WO1997001334A1 - Cytotoxic triterpenes from a marine sponge - Google Patents

Cytotoxic triterpenes from a marine sponge Download PDF

Info

Publication number
WO1997001334A1
WO1997001334A1 PCT/GB1996/001550 GB9601550W WO9701334A1 WO 1997001334 A1 WO1997001334 A1 WO 1997001334A1 GB 9601550 W GB9601550 W GB 9601550W WO 9701334 A1 WO9701334 A1 WO 9701334A1
Authority
WO
WIPO (PCT)
Prior art keywords
sodwanone
formula
different
same
cytotoxic
Prior art date
Application number
PCT/GB1996/001550
Other languages
French (fr)
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 AU62364/96A priority Critical patent/AU6236496A/en
Publication of WO1997001334A1 publication Critical patent/WO1997001334A1/en

Links

Classifications

    • 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
    • C07D493/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • This invention relates to cytotoxic triterpenes isolated from a marine sponge.
  • the sodwanones are polyepoxysqualene-derived triterpenes. Similar secondary metabolites were earlier isolated from the Red Sea Sponge Siphonochalina siphonella (Reference 3- S. Carmely and Y. Kashman, Tetrahedron Lett., 24, 3673, (1983)) and from the Mediterranean sponge Raspaciona aculeata (Reference 4: G. Cimino, A. Crispino, R. de A. Epifanio, A. Madaio, CA. Mattia, R. Puliti, E. Trivellone, M. J. Uriz, Tetrahedron 48, 9013, (1992); and Reference 5: G. Cimino, A. Crispino, A. Madaio, E. Trivellone, M. J. Uriz, J. Nat. Prod. 56, 534 (1993) and references therein).
  • the present invention is concerned with the provision of compounds with antitumor activity.
  • the invention is further concerned with new sodwanones SUMMARY OF THE INVENTION
  • the present invention provides antitumoral compositions containing as an active ingredient a cytotoxic triterpene of the general formula (I):
  • R 1 O or -OH
  • R , R and R 4 are the same or different and each represents -H, -OH, -CH 3 or -OCH 3
  • R 5 O or -OH
  • R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and each represents -H, -OH, -CH 3 or -OCH 3
  • R 7 and R 8 are - H or together form a group -CH 2 -O-
  • R 11 O or -OH
  • R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are the same or different and each represents -H, -OH, -CH 3 or -OCH
  • the dotted bond indicates that there is a single or double bond in the ring.
  • the present invention further provides as new compounds the compounds of the general formula (I) with the exception of the known compounds sodwanone A and sodwanone B which are of the formula'
  • Particularly preferred compounds of this invention are the new compounds sodwanone G of formula:
  • compositions of this invention contain sodwanone A, G or H.
  • the new compounds sodwanone G and sodwanone H are preferably isolated from the sponge Axinella weltneri
  • These and the other new compounds of this invention may be made by synthesis starting from the available sodwanones or from related compounds.
  • two cyclic systems may be separately prepared and united, as illustrated by the following reaction scheme involving uniting molecules (A) and (B):
  • the compounds of the present invention notably sodwanone A, G and H, exhibit antitumor activity against cell line 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 any mammal affected by a malignant tumor sensitive to a compound of this invention, or a pharmaceutical composition thereof.
  • compositions of this invention include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or 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.
  • the correct dosage of active ingredient in a pharmaceutical composition of this invention will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and bacteria or 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 1x10 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% CO2 in a 98% humid atmosphere, an approximately 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 2xl0 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 control.
  • sodwanones A to F afforded sodwanones A to F and in addition, the new sodwanone G, also referred to as compound 1.
  • the sponge From yet another collection of the sponge (TASA-328, August 1994), three sodwanones of almost the same polarity were isolated, where the second compound was sodwanone H, also referred to as compound 2.
  • sodwanone I also referred to as compound 3 was also isolated, but is not part of the present invention.
  • Axinella weltneri (Von Lendenfeld) (class Demospongiae, order Halichondria, family Axinellidae) (No. TASA-262) was collected in Sodwana Bay, South Africa by Scuba diving during the winter of 1994.
  • a voucher sample of the organism (the sponge Axinella weltneri) from which Sodwanone G has been isolated, has been deposited at the Oceanographic Research Institute, having the Deposit Number 262 and having been deposited on 29 March 1994.
  • Two voucher samples o ⁇ Axinella sp.
  • COMPOUND 1 COMPOUND 2 ⁇ c ⁇ H d HMBC (C to H) ⁇ c d ⁇ H HMBC (C to H)
  • the second half ofthe molecule, of 2 embodies a tetra-substituted ⁇ , ⁇ -unsaturated ketone ( ⁇ c 200.0s, 168.5s and 129.4s), a secondary hydroxyl group ( ⁇ c 74.9d, ⁇ H 3.48 brs) and it carries four methyl groups.
  • the two functionalities could further be expanded from the nmr data by the -C(17)H 2 C(18)H and -C(20)H 2 C(21)H 2 C(22)HOH- moieties.
  • the right part of 2 has also to be bicyclic.
  • a third compound was isolated from the sponge was sodwanone I, C 30 H 5 oO 5 , m/z 490.3672 (M + ), also referred to as compound 3.
  • the nmr data implied that the left half of the molecule (C-2 to C-13) is identical to the left half of sodwanone F and that the other half differs from all the corresponding parts of the other sodwanones.
  • the chemical shifts, COSY and HMBC experiments suggested for compound 3 a -CH 2 CH 2 COCH(CH 3 ) 2 moiety and an ethereal bridge ( ⁇ c 86.4s and 82Jd; ⁇ H 3.96d).
  • HMBC correlations set the quaternary ethereal C-atom between Me- 28 and Me-29 of the C(17)H 2 C(16)H 2 C(15)HCH 3 (28) moiety (determined by a COSY experiment).
  • the above data suggested an oxabicyclo [3JJ] heptane system which was unequivocally confirmed by a NOESY experiment.

