CN1429203A - Sponge antitumor compounds - Google Patents

Sponge antitumor compounds Download PDF

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CN1429203A
CN1429203A CN01809444A CN01809444A CN1429203A CN 1429203 A CN1429203 A CN 1429203A CN 01809444 A CN01809444 A CN 01809444A CN 01809444 A CN01809444 A CN 01809444A CN 1429203 A CN1429203 A CN 1429203A
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田中淳一
比嘉辰雄
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Pharmamar SA
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C47/273—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups containing halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
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Abstract

New antitumor compounds isolated from a sponge are of the formulae (1), (2), (3) and (4).

Description

Sponge antitumor compounds
The antineoplastic compound that the present invention relates to from Spongia, obtain.
Background of invention
We have reported recently and have derived from Nudibranchia Reticulidia fungia 1The separation and the structural analysis of two kinds of new sesquiterpene dichloro carbonization imines (carbonimidic dichloride) (8,10).
Figure A0180944400041
Because having described related compound in the early time only comes from minority Spongia class 2-6, so Nudibranchia class composition obviously is derived from Spongia.But we find the thing class that seems desirable near can't assembling ground the nudibranch on Okinawa Prefecture Yi Liang portion island.
The Spongia that the Spongia that we collect the karang of Iriomote island one band of 150km to the west of Yi Liang portion island promptly was named as Stylotella aurantium afterwards (produces the phase jljl class of dichloro carbonization imines in Australia 6) cytotoxin form and to check.Our sample has also obtained sesquiterpene dichloro carbonization imines, comprises five kinds of new congenerss (1-5), and they are to cause the Cytotoxic reason of this poriferous lipotropy extraction liquid.
Thus, we provide five kinds of obtaining by Spongia Stylotella aurantium separated have dichloro carbonization imines or a functional new sesquiterpene of aldehyde (1-5), they exist with seven kinds of known related compounds (6-12).All new compounds is by the spectroscopic data explanation.Determined the absolute stereo chemistry of the reticulidin A (10) of previous report.Four kinds in the described new compound demonstrate with respect to several cancerous cell line IC 50Value is the cytotoxicity of 0.1-1 μ g/mL.
Figure A0180944400051
Figure A0180944400081
The Dr.J.N.A.Hooper in museum, Queensland has confirmed that this Spongia (OP-98-30) is Stylotella aurantium Kelly-Borges ﹠amp; Bergquist, 1988 (Porifera, Demospongiae, Halichondrida, Axinellidae).Authority sample (QM G317008) is kept at museum, Australian southern Brisbane Queensland.Anti-tumor activity:
???????????????????IC50(μg/ml)
Compound The P388 leukemia A549 (people's lung) HT29 (people's colon) MEL28 (melanoma)
????1 ????1 ????0.1 ????0.1 ????0.1
????2 ????1 ????1 ????1 ????1
????3 ????1 ????1 ????1 ????1
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Preferred embodiment
Consider external activity, expect compound of the present invention, compound (1)-(4) can be used for treating cancer.
Therefore, the invention provides a kind of method that cancered any Mammals (particularly human) is treated, this method comprises The compounds of this invention or its medicinal compositions that gives the patient treatment significant quantity.
The invention still further relates to medicinal compositions and preparation method thereof, this medicinal compositions comprises the The compounds of this invention as activeconstituents.
The example of medicinal compositions comprises any solid (tablet, pill, capsule, granule etc.) with suitable composition or liquid (solution, suspensoid or emulsion) or oral, topical or administered parenterally, and they can comprise described pure compound or combine with any carrier or other pharmacologically active chemical compounds.When carrying out administered parenterally, need sterilize to these compositions.
The administration of The compounds of this invention or composition can be undertaken by any appropriate means, as venoclysis, oral preparations, intraperitoneal and intravenous administration.We mostly are 24 hours most the preferred infusion time, and more preferably 2-12 hour, most preferably 2-6 hour.It is desirable to the short period of time infusion especially, the short period of time infusion can need not the treatment of spending the night in hospital.But if desired, then the infusion time can be 12-24 hour or even longer.Infusion can be with reasonable time at interval as carrying out in 2-4 week.The medicinal compositions that comprises The compounds of this invention can be by carrying out administration with the liposome in the slowly-releasing prescription or millimicro bag capsule mode or by other standard transfer mode.
