WO1997010242A1 - Trois nouveaux macrolides cytotoxiques extraits d'une eponge marine - Google Patents

Trois nouveaux macrolides cytotoxiques extraits d'une eponge marine Download PDF

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Publication number
WO1997010242A1
WO1997010242A1 PCT/GB1996/002240 GB9602240W WO9710242A1 WO 1997010242 A1 WO1997010242 A1 WO 1997010242A1 GB 9602240 W GB9602240 W GB 9602240W WO 9710242 A1 WO9710242 A1 WO 9710242A1
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WO
WIPO (PCT)
Prior art keywords
compounds
compound
latrunculin
zampanolide
sponge
Prior art date
Application number
PCT/GB1996/002240
Other languages
English (en)
Inventor
Tatsuo Higa
Jun-Ichi Tanaka
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 AU69365/96A priority Critical patent/AU6936596A/en
Publication of WO1997010242A1 publication Critical patent/WO1997010242A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to new macrolides from marine sponge. Such compounds have antitumor activity.
  • Latrunculins have since then been isolated from other sponge species and nudibranchs. Most notably, latrunculin A and the laulimalides (or fijianolides, compounds 3 and 4), another class of macrolides, have been reported to co-occur in three specimens of Pacific sponges described as Hyatella sp., see J. Org. Chem.. 1988, 53. 3644, Spongia mycofijiensis, see J. Org. Chem.. 1988, 53, 3642, and unidentified species, see J. Nat. Prod., 1992. 55, 506.
  • the present invention provides compounds designated latrunculin S, neolaulimalide and zampanolide, also referred to as compounds (5), (6) and (7).
  • the structures of these three compounds are as follows:
  • the compounds show antitumor activity.
  • the invention also provides antitumor compositions and methods using at least one of the compounds of this invention.
  • a method of isolating the compounds is also provided, by extraction from the sponge Fasciospongia rimosa.
  • compositions provided by this invention include solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) formulations with a suitable composition for oral, topical or parenteral administration. They may contain the pure compound or in combination with any other pharmacologically active compound. These compositions may need to be sterile when administered parentally.
  • the correct dosage of pharmaceutical composition comprising a compound of the invention 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.
  • Compounds of the invention can be made by isolation from marine sources, notably by a process of this invention which comprises extraction from Fasciospongia rimosa, or by synthetic or semi-synthetic procedures.
  • the present invention is illustrated by the following Examples, which include details of the isolation of the compounds from marine sponge Fasciospongia rimosa collected in Okinawa and for which a voucher specimen (G301467) was deposited at Queensland Museum. Australia, and details of the biological activity of the compounds. A second voucher specimen (QMG312707) has been deposited at the same Museum. Taxonomically. the correct generic and family assignments of the sponge are a problem, which possibly is more correctly identified as
  • rimosa (Lamarck) (order dictyoceratida: family ?Spongiidae).
  • Spongia mycofijiensis Bakus e.g. Quinoa. Kakou & Crews (1998), J. Org.
  • the sponge Fasciospongia Rimosa was collected from underwater caves on Shimoji-jima. an island located in the southwest of Okinawa. A sample (wet. 4.48 kg) was extracted by steeping in acetone, and the residue after concentration was reextracted with EtOAc to give 39 g of an oil. The oil showed potent cytotoxicity (IC 50 0.002-0.1 ⁇ g/ml) against P388. A549, and HT29 cell lines. Separation of the extract as shown in Scheme 1 gave latrunculin A (compound 1. 17.2% of the extract), laulimalide (compound 3. 4.2%), isolaulimalide (compound 4. 0.31%). and two new minor constituents designated as latrunculin S (compound 5. 0.012%) and neolaulimalide
  • Table 1 shows the molecular formulae and some physical properties for the new compounds 5. 6 and 7. Comparison of the 1 H and 13 C NMR spectra ( Figure 2) with those of latrunculin A (compound 1 ) and 2D NMR analysis suggested the structure of latrunculin S to be depicted as shown for compound 5. Structural correlation of compound 5 with compound 1 was secured by NaBH 4 reduction of compound 1 which yielded two diastereomeric products compound 5 and compound 8 (Scheme 2). One of them was identical with latrunculin S (compound 5). The absolute configuration at C17 or 5 was R, as determined by modified Mosher's method.
  • Neolaulimalide (6) had the same molecular formula C 30 H 42 O 7 with those of laulimalide (3) and isolaulimalide (4), suggesting a related isomeric structure.
  • the structure (6) was determined by 2D NMR analysis including
  • zampanolide (7) was found to be C 29 H 37 NO 6 by HRFABMS.
  • the structure was elucidated by analysis of 2D NMR spectra (BCOSY, TOCSY, HMQC, HMBC and PSNOESY, Figures 5-6) as a new 20-membered macrolide having an amide of a 2.4-hexadienoic acid on the side chain.
  • P-388 were seeded into 16 mm wells at 1 ⁇ 10 4 cells per well in 1 ml aliquots of MEM 5FCS containing the indicated concentration of drug. A separate set of cultures without drug were seeded as control growth to ensure that these cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO 2 in an atmosphere of 98% humidity, the wells were stained with 0.1% Crystal Violet. An approximate IC 50 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 ⁇ 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% CO 2 in an atmosphere of 98% humidity, the wells were stained with 0.1% Crystal Violet. An approximate IC 50 was determined by comparing the growth in wells with drug to the growth in wells control. Results:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Il est possible d'isoler de nouveaux composés à activité antitumorale à partir de l'éponge Fasciospongia rimosa, à savoir latrunculine S, néolaulimalide et zampanolide, également référencés comme étant les composés (5), (6) et (7), respectivement, répondant aux formules suivantes (5, 6, 7).
PCT/GB1996/002240 1995-09-11 1996-09-11 Trois nouveaux macrolides cytotoxiques extraits d'une eponge marine WO1997010242A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69365/96A AU6936596A (en) 1995-09-11 1996-09-11 Three new cytotoxic macrolides from a marine sponge