Abstract

Antitumoral triterpenes are of general formula (I), where R1 represents =O or -OH; R?2, R3 and R4¿ are the same or different and each represents -H, -OH, -CH¿3? or -OCH3; R?5¿ represents =O or -OH; R?6, R7, R8, R9 and R10¿ are the same of different and each represents -H, -OH, -CH¿3? or -OCH3; R?7 and R8¿ are -H or together form a group -CH¿2?-O-; R?11¿ represents =O or -OH; R?12, R13, R14, R15, R16 and R17¿ are the same or different and each represents -H, -OH, -CH¿3? or -OCH; and the dotted bond indicates that there is a single or double bond in the ring. New compounds include sodwanone G of formula (II) and sodwanone H of formula (III).

Description

Cytotoxic Triterpenes from a Marine Sponge
This invention relates to cytotoxic triterpenes isolated from a marine sponge.
BACKGROUND OF THE INVENTION
The isolation and structure elucidation of sodwanones A to F from the Indo- Pacific sponge Axinella weltneri has been reported (Reference 1 : A. Rudi, I. Goldberg, Z. Stein, Y. Benayahu, M. Schleyer and Y. Kash an, Tetrahedron Lett., 34, 3943 (1993); and Reference 2: A. Rudi, Y. Kashman, Y. Benayahu and M. Schleyer, J. Nat. Prod 57, 1416 (1994)).
The sodwanones are polyepoxysqualene-derived triterpenes. Similar secondary metabolites were earlier isolated from the Red Sea Sponge Siphonochalina siphonella (Reference 3- S. Carmely and Y. Kashman, Tetrahedron Lett., 24, 3673, (1983)) and from the Mediterranean sponge Raspaciona aculeata (Reference 4: G. Cimino, A. Crispino, R. de A. Epifanio, A. Madaio, CA. Mattia, R. Puliti, E. Trivellone, M. J. Uriz, Tetrahedron 48, 9013, (1992); and Reference 5: G. Cimino, A. Crispino, A. Madaio, E. Trivellone, M. J. Uriz, J. Nat. Prod. 56, 534 (1993) and references therein).
OBJECTS OF THE INVENTION
The present invention is concerned with the provision of compounds with antitumor activity. The invention is further concerned with new sodwanones SUMMARY OF THE INVENTION
The present invention provides antitumoral compositions containing as an active ingredient a cytotoxic triterpene of the general formula (I):
Figure imgf000004_0001
where R1 represents =O or -OH; R , R and R4 are the same or different and each represents -H, -OH, -CH3 or -OCH3; R5 represents =O or -OH; R6, R7, R8, R9 and R10 are the same or different and each represents -H, -OH, -CH3 or -OCH3; R7 and R8 are - H or together form a group -CH2-O-; R11 represents =O or -OH; R12, R13, R14, R15, R16 and R17 are the same or different and each represents -H, -OH, -CH3 or -OCH; and the dotted bond indicates that there is a single or double bond in the ring.
The present invention further provides as new compounds the compounds of the general formula (I) with the exception of the known compounds sodwanone A and sodwanone B which are of the formula'
Figure imgf000004_0002
where R is -OH or -H respectively for sodwanone A or B. PREFERRED EMBODIMENTS
Particularly preferred compounds of this invention are the new compounds sodwanone G of formula:
Figure imgf000005_0001
and sodwanone H of formula:
Figure imgf000005_0002
Particularly preferred antitumor compositions of this invention contain sodwanone A, G or H.
The new compounds sodwanone G and sodwanone H are preferably isolated from the sponge Axinella weltneri These and the other new compounds of this invention may be made by synthesis starting from the available sodwanones or from related compounds. For example, two cyclic systems may be separately prepared and united, as illustrated by the following reaction scheme involving uniting molecules (A) and (B):
Figure imgf000005_0003
(A)
Figure imgf000006_0001
Figure imgf000006_0002