The correct dose of described compound will change according to concrete formulation, application model and concrete position, patient and the tumour that will treat.Also need consider other factors such as age, body weight, sex, diet, administration time, discharge rate, patient's symptom, medicine combination, reaction sensibility and disease severity.Can successive administration or administration regularly in the maximum permissible dose (MPD) scope.
Compound of the present invention and composition can use so that combination therapy to be provided with other medicines.Described other medicines can form the part of this same composition, perhaps carry out administration as independent composition in identical time or different time.Characteristic to other medicines is not particularly limited, suitable used medicine comprises: the medicine that a) has the antimitotic effect, especially those are the medicine of target with the cytoskeleton composition, comprise microtubule conditioning agent such as Taxan medicine (as taxol, taxol, taxotere, docetaxel), podophyllin or vinca alkaloids (vincristine(VCR), vinealeucoblastine(VLB)); B) antimetabolite such as 5 FU 5 fluorouracil, cytosine arabinoside, gemcitabine, purine analogue (as pentostatin, methotrexate); C) alkylating agent such as mustargen (as endoxan or ifosfamide); D) with DNA be medicine such as antracycline medicine Zorubicin, Dx, pidorubicin or the epirubicin of target; E) with the topology isomerase be the medicine such as the Etoposide of target; F) hormone or hormone agonist or antagonist such as oestrogenic hormon, estrogen antagonist (tamoxifen and related compound) and male sex hormone, flutamide, Leuprolide, goserelin, cyprotrone or Sostatin; G) be the medicine of target with signal transduction in the cancer cells, comprise antibody derivatives such as herceptin; H) alkylation medicine such as platinum medicine (cis-platinum, carboplatin, oxaliplatin, carbon platinum) or Nitrosourea; I) might influence the medicine such as the matrix metallo-proteinase inhibitor of metastasis of cancer; J) gene therapy and antisense reagent; K) Antybody therapy agent; L) from marine other bioactive compounds, especially ecteinascidin such as Et-743 or peaceful from generation to generation as aplidine.
The present invention also prolongs and is used for the treatment of The compounds of this invention in the method, and described compound is used for the treatment of application in the composition of cancer in preparation.Embodiments of the invention
With the sample (90g, weight in wet base) of acetone extract S.Aurantium Kelly-Borges and bergquist (familyAxinellidae), and should between ethyl acetate and water, distribute by spissated extraction liquid.EtOAc extraction liquid (0.65g) is also separated by preparation TLC and/or HPLC subsequently through silica gel, obtain sesquiterpene 1-12, output is 1.5-12.0mg.
General testing sequence.On JASCO FT/IR 300, measure IR spectrum, on the UVIDEC610 spectrophotometer, measure UV spectrum.On JEOL A500 instrument 500 Mhz ( 1H) and 125Mhz ( 13C) under, record NMR spectrum.Obtain LREIMS and HREIMS with the M-2500 of Hitachi mass spectrograph.On JASCO DIP-1000 polariscope, obtain specific rotation.
Animal material.In May, 1998 is on Iriomote island, Okinawa, uses the self-carrying aqualung at-15m place, inscribes with the hand collection and states poriferous sample (90g, weight in wet base).Authority sample (QM G317008) is kept at museum, Brisbane ,Australia Queensland, and this sample is by museum, Brisbane Queensland, Queensland ,Australia south, and Natural EnvironmentProgram confirms through Dr.John N.A.Hooper.
