+

WO1996032388A1 - Antheliatine, zahavine a et zahavine b a titre de nouveaux diterpenes de xenicane cytotoxiques - Google Patents

Antheliatine, zahavine a et zahavine b a titre de nouveaux diterpenes de xenicane cytotoxiques Download PDF

Info

Publication number
WO1996032388A1
WO1996032388A1 PCT/GB1996/000903 GB9600903W WO9632388A1 WO 1996032388 A1 WO1996032388 A1 WO 1996032388A1 GB 9600903 W GB9600903 W GB 9600903W WO 9632388 A1 WO9632388 A1 WO 9632388A1
Authority
WO
WIPO (PCT)
Prior art keywords
zahavin
antheliatin
ppm
xenicane
glauca
Prior art date
Application number
PCT/GB1996/000903
Other languages
English (en)
Inventor
Amira Rudi
Yoel Kashman
Dolores Garcia Gravalos
Original Assignee
Pharma Mar, S.A.
Ruffles, Graham, Keith
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharma Mar, S.A., Ruffles, Graham, Keith filed Critical Pharma Mar, S.A.
Priority to AU53389/96A priority Critical patent/AU5338996A/en
Publication of WO1996032388A1 publication Critical patent/WO1996032388A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein

Definitions

  • the present invention relates to new cytotoxic xenicane diterpenes.
  • Anthelia belongs to the Xeniidae along with other Indo- Pacific genera of this family such as Cespituluria, Effatounaria, Heteroxemia and Xenia, all of which associate with symbiotic algae (zooxanthellae).
  • Anthelia is characterized by having individual, non-retractile polyps united by a thin membrane and in this respect it differs from the related genera. Anthelia colonies tend to grow among other soft corals mainly of the Xeniidae family (Reference 14: Y. Benayahu, Proc. 5th Int.
  • A. glauca (Lammarck, 1816) is the most common species of the genus and has a wide zoogeographical distribution throughout the Indo- Pacific region. On the coral reefs of Sodwana Bay, South Africa, A. glauca is sporadic in its abundance and appears on the reefs in small clusters of colonies at a depth range of 14-22 meters.
  • a recent survey of the soft coral fauna of Sodwana Bay (Reference 12: Y. Benayahu, Invest. Rep. Oceanogr. Res. Inst. (Durban), No. 67, 1 (1993)) lists eight xeniid species. Unlike other reef areas such as the Red Sea (Reference 14), at Sodwana Bay, A. glauca is the most abundant xeniid.
  • Alcyonium belongs to the family Alcyoniidae (Reference 15: J. Verseveldt and F.M. Bayer, Zool. Verhand Leiden, 245, 1 (1988)), and Alcyonium comprises species recorded within a large latitudinal range and found in various habitats along a wide depth gradient (Reference 16: J. Verseveldt, Zool. Med Leiden, 39, 153 (1964); Reference 17: J. Verseveldt, Amer. Mus. Nov., 2282, 1 (1967); Reference 18: J. Verseveldt, Zool. Verhand Leiden, 117, 1 (1971); Reference 19: J. Verseveldt, Zool.
  • aurea is an azooxanthellated species collected at Sodwana Bay (Reference 13: Y Benayahu and M. Schleyer, in press). A. aurea was found at a depth of 28-36 meters, where almost no soft corals associated with endosymbiotic algae appear. There is no doubt that at Sodwana Bay A. aurea belongs to communities living below the euphotic zone.
  • the present invention provides three new compounds extracted and isolated from soft corals.
  • the compounds are antheliatin, zahavin A and zahavin B, the following formulae (I) and (II):
  • the compounds of the present invention exhibit antitumor activity.
  • the present compounds exhibit antitumour activity against cell lines derived from human tumors, such as P-388 mouse lymphoma, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma.
  • the present invention also provides a method of treating a mammal affected by a malignant tumor sensitive to antheliatin, zahavin A, or zahavin B , which comprises administering a therapeutically effective amount of antheliatin, zahavin A, and zahavin B, or a pharmaceutical composition thereof.
  • the present invention further provides pharmaceutical compositions which contain as active ingredient the compound antheliatin, zahavin A or zahavin B, as well as a process for their preparation.
  • a further aspect of the invention is a method for preparing the compounds, which comprises extraction and isolation from the respective soft coral, Anthelia glauca for antheliatin or Alcyonium aurea for zahavin a and zahavin B.
  • pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable formulation for oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