where -X and -Y are halogen or other appropriate leaving group, -P is a protecting group, and the multiple arrows indicate one or more steps. The scheme can readily be modified, as for example in order to prepare the compounds where the dotted bond in the claimed compounds is a double bond. Moreover, variations may be adopted within the skill of the competent synthetic chemist.
The compounds of the present invention, notably sodwanone A, G and H, exhibit antitumor activity against cell line 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 any mammal affected by a malignant tumor sensitive to a compound of this invention, or a pharmaceutical composition thereof.
Examples of pharmaceutical compositions of this invention include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or 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.
The correct dosage of active ingredient in a pharmaceutical composition of this invention will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and bacteria or 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.
ANTITUMOR ACTIVITY
A simple screening procedure was carried out to determine and compare the antitumor activity of the compounds, using an adapted form of the method described by Bergeron et al.. 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).
Cells were maintained in logarithmic phase of growth in Eagle's Minimum Essential Medium, with Earles's Balanced Salts, with 2.0 mM L-glutamine, with non¬ essential amino acids, without sodium bicarbonate and OJg/1 penicillin-G + streptomycin sulfate.
P-388 cells were seeded into 16 mm wells at 1x10 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% CO2 in a 98% humid atmosphere, an approximately IC50 was determined by comparing the growth in wells with drug to the growth in wells control.
A-549, HT-29 and MEL-28 cells were seeded into 16 mm wells at 2xl04 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 control.
IC50(μg /ml)
COMPOUND P-388 A-549 HT-29 MEL-28
SODWANONE G 1.0 OJ 1 1
SODWANONE H 5 0.01 5 5
SODWANONE A 5 0.5 10 n.t.*
* n.t. indicates not tested.
literature references
Raymond J Bergeron, Paul F Cavanaugh, Jr., Steven J Kline, Robert G Hughes, Jr., Gary T Elliot and Carl W Porter. Antineoplastic and antiherpetic activity of spermidine catecholamide iron chelators. Biochem. Bioph. Res Comm. 1984, 121(3). 848-854.
Alan C Schroeder, Robert G Hughes, Jr. And Alexander Bloch. Effects of Acyclic Pyrimidine Nucieoside Analogues. J. Med. Chem. 1981, 24 1078-1083.
ISOLATION OF SODWANONES G AND H The present invention will be further illustrated with reference to the following examples which aid in the understanding of the present invention, but which are not to be construed as limitations thereof. All percentages reported herein, unless otherwise specified, are present by weight. All temperatures are expressed in degrees Celsius. All incubations are carried out at 28°C and flasks are shaken in an orbital shaker at 250 φm. All media and recipients are sterile and all culture processes aseptic.
Ir spectra were recorded on a Nicolet 205 Ft-ir spectrophotometer. High resolution mass spectra (HRMS) were obtained on a VG Fison autospec Q instrument. H and 13C-nmr were recorded on Bruker AMX-360 and ARX-500 spectrometers. All chemical shifts are reported with respect to TMS (δH = 0). Optical rotations were measured on a Perkin-Elmer Model 141 polarimeter using a 1-cm microcell.