The extraction and separate.Sponge sample is kept freezing until extraction.Whole animal Me 2CO (500mL) extraction three times.With the extraction liquid vacuum concentration that merges, with resistates at EtAOc and H 2Divide to be equipped with between the O and obtain lipotropy extraction liquid (0.70g).By on silicagel column, using heptane, heptane-CH 2Cl 2, CH 2Cl 2, CH 2Cl 2-EtOAc, EtOAc, EtOAc-MeOH and MeOH be wash-out progressively, and separating most extraction liquid (0.65g) obtains nine flow points.First flow point (12.7mg) is passed through preparation TLC (SiO 2, heptane-CH 2Cl 2, 10: 1) and subsequently by HPLC (RP 13, MeOH-H 2O, 15: 1) separate, obtain compound 5 (2.0mg) and 6 (1.9mg).Second flow point (39.8mg) is passed through HPLC (SiO 2, heptane-CH 2Cl 2, 9: 1) separate, obtain compound 1 (6.1mg), 4 (1.6mg) and 6 (8.0mg).The 4th flow point (64.0mg) is passed through HPLC (SiO 2, heptane-CH 2Cl 2, 3: 1) separate, obtain 11 (1.5mg) and 12 (1.7mg).The 5th flow point (88.7mg) is passed through preparation TLC (SiO 2, for the first time: heptane-EtOAc, 9: 1; For the second time: heptane-CH 2Cl 2, 3: 2; For the third time: CH 2Cl 2) separate repeatedly, obtain 2 (1.6mg), 3 (1.6mg), 8 (9.1mg) and 9 (5.8mg).With the 6th flow point (184.5mg) through silicagel column (heptane-CH 2Cl 2-EtOAc) also subsequently by preparation TLC (heptane-CH 2Cl 2, 3: 2) separate, obtain 7 (12.0mg) and 10 (4.6mg).
Compound 1: water white oil; [α] 25 D+ 4.5 ° of (c0.20, CHCl 3); UV (MeOH) λ Max(log ε) 205 (3.6nm; IR (pure) ν Max1655,877cm -1 1H NMR (CDCl 3) δ 0.84 (3H, s, H 3-13), 1.16 (3H, s, H 3-12), 1.74 (1H, m, H-7a), 1.77 (1H, m, H-5), 1.81 (1H, m, H-7b), 1.86 (1H, m, H-2 β), 1.91 (1H, m, H-8a), 2.04 (1H, dt, J=4,13Hz, H-1 α), 2.12 (1H, dq, J=13.4Hz, H-2 α), 2.38 (1H, m, H-8b), 2.41 (1H, m, H-1 β), 3.84 (2H, d, J=7Hz, H-11), 3.90 (1H, dd, J=4,11Hz, H-3) 4.60 (1H, t, J=7Hz, H-10), 4.66 (1H, s, H-14a), 4.95 (1H, s, H-14b), 5.07 (1H, s, H-15a), 5.19 (1H, s, H-15b; 13C NMR (CDCl 3) δ 15.9q (C-13), 24.3 t (C-7), 27.2q (C-12), 30.7t (C-8), 34.5t (C-2), 35.4t (C-1)-4) 52.4d (C-5), 59.3t (C-11), 62.2d (C-10), 70.9d (C-3), 109.2t (C-14), 114.4t (C-15), 127.0s (C-16), 145.6s (C-6), 146.3s (C-9); ESIMS m/z 369 ([M +], 62rel%); EIMS m/z 334 ([M-Cl] +, 100), 336 (98), 338 (32), 298 (65), 300 (40), 302 (7), 262 (30), 264 (12rel%): HREIMS m/z 334.0870 (calculates C 16H 25 35Cl 3N, 334.0894).
Compound 2: water white oil; [α] 25 D+ 16 ° of (c0.13, CHCl 3), UV (MeOH) λ Max(log ε) 235 (3.3) nm; IR (pure) ν Max3458,1714,1668cm -1 1H NMR (CDCl 3) δ 1.11 (6H, s, H 3-12,13), 1.14 (3H, s, H 3-11), 1.98 (1H, dd, J=3,12Hz, H-5), 1.52 (1H, br d, J=14Hz, H-1 α), 1.65 (1H, dq, J=4,13HzH-6 β), 1.98 (1H, m, H-6 α), 2.02 (2H, m, H 2-9), 2.05 (1H, m, H-7 α), 2.06 (1H, dd, J=3,14Hz, H-1 β), 2.35 (1H, br s, OH), (3.50 1H, br d, J=14Hz, H-7 β), 3.94 (1H, d, J=3Hz, H-3), 4.18 (1H, q, J=3Hz, H-2), 5.78 (1H, d, J=8Hz, H-14), 10.02 (1H, d, J=8Hz, H-15); 13CNMR (CDCl 3) δ 17.8 (C-13) 20.8q (C-11), 23.9t (C-6), 29.5t (C-7), 30.4q (C-12), 36.7s (C-10), 39.5s (C-4), 45.1t (C-1), 54.1d (C-5), 55.8t (C-9), 71.9d (C-2), 76.3d (C-3), 127.5d (C-14), 163.5s (C-8), 190.1d (C-15) EIMS m/z 270 (M +, 100), 272 (33), 255 (18), 226 (48), 217 (74rel%); HREIMS m/z 270.1363 (calculates C 16H 23ClCO 2, 270,1384).