  • a pharmaceutical composition comprising antheliatin, zahavin A or zahavin B, will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • the antitumor cells employed were P-388 (suspension culture of a lymphoid neoplasm from DBA/2 mouse), A-549 (monolayer culture of a human lung carcinoma), HT-29 (monolayer culture of a human colon carcinoma) and MEL-28 (monolayer culture of a human melanoma).
  • P-388 cells were seeded into 16 mm wells at 1 x 10 cells per well in 1 ml aliquots of MEM 5FCS containing the indicated concentration of drug. A separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO in a 98% humid atmosphere, an approximate IC50 was determined by comparing the growth in wells with drug to the growth in wells control.
  • HT-29 and MEL-28 cells were seeded into 16 mm wells at 2 x 10 4 cells per well in 1 ml aliquots of MEM 10FCS containing the indicated concentration of drug.
  • a separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO2 in a 98% humid atmosphere, the wells were stained with 0.1% Crystal Violet. An approximate IC50 was determined by comparing the growth in wells with drug to the growth in wells in control.
  • Antheliatin (1) The soft coral Anthelia glauca was collected in Sodwana Bay South Africa, in May 1994 by divers using scuba A voucher (TASA 293) is deposited in the Zoological Department at Tel Aviv University
  • TASA 217 A voucher (TASA 217) is deposited in the Zoological Department at Tel Aviv University.
  • the gum was chromatographed first over a Sephadex LH-20 column eluted with MeOH- CHCl 3 -hexane, 1; 1;2) and then several times over Si gel columns eluted with hexane- EtOAc (8:2) to afford 2 (30 mg); Rf 0.7 (EtOAc-hexane, 1.1), and 3 (5 mg) Rf 0.65.
  • the Sodwana Bay A. glauca in contrast to the Red Sea species, was found to contain a single diterpenoid designated antheliatin (1), a crystalline material, m.p. 165°C (MeOH), [ ⁇ ] D + 3.5° (c, 1.2, CHC1 3 ), 0.2 % dry wt.
  • the four additional carbon atoms were assigned to (a) a polarized double bond ( ⁇ 13c 138.2 ppm(d) and 113.4 p ⁇ m( ⁇ )), (b) a lactol-methine ( ⁇ 13c 91.9 ppm (d), ⁇ , 5.77 ppm(d)) and (c) an additional aliphatic methine ( ⁇ J3c 38.4 ppm (d)).
  • the low-field nmr signal of the lactol-proton ( ⁇ 1H , 5.77 ppm) suggested that the third acetate was attached to this position (7).
  • HMBC CH-Hetero correlations in the nmr spectrum of 1, between (a) and C-atom of the methine C-4a, ( ⁇ 13C 38.9 ppm), the allylic pair H-6 and 6' and protons H-5 and 5' of B, the other end-methine of moiety B (H-l la), and H-3, and (b) between C-4 ( ⁇ 13C 1 13.4 ppm), one of the polarized double bond carbon atoms, and protons H-5 and 5' of site B and H-12 of A ( ⁇ 1H 5.69 ppm), suggested C-4 and C-4a to be the link between moieties A and B, a connection which was further extended by correlations between C-12 and H-3.
  • the location of this OH-group was suggested mainly on the basis of the following CH-correlations, deduced from an HMBC experiment: C-8/H-10; C- lO/H-19; C-1 la/H-19 as well as from homo-COSY correlations i.e. H-l 0/9,9' and H- 88/9,9'.
  • the chemical shifts of C-9 and C-1 la also support the C'lO location of the OH-group; (If the OH group was on C-9 the line of C-10 should have been at ca.
  • Zahavin B (3) is very unstable both under mild basic and mild acidic conditions; the compound decomposes readily under acetylation conditions (Ac 2 O, pyridine, CH 2 C1 2 ) or in a CDC1 3 solution.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On a isolé l'anthéliatine, la zahavine A et la zahavine B, trois nouveaux diterpénoïdes de xenicane, à partir des coraux mous Anthelia glauca et Alcyonium aurea habitant les récifs des océans indien et pacifique. On a établi les structure de ces trois composés à partir de données obtenues par R.M.N. unidimensionnelle et bidimensionnelle.
PCT/GB1996/000903 1995-04-13 1996-04-15 Antheliatine, zahavine a et zahavine b a titre de nouveaux diterpenes de xenicane cytotoxiques WO1996032388A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53389/96A AU5338996A (en) 1995-04-13 1996-04-15 Antheliatin, zahavin a and zahavin b: new cytotoxic xenicane diterpenes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9507908.3 1995-04-13
GBGB9507908.3A GB9507908D0 (en) 1995-04-13 1995-04-13 Antheliathin,zahavin A and zahavin B:new cytotoxic xenicane diterpenes