A recollection of J. Weltneri (May 1993) afforded sodwanones A to F and in addition, the new sodwanone G, also referred to as compound 1. From yet another collection of the sponge (TASA-328, August 1994), three sodwanones of almost the same polarity were isolated, where the second compound was sodwanone H, also referred to as compound 2. A new compound, sodwanone I also referred to as compound 3, was also isolated, but is not part of the present invention.
Axinella weltneri (Von Lendenfeld) (class Demospongiae, order Halichondria, family Axinellidae) (No. TASA-262) was collected in Sodwana Bay, South Africa by Scuba diving during the winter of 1994. A voucher sample of the organism (the sponge Axinella weltneri) from which Sodwanone G has been isolated, has been deposited at the Oceanographic Research Institute, having the Deposit Number 262 and having been deposited on 29 March 1994. Two voucher samples oϊ Axinella sp. (unknown species) from which sodwanones H and I have been isolated, have been deposited at the Oceanographic Research Institute, having the Deposit Numbers 328 and 329 respectively, having both been deposited on 7 September 1994. The freshly collected sponge was immediately frozen at -25°C. The freeze dried sponge (5g) was then extracted with EtOAc to give a brown gum (160 mg). The latter gum was chromatographed first on a Sephadex LH-20 column, eluted with MeOH- CHC13-Hexane (1 : 1 :2) and then several times on Si gel columns eluted with hexane/EtOAc mixtures to afford: 1 (10 mg, 0.2%), 2 (3 mg, 0.06%), 3 (3 mg, 0.06%); Rf values (EtOAc-hexane 1:1) are 0.62, 0.58, 0.57, respectively.
Sodwanone G [compound 1]. Mp 245° (MeOH); [α]D - 14.5°; (c = 0.9, CHC13); ir vmax (neat) 3510, 3400, 2970, 1715, 1613 cm"1; 13C nmr, see Table 1; Η-nmr δH 3.21 ddd (7=16.4, 11.2, 3.7), 3J0 dd (7=10.7, 5.1) , 2.75dd (7=4.2, 2.1), 2.74 ( =9.1), 2.62 dd (7=10.1, 9.1), 2.58d (7=4.2), 2.50 dt (7=5.1, 13.0), 2.36 dd (7=13.5, 9.1). COSY - in addition to the correlation observed for sodwanone B: H-9a, 9b/- 27a-27b; H-l 1 -27a,- 27b, H-27a-27b; HREIMS 498.2942 (M\C30H42O6 (calcd. 498,2981).
Sodwanone H [compound 2]. - Amoφhous powder [α]D-8; (c=0J, CHC13), ir vmax(neat) 3400, 2950, 1700 cm"1; 13C nmr see Table 1; 1H-nmr δH 3.25 ddd (7=16.2, 11.3, 3.0), 2.97 dd (7=1 1.8, 4.3), 2.38 dd (7=16.8, 6.5), 2.36 dd (7=16.8, 12.5), 2.28 dt (7=12.5, 6.2), 2.20 dd (7=12.5, 6.5), 2.15 ddd (7=1.3.0, 5.3), 2.10 tt (7=14.2, 3.0). COSY in addition to correlation observed in Sodwanone B; H-l 7a- 17b, 18; H-l 7b- 18; H-22-21a-21b-20a-20b; HREIMS 472.3517 (M", C30H4gO4 (calcd. 472.3553).
Table 1 : Nmr Data (125 and 500 MHz) including CH-correlations of Sodwanones G. H (IJ)1 a-d
COMPOUND 1 COMPOUND 2 δc δH d HMBC (C to H) δc d δH HMBC (C to H)
2 82.5s 7,24,25 82.3s 7,24,25
3 216.0s 4a,4b,5a,24,25 217.8s 4a,4b,5a,24,25
4 35.0s 3.21 ddd 35. lt 3.25dd 2.18m 2J0tt
5 33.4t 1.92m 40.4t 1.90m 7,26 1.90m 1.19m
6 43.1s 26 40.3s 26
7 79.8d 3J0dd 8a,8bJ l,26 82.0d 2.97dd 24,25
8 29.8t 1.80m 31. lt 1.65m 1.75m 1.48m
9 21.8t 1.78m 28.2t 1.90m 27 1.78m
10 58.3s 9a,9b, HJ2aJ2b, 28.6d 1.92m 27 13a
11 50.5d 1.49m 26 51.6d 1.13m 27
12 39.3t 1.40m 4a,4b,7,26 25.8t 1.60m 0.80m 1.45m
13 33.0t 2.50dt 28.6t 2.28dt 2.20m 1.95m
14 164.7s 13aJ3b,28,29 168.5s 13a,28,29
15 128.8s 13aJ3b,28 129.4s 13a,28
16 181.5s OH- 17,28 200.0s 17aJ7bJ8,28
17 141.8s OH- 17 34.5t 2.38dd 2.36dd
18 137.6s OH-17,29,30,31 43.3d 2.20dd 29
19 42.7s 13a,29,30 41.3s 21a,29
20 27.3t 2.36dd 27.3t 1.62m 18.29 1.68m 1.62m
21 32.6t 2.74d 25.2t 2J5ddd 2.62dd 1.93m
22 212.0s 20a,21a,21b,30,31 74.9d 3.48bs 30.31
23 48.0s 30,31 37.3s 30.31
24 20.2q 1.34s 20.4q 1.27s 25
25 26.4q 1.27s 26.0q 1.21s 24
26 11.9q 0.96s 13.4q 0.97s 7
27 50.3t 2.75dd 26 14.5q 0.95d 2.58d
28 11.9q 1.96s 11.3q 1.68s
29 21.6q 1.09s 17.8q 0.94s
30 20.8q 1.51s 21.6q 0.91s
31 24.3q 1.47s 26.4q 0.93s