Compound 3: water white oil; [α] 20 D-28 ° (c0.13, CHCls), UV (MeOH) λ Max(log ε) 24-0 (3.9), 285 (3.1) nm; IR (pure) ν Max3467,1716,1651cm -1 1H NMR (CDCL 2) δ 1.09 (3H, s, H 3-12), 1.10 (3H, s, H s-13), 1.16 (3H, s, H s-11), 1.38 (1H, dd, J=2.5,13.0Hz, H-5), 1.58 (1H, m, H-1 α), 1.67 (1H, dq, J=4.0,13.0Hz, H-6 β), 1.80 (1H, d, J=13.0Hz, H-9 α), 1.96 (1H, m, H6 α), 2.09 (1H; Dd, J=2.5,14.5Hz, H-1 β), 2.26 (1H, dt, J=6.0,13.0Hz, H-7 α), 2.36 (1H, s, OH), (2.49 1H, br d, J=13.0Hz, H-7 β), 3.02 (1H, br d, J=13.0Hz, H-9 β), 3.94 (1H, d, J=3.0Hz, H-3), 4.19 (1H, br s, H-2), 5.95 (1H, d, J=8.1Hz, H-14), 9.95 (1H, d, J=8.1Hz, H-15); 1BC NMR (CDCL 3) δ 17.8q (C-13), 20.9q (C-11), 24.2t (C-6)), 30.3q (C-12), 36.5a (C-10), 37.9t (C-7), 39.5a (C-4), 45.1t (C-1), 47.2t (C-9), 54.2d (C-5), 71.9d (C-2), 76.3d (C-3), 127.7d (C-14), 163.7s (C-8), 190.5d (C-15); EIMS m/z 270 (M +, 98), 272 (34), 255 (42), 226 (70), 217 (100rel %); HREIMS m/z 270.1400 (calculates C 15H 23 3GC10 2, 270.1384).
Compound 4: water white oil; [α] 25 D+ 40 ° of (c0.13, CHCl 3), UV (MeOH) λ Max(log ε) 288 (4.2) nm; IR (pure) ν Max1640; 900cm -1 1HNMR (CDCl 3) δ 0.94 (3H, s, H 3-13), 1.03 (3H, s, H 3-11), 1.10 (3H, s, H 3-12), 120 (1H, dd, J=2,13Hz, H-5) 1.38 (1H, dt, J=4,13Hz, H-1a), 1.57 (1H, t, J=3Hz, H-6 β), 1.59 (1H, t, J=3Hz, H-1 β), 1.89 (1H, br dd, J=7,13Hz, H-6a), (2.01 1H, m, H-2 α), 2.07 (1H, m, H-2 β), 2.21 (1H, m, H-7 α), 2.36 (1H, dd, J=6,17Hz, H-7 β), 3.75 (1H, dd, J=5,12Hz, H-3), 5.59 (1H, s, H-9), 6.51 (1H, d, J=13Hz, H-14), 6.70 (1H, d, J=13Hz, H-15); 13C NMR (CDCl 2) δ 16.6q (C-13), 19.2t (C-6), 20.8q (C-11), 26.2t (C-7), 28.9q (C-12), 29.8t (C-2), 36.0s (C-10), 38.8t (C-1), 40.0s (C-4), 51.3d (C-5), 72.4d (C-3), 124.0s (C-16), 128.9d (C-15), 130.6s (C-8), 137.7d (c-14), 146.4d (C-9); EIMSm/z 333 (M +, 52), 335 (52), 337 (17), 339 (1), 298 (100,300 (65), 302 (12), 262 (75), 264 (26), 226 (36rel%); HREIMS m/z 333.0823 (calculates C 16H 22 28Cl sN, 333.0816).