Publications (1)

Publication Number Publication Date
WO1996032388A1 true WO1996032388A1 (fr) 1996-10-17

Family

ID=10773172

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/000903 WO1996032388A1 (fr) 1995-04-13 1996-04-15 Antheliatine, zahavine a et zahavine b a titre de nouveaux diterpenes de xenicane cytotoxiques

Country Status (3)

Country Link
AU (1) AU5338996A (fr)
GB (1) GB9507908D0 (fr)
WO (1) WO1996032388A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100350891B1 (ko) * 2000-03-08 2002-09-05 한국해양연구원 아칼리시제니올리드 ｃ, ｄ, ｅ 및 ｆ
WO2011111804A1 (fr) * 2010-03-11 2011-09-15 学校法人早稲田大学 Composé antiprotozoaire provenant de coelentérés
CN113402391A (zh) * 2021-05-07 2021-09-17 宁波大学 波伦鳞花软珊瑚来源的二萜类化合物及其制备方法和用途

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BOWDEN B F ET AL: "Studies of Australian soft corals. XXVIII. The structure determination of two new diterpenes from the genus Xenia (Alcyonacea)", AUST. J. CHEM. (AJCHAS,00049425);82; VOL.35 (5); PP.997-1002, JAMES COOK UNIV. NORTH QUEENSLAND;DEP. CHEM. BIOCHEM.; TOWNSVILLE; 4811; AUSTRALIA (AU), XP002006328 *
BRAEKMAN J C ET AL: "Chemical studies of marine invertebrates. XXXIX. Three novel diterpenoids from the soft coral Xenia novae-britanniae", BULL. SOC. CHIM. BELG. (BSCBAG,00379646);79; VOL.88 (1-2); PP.71-7, UNIV. LIBRE BRUXELLES;FAC. SCI.; BRUSSELLS; B-1050; BELG., XP002006327 *
COVAL S J ET AL: "Two new xenicin diterpenoids from the octocoral Anthelia edmondsoni", TETRAHEDRON (TETRAB,00404020);84; VOL.40 (19); PP.3823-8, UNIV. HAWAII;DEP. CHEM.; HONOLULU; 96822; HI; USA (US), XP002006326 *
GREEN D ET AL: "Antheliolide A and B: two new C24-acetoacetylated diterpenoids of the soft coral Anthelia glauca", TETRAHEDRON LETT. (TELEAY,00404039);88; VOL.29 (13); PP.1605-8, TEL AVIV UNIV.;SCH. CHEM.; RAMAT AVIV; 69978; ISRAEL (IL), XP002006325 *
OCHI M ET AL: "Acalycigorgins A, B, and C, three new biologically active diterpenoids from the gorgonian Acalycigorgia sp", HETEROCYCLES (HTCYAM,03855414);93; VOL.36 (1); PP.41-4, KOCHI UNIV.;FAC. SCI.; KOCHI; 780; JAPAN (JP), XP002006324 *
OCHI M ET AL: "Biologically active xenicane diterpenoids from the gorgonian Acalycigorgia sp", HETEROCYCLES (HTCYAM,03855414);94; VOL.38 (1); PP.151-8, KOCHI UNIV.;FAC. SCI.; KOCHI; 780; JAPAN (JP), XP002006323 *
RUDI A ET AL: "Antheliatin and zahavins A and B, three new cytotoxic xenicane diterpenes from two soft corals", J. NAT. PROD. (JNPRDF,01633864);95; VOL.58 (10); PP.1581-6, TEL AVIV UNIV.;SCH. CHEM.; TAL AVIV; 69978; ISRAEL (IL), XP002006322 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100350891B1 (ko) * 2000-03-08 2002-09-05 한국해양연구원 아칼리시제니올리드 ｃ, ｄ, ｅ 및 ｆ
WO2011111804A1 (fr) * 2010-03-11 2011-09-15 学校法人早稲田大学 Composé antiprotozoaire provenant de coelentérés
CN102812015A (zh) * 2010-03-11 2012-12-05 学校法人早稻田大学 来自腔肠动物的抗原虫化合物
EP2546245A1 (fr) * 2010-03-11 2013-01-16 Waseda University Composé antiprotozoaire provenant de coelentérés
EP2546245A4 (fr) * 2010-03-11 2013-05-29 Univ Waseda Composé antiprotozoaire provenant de coelentérés
US8722909B2 (en) 2010-03-11 2014-05-13 Waseda University Antiprotozoal compound derived from coelenterata
JP5721186B2 (ja) * 2010-03-11 2015-05-20 学校法人早稲田大学 腔腸動物由来抗原虫化合物
CN113402391A (zh) * 2021-05-07 2021-09-17 宁波大学 波伦鳞花软珊瑚来源的二萜类化合物及其制备方法和用途
CN113402391B (zh) * 2021-05-07 2022-04-26 宁波大学 波伦鳞花软珊瑚来源的二萜类化合物及其制备方法和用途