a CDC13: Bruker ARX 500, chemical shifts refer to TMS (δH = 0) and
CDC13, δc = 77.0 b Assignments aided by HMQC, HMBC, homo COSY, TOCSY and NOESY experiments, c Ha- the lower field proton in a geminal pair and Hb- the higher field one. d For J-values, see experimental. For completeness, we also report Sodwanone I [compound 3]. -Oil; [α]D+2; (c=0.2, CHC13), 13C nmr, and Η-nmr Table 4; HREIMS 490.3700 (M", C3oH5oO5 (calcd. 490.3658).
Structure elucidation of compound 1 began by intensive study of spectrometric data. The molecular formula C30H12O6 (M") was established by HREIMS and by the C and H count obtained from nmr. Comparison of the nmr data with the data of sodwanones A and B pointed clearly to the identify of fragments C-2 to C-9 and C-12 to C-31 (the left half), whereas, differences were observed in fragment C-8 to C-11. Two carbon atom resonances at δ 58.3s and δ50.3t (δH 2.75dd and 2.58d, IH each) suggested an exocyclic epoxide (on C-10 (C-27)). Indeed, sodwanone G contains only seven methyl groups, the eighth one being transformed into the epoxide via the C-10 (C-27) methylene, as in sodwanone D (1,2).
2D-Nmr, COSY, TOCSY and HMBC experiments (Table 1) confirmed the 10(27) location of the epoxide.
Unequivocal proof of the complete structure and relative stereochemistry of sodwanone G were established by the X-ray diffraction analysis. The relative stereochemistry ofthe two halves of the molecule is identical to that in sodwanone A (Reference 1).
From yet another collection of the sponge (TASA-328, August 1994), three sodwanones of almost the same polarity were isolated. The first compound was determined to be the known sodwanone F (2). The second compound, sodwanone H, also referred to as compound 2, an amoφhous powder, gave a molecular ion in the HREIMS at m/z 472.3537 (M+) corresponding to a molecular formula of C30H4804. Comparison of the nmr data of [2] with those of the known sodwanones (References 1, 2) determined the identify ofthe left part (moiety C-2 to C-13) of 2 and the same bicyclic system in sodwanone B (Table 1). According to the nmr data, the second half ofthe molecule, of 2, embodies a tetra-substituted α, β-unsaturated ketone (δc 200.0s, 168.5s and 129.4s), a secondary hydroxyl group (δc 74.9d, δH 3.48 brs) and it carries four methyl groups. The two functionalities could further be expanded from the nmr data by the -C(17)H2 C(18)H and -C(20)H2 C(21)H2 C(22)HOH- moieties. According to the seven degrees of unsaturation of 2 and the above functionalities, the right part of 2 has also to be bicyclic. Based on the nmr data, a similar decalin system to the one existing in sodwanones A, B, C and G was suggested. The latter suggestion was unequivocally confirmed by the HMBC correlations (Table 1). The stereochemistry of the right half of 2 was established from a NOESY experiment.
A third compound was isolated from the sponge was sodwanone I, C30H5oO5, m/z 490.3672 (M+), also referred to as compound 3. The nmr data implied that the left half of the molecule (C-2 to C-13) is identical to the left half of sodwanone F and that the other half differs from all the corresponding parts of the other sodwanones. The chemical shifts, COSY and HMBC experiments suggested for compound 3 a -CH2CH2COCH(CH3)2 moiety and an ethereal bridge (δc 86.4s and 82Jd; δH 3.96d). Furthermore, the HMBC correlations set the quaternary ethereal C-atom between Me- 28 and Me-29 of the C(17)H2 C(16)H2 C(15)HCH3(28) moiety (determined by a COSY experiment). The above data suggested an oxabicyclo [3JJ] heptane system which was unequivocally confirmed by a NOESY experiment.
OH °
o o
H