Compound 5: water white oil; 1H NMR (CDCl 3) δ 1.61 (6H, s, H 3-13,14), 1.68, s, H 3-12), 1.99 (2H, t, J=7Hz, H-8), 2.07 (2H, q, J=7,13Hz, H-9), 2.23 (2H, m, H-5), 2.28 (2H, m, H-4), 5.09 (1H, br t, J=7Hz, H-10), 5.16 (1H, tq J=7.2Hz, H-6), 5.19 (1H, br s, H-15a), 5.23 (1H, br s, H-15b), 6.62 (1H, d, J-13Hz, H-2), 6.87 (1H, d, J=13Hz, H-1); 13C NMR (C-5), 26.7t (C-9), 32.1t (C-4), 39.7t (C-8), 120.3t (C-15), 123.4d (C-6), 124.3d (C-10), 125.2s (C-16), 130.8d (C-1), 131.4s (C-11), 135.9s (C-7,137.0d (C-2), 143.9s (C-3).
(R)-MTPA ester of 10.With .035mg reticulidin A (10), 0.31mg DCC, 0.35mg (R)-MTPA and 0.12mg DMAP at 0.15mL CH 2Cl 2In mixture at room temperature left standstill 3 hours.Remove and desolvate, then resistates is passed through preparation TLC (SiO 2, hexane-EtOAc, 4: 1) separate, obtain 0.30mg (R)-MTPA ester: 1H NMR (CDCl 3) δ 1.034 (3H, s, H 3-13), 1.156 (6H, s, H 2-11,12), 2.025 (1H, dd, J=4,12Hz, H-1 β), 3.741 (1H, d, J=11Hz, H-3), 5.387 (1H, dt, J=5,11Hz, H-2), 5.562 (1H, s, H-9), 6.486 (1H, d, J=13Hz, H-14), 6.712 (1H, d, J=13Hz, H-15).
(S)-MTPA ester of 10.With (S)-MTPA, adopt aforesaid method to prepare this ester similarly: 1H NMR (CDCl 3) δ 1.028 (3H, s, H 3-13), 1.148 (3H, s, H 3-12), 1.172 (3H, s, H 3-11), 2.112 (1H, dd, J=4,12Hz, H-1 β), 3.720 (1H, d, J=11Hz, H-3), 5.417 (1H, dt, J=5,11Hz, H-2), 5.610 (1H, s, H-9), 6.507 (1H, d, J=13Hz, H-14), 6.729 (1H, d, J=13Hz, H-15).
With acid treatment Reticulidin B (8).The mixture of tosic acid monohydrate in the 0.5mL 30%THF aqueous solution of 1.0mg reticulidin B (8) and catalytic amount at room temperature left standstill 12 hours.Reaction mixture is at TLC (SiO 2, heptane-EtOAc, 3: 2) on only show a spot, reclaim unreacted reactant 8 (0.8mg).