Also Published As

Publication number Publication date
AU5338996A (en) 1996-10-30
GB9507908D0 (en) 1995-05-31

Similar Documents

Publication Publication Date Title
JP2626889B2 (ja) ブリオスタチン類
Sekine et al. Structure and relative stereochemistry of a new polycyclic alkaloid, asparagamine A, showing anti-oxytocin activity, isolated from Asparagus racemosus
US6358957B1 (en) Phenylahistin and the phenylahistin analogs, a new class of anti-tumor compounds
GB2033398A (en) L compositions containing them cyclosporin derivatives their production and pharmaceutica
CA1060003A (fr) Les n-trifluoroacetyladriamycin-14-alcanoates et produits therapeutiques qui en contiennent
US5196447A (en) Neristatin 1
KOMIYAMA et al. Structural study of a new antitumor antibiotic, kazusamycin
JPH0977791A (ja) ペプチド誘導体及びその用途
US5661175A (en) Hemiasterlin and geodiamolide TA
Zeng et al. Two new polycyclic aromatic alkaloids from the Okinawan marine sponge Biemna sp.
Chu et al. A new potent antifungal agent from Actinoplanes sp
WO1996032388A1 (fr) Antheliatine, zahavine a et zahavine b a titre de nouveaux diterpenes de xenicane cytotoxiques
EP0687673A1 (fr) Dérivés d'oxazole comme agents anti-tumoraux
EP0647625A1 (fr) Delaminomycines, antibiotiques nouveaux presentant une activite immunosuppressive, et leur production
US7439265B2 (en) Irciniastatins a and b
US4895852A (en) Antitumor alkaloids
US6476065B2 (en) Discalamide compounds and their use as anti-proliferative agents
US5514708A (en) Cytotoxic metabolites from Myriapora truncata
KR100533244B1 (ko) 스폰지로부터 분리한 아스마린 ａ 및 ｂ를 포함하는 세포독성 알칼로이드 유도체
WO1997010242A1 (fr) Trois nouveaux macrolides cytotoxiques extraits d'une eponge marine
Itoh et al. Isolation of two unusual tetrahydroisoquinoline-monoterpene glucosides from Alangium lamarckii as possible intermediates in the non-enzymatic formation of alangimarine from alangiside
US6420357B1 (en) Cytotoxic alkaloid derivatives including Asmarine A and B isolated from a sponge
US4912133A (en) BU-3862T antitumor antibiotic
US3095418A (en) 3-[2-(5-acetoxy-2-hydroxy-3, 5-dimethylcyclohexyl)-2-hydroxyethyl] glutarimide and derivatives thereof
US20040127540A1 (en) Antibiotic Cyan426-A

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载