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9518536.9 1995-09-11
GBGB9518536.9A GB9518536D0 (en) 1995-09-11 1995-09-11 Three new cytotoxic macrolides from a marine sponge

Publications (1)

Publication Number Publication Date
WO1997010242A1 true WO1997010242A1 (fr) 1997-03-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/002240 WO1997010242A1 (fr) 1995-09-11 1996-09-11 Trois nouveaux macrolides cytotoxiques extraits d'une eponge marine

Country Status (3)

Country Link
AU (1) AU6936596A (fr)
GB (1) GB9518536D0 (fr)
WO (1) WO1997010242A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021765A2 (fr) * 1999-09-21 2001-03-29 Universita' Degli Studi Di Roma 'la Sapienza' Methode de protection selective de cellules normales proliferantes et d'eradication selective de cellules tumorales ayant une voie p53 inactive
WO2001054689A1 (fr) * 2000-01-28 2001-08-02 University Of Hawaii Composés à base de laulimalide utilisés comme agents de stabilisation de microtubules
WO2002064589A1 (fr) * 2001-02-09 2002-08-22 Kosan Biosciences, Inc. Derives laulimalide
WO2005030779A2 (fr) * 2003-09-23 2005-04-07 Eisai Co. Ltd. Analogues de laulimalide et utilisations de ceux-ci
WO2007079312A2 (fr) * 2005-12-02 2007-07-12 Regents Of The University Of Colorado Compositions et procédés de traitement d’affections pathologiques médiées par l'actine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AMIRAM GROWEISS ET AL: "Marine toxins of ...", J. ORG. CHEM., vol. 48, no. 20, 1983, pages 3512 - 3516, XP002020711 *
CHEM. LETT., vol. 4, pages 255 - 256 *
CHEMICAL ABSTRACTS, vol. 124, no. 23, 3 June 1996, Columbus, Ohio, US; abstract no. 312574n, TANAKA, JUNG-ICHI ET AL: "New cytotoxic macrolides from the sponge Fasciospongia rimosa" XP002020713 *
D.G. CORLEY ET AL: "Laulimalides: new potent cytotoxic macrolides ...", J. ORG. CHEM., vol. 53, no. 15, 1988, pages 3644 - 3646, XP002020710 *
E. QUINOA ET AL: "Fijianolides, polyketide heterocycles from a marine sponge", J. ORG. CHEM., vol. 53, no. 15, 1988, pages 3642 - 3644, XP002020712 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021765A2 (fr) * 1999-09-21 2001-03-29 Universita' Degli Studi Di Roma 'la Sapienza' Methode de protection selective de cellules normales proliferantes et d'eradication selective de cellules tumorales ayant une voie p53 inactive
WO2001021765A3 (fr) * 1999-09-21 2001-10-11 Univ Roma Methode de protection selective de cellules normales proliferantes et d'eradication selective de cellules tumorales ayant une voie p53 inactive
WO2001054689A1 (fr) * 2000-01-28 2001-08-02 University Of Hawaii Composés à base de laulimalide utilisés comme agents de stabilisation de microtubules
US7435754B2 (en) 2000-01-28 2008-10-14 Utah State University Laulimalide microtubule stabilizing agents
WO2002064589A1 (fr) * 2001-02-09 2002-08-22 Kosan Biosciences, Inc. Derives laulimalide
US6670389B2 (en) 2001-02-09 2003-12-30 Kosan Biosciences, Inc. Laulimalide derivatives
US6815463B2 (en) 2001-02-09 2004-11-09 Kosan Biosciences, Inc. Laulimalide derivatives
WO2005030779A2 (fr) * 2003-09-23 2005-04-07 Eisai Co. Ltd. Analogues de laulimalide et utilisations de ceux-ci
WO2005030779A3 (fr) * 2003-09-23 2008-01-24 Eisai Co Ltd Analogues de laulimalide et utilisations de ceux-ci
WO2007079312A2 (fr) * 2005-12-02 2007-07-12 Regents Of The University Of Colorado Compositions et procédés de traitement d’affections pathologiques médiées par l'actine
WO2007079312A3 (fr) * 2005-12-02 2008-02-21 Univ Colorado Compositions et procédés de traitement d’affections pathologiques médiées par l'actine

Also Published As

Publication number Publication date
AU6936596A (en) 1997-04-01
GB9518536D0 (en) 1995-11-08

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