Claims

CLAIMS:
1. An antitumoral composition containing as an active ingredient a cytotoxic triteφene of the general formula (I):
Figure imgf000014_0001
where R1 represents =O or -OH; R , R and R4 are the same or different and each represents -H, -OH, -CH3 or -OCH3; R5 represents =O or -OH; R6, R7, R8, R9 and R10 are the same or different and each represents -H, -OH, -CH3 or -OCH3; R7 and R8 are - H or together form a group -CH2-O-; Rπ represents =O or -OH; R12, R13, R14, R15, R16 and R17 are the same or different and each represents -H, -OH, -CH3 or -OCH; and the dotted bond indicates that there is a single or double bond in the ring; together with a pharmaceutically acceptable carrier.
2. An antitumoral composition according to claim 1, wherein the cytotoxic triteφene of the general formula (I) is sodwanone G of formula:
0
\ \.- ^0
3. An antitumoral composition according to claim 1, wherein the cytotoxic triteφene of the general formula (I) is sodwanone H of formula:
Figure imgf000015_0001
4. An antitumoral composition according to claim 1, wherein the cytotoxic triteφene of the general formula (I) is sodwanone A of formula:
Figure imgf000015_0002
where R is -H.
A triteφene of the general formula (I):
Figure imgf000015_0003
where R1 represents =O or -OH; R , R and R are the same or different and each represents -H, -OH, -CH3 or -OCH3; R represents =O or -OH; R , R , R8, R9 and R 10 are the same or different and each represents -H, -OH, -CH, or -OCH3; R7 and R8 are - H or together form a group -CH2-O-; Ru represents =O or -OH; R12, R13, R14, R15, R16 and R17 are the same or different and each represents -H, -OH, -CH3 or -OCH; and the dotted bond indicates that there is a single or double bond in the ring; with the exception of sodwanone A and sodwanone B which are of the formula:
Figure imgf000016_0001
where R is -OH or -H respectively for sodwanone A or B.
Sodawanone G of formula:
Figure imgf000016_0002
Sodwanone H of formula:
Figure imgf000016_0003
8. A process for the preparation of sodwanone G or sodwanone H, as defined in claim 6 or 7, which comprises isolation from the sponge Axinella weltneri.
PCT/GB1996/001550 1995-06-27 1996-06-27 Cytotoxic triterpenes from a marine sponge WO1997001334A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62364/96A AU6236496A (en) 1995-06-27 1996-06-27 Cytotoxic triterpenes form a marine sponge

