtained from Rubiae Radix, Rubiaceae. Ⅲ. On derivatives of RA-Ⅴ and their in vivo activities. Chem Pharm Bull　32：3216-3226, 1984

　36：1837-1843, 1993

37) Itokawa H, Kondo K, Hitotsuyanagi Y, et al：Preparation and cytotoxicity of cyclic hexapeptides, RA derivatives. Chem Pharm Bull　41：1266-1269, 1993

38) 一栁幸生，竹谷孝一：チオアミドを利用した抗腫瘍性環状ペプチドRA-Ⅶの化学修飾と配座構造一活性相関の解明．有機合成化学協会誌　62：993-1005，2004

39) Hitotsuyanagi Y, Ishikawa H, Naito S, et al：Synthesis of l,l-cycloisodityrosines by copper(Ⅱ)acetate-DMAP-mediated intramolecular O-arylation of phenols with phenylboronic acids. Tetrahedron Lett　44：5901-5903, 2003

40) Lee JE, Hitotsuyanagi Y, Kim IH, et al：A novel bicyclic hexapeptide, RA-XVIII, from Rubia cordifolia：structure, semi-synthesis, and cytotoxicity. Bioorg Med Chem Lett　18：808-811, 2008

41) Lee JE, Hitotsuyanagi Y, Takeya K：Structures of cytotoxic bicyclic hexapeptides, RA-XIX, -XX, -XXI, and -XXII, from Rubia cordifolia L. Tetrahedron　64：4117-4125, 2008

42) Lee JE, Hitotsuyanagi Y, Fukaya H, et al：New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L. Chem Pharm Bull　56：730-733, 2008

43) Lee JE, Hitotsuyanagi Y, Nakagawa Y, et al：Design and synthesis of a bis(cycloisodityrosine)analogue of RA-Ⅶ, an antitumor bicyclic hexapeptide. Bioorg Med Chem Lett　18：6458-6461, 2008