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9513101.7 1995-06-27
GBGB9513101.7A GB9513101D0 (en) 1995-06-27 1995-06-27 Cytotoxic triterpenes from a marine sponge

Publications (1)

Publication Number Publication Date
WO1997001334A1 true WO1997001334A1 (en) 1997-01-16

Family

ID=10776761

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/001550 WO1997001334A1 (en) 1995-06-27 1996-06-27 Cytotoxic triterpenes from a marine sponge

Country Status (3)

Country Link
AU (1) AU6236496A (en)
GB (1) GB9513101D0 (en)
WO (1) WO1997001334A1 (en)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AMIRA RUDI ET AL.: "SODWANONES A-FTRITERPENOIDS FROM THE MARINE SPONGE", JOURNAL OF NATURAL PRODUCTS, vol. 57, no. 10, October 1994 (1994-10-01), USA, pages 1416 - 1423, XP000602887 *
AMIRA RUDI ET AL.: "SODWANONES G,H,I, CYTOTOXIC TRITERPENES FROM A MARINE SPONGE", JOURNAL OF NATURAL PRODUCTS, vol. 58, no. 11, November 1995 (1995-11-01), USA, pages 1702 - 1712, XP000602885 *

Also Published As

Publication number Publication date
AU6236496A (en) 1997-01-30
GB9513101D0 (en) 1995-08-30

Similar Documents

Publication Publication Date Title
US4560774A (en) Macrocyclic lactones
US6358957B1 (en) Phenylahistin and the phenylahistin analogs, a new class of anti-tumor compounds
US5468769A (en) Paclitaxel derivatives
US4268676A (en) Mitomycin analogs
AU716656B2 (en) Selected derivatives of K-252a
JPH0977791A (en) Peptide derivative and its use
US6403636B1 (en) Xanthone compounds, their preparation and use as medicament
Chu et al. A new potent antifungal agent from Actinoplanes sp
NZ208757A (en) Rifampicin derivatives and pharmaceutical compositions
WO1997001334A1 (en) Cytotoxic triterpenes from a marine sponge
AU2002239565B2 (en) Saframycins, analogues and uses thereof
US5298523A (en) Method for treating transplant patients using mycalamide compounds
US20030100589A1 (en) Synthetic diazonamides as novel anti-mitotic agents
CN110903289B (en) Purine-aminomethyl-pyridone derivative, preparation method and application thereof
US4460599A (en) Mitomycin analogs
JPH0774220B2 (en) Novel hydroxide mediated FK-506 rearrangement product
US4895852A (en) Antitumor alkaloids
Taylor et al. Plant anticancer agents. 28. New antileukemic jatrophone derivatives from Jatropha gossypiifolia: structural and stereochemical assignment through nuclear magnetic resonance spectroscopy
RU2221800C2 (en) Alkaloids, method for their preparing, method for treatment, pharmaceutical composition
US6420357B1 (en) Cytotoxic alkaloid derivatives including Asmarine A and B isolated from a sponge
EP1758904B1 (en) Flavopereirine derivatives for cancer therapy
WO1996032388A1 (en) Antheliatin, zahavin a and zahavin b: new cytotoxic xenicane diterpenes
MXPA02002615A (en) New active marine alkaloids.
MXPA00007381A (en) New cytotoxic tris(oxazole)-containing macrolides.
RU2200163C2 (en) Carbocyclic analogs of 20(s)-camptothecin, methods of their synthesis, pharmaceutical composition, method of treatment

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 IL 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

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