Separating compound 1, [α] D+ 4.5 ° of (c0.20, CHCl 3), be colorless oil.By in ESIMS m/z 369 times and at HREIMS at m/z 334.0870 ([M-Cl] +) descend the monitoring molion to determine molecular formula C 16H 23NCl 4As reporting in the early time 2-6The same, from the carbon signal of δ 127.0s and also by at 1655cm -1IR absorb and to infer and have dichloro carbonization imine. 1H and outer methylene radical [δ 4.66s, 4.95s, 5.07s, 5.19s; δ 109.2t (C-14), 114.4t (C-15), 145.6s (C-6), 146.3s (C-9)], with methyne [δ 3.90dd, the 4.60t of two chlorine; δ 62.2d (C-10), 70.9d (C-3)], with methylene radical [the δ 3.84d of a nitrogen; δ 59.3t (C-11)] and two methyl [δ 0.84s, 1.16s; δ 15.9q (C-12), 27.2q (C-13)].These data and unsaturated requirement are taken into consideration, infer that 1 is monocycle.(HMBC) spectrum has been established consistence for COSY, HMQX by resolving 2D NMR.COSY (H-1 α β H-2 α β, H-2 α β, H-2 α β/H-3, H-1 α/H-5, H-1 α/H-14a, H-1 β/H-14b and H-5/H-14ab) and HMBC data (H-1 α β/C-2 ,-3 ,-5 ,-6 ,-14, H-2 α β/C-1 ,-3 ,-4 ,-6, H-3/C-4 ,-12 ,-13, H-5/C-3,-4 ,-6 ,-8 ,-14, and Ha-12 ,-13/C-3 ,-4 ,-5) show and to have six-ring.By COSY (H-5/H-7ab ,-8ab; H-7ab/H-8ab, H-8ab/H-15ab, H-10/H-11 ,-15b) and HMBC (H-10/C-15, H 2-11/C-16) consistence between ring and the terminal dichloro carbonization imines is established at intersection peak (cross-peak).By monitoring positive NOEs (H-3/H-5, H-3/H a-12, H-7/H 3-13) explain the relative stereochemistry of understanding ring.Stereochemistry at C-10 is waited until solution.
Obtain compound 2, [α] D+ 16 ° of (c0.13, CHCl 3), be flint glass shape thing.2 EIMS is presented at the molion of m/z 270.The high resolution at this peak is measured and has been provided molecular formula C 16H 25ClO 2This formula shows four degrees of unsaturation.NMR spectrum demonstrates three the unimodal signal of methyl [δ 1.11 (H a-12), 1.11 (H 3-13), 1.14 (H 3-11); δ 17.8q, 23.9t, 30.4q], α, beta-unsaturated aldehyde [δ 10.02d; δ 127.5d (C-14), 163.5s (C-8), 190.1d (C-15)], with two methynes [δ 3.93d, 4.18q of a chlorine and/or a hydroxyl; δ 71.9d (C-2), 76.3d (C-3)].At 1666cm -1The IR absorption band also show and have α, beta-unsaturated aldehyde.The data of these data and 2D NMR data and reticulidin B (8) are compared, can infer that 2 olefine aldehydrs by the dichloro carbonization imines in dicyclo part that is similar to reticulidin B and the replacement 8 partly constitute.As previously mentioned 1, determine hydroxyl (Δ δ-0.115) on C-2 by deuterium-induce displacement experiment.By between H-9 and the H-14 and the positive NOEs between H-7 β and H-15 show that two key geometric configurations of olefine aldehydr are the E type.(H-2/H-3 H-3/H-5) determines that compound 2 has the relative stereochemistry identical with 8 through NOE observation.Because aldehyde can be obtained by 8 hydrolysis, so guess that 2 may be the artifact that forms during separating step.But when handling 8 (room temperature, 12 hours) with the p-TsOH in the THF aqueous solution, 8 are recovered and reactionless sign, infer that 2 is natural product really.
Compound 3, [α] D-28 ° of (c0.13, CHCl 3) have with 2 in the identical molecular formula C that determines through HREIMS 16H 23ClO 2Except different with the signal of C-9 (Δ δ-8.6) for C-7 (Δ δ 8.4), 3 13C NMR spectrum is almost completely identical with 2. 1In the H NMR spectrum, 3 and 2 main difference is chemical shift H-7 (Δ δ 0.21 ,-1.01), H-9 (0.22,1.00), and H-14 (0.17) and H-15 (0.07), supposition is the configuration difference around two keys.(H-7 β/H-14, H-9 β/H-15) have disclosed the Z-configuration of two keys in the observation of positive NOEs.Measure to confirm through NOE, the relative stereochemistry on the dicyclo part with 2 the same.Through deuterium-induce displacement (Δ δ-0.115) to confirm that also the position of hydroxyl is on C-2.
Compound 4, [α] D+ 40 ° of (c0.13, CHCl 3) have a molecular formula C 16H 22NCl 3(HREIMS, Δ+0.7mmu).It comprises dichloro carbonization imines (1640cm -1δ 124.0s), two two key [δ 5.59s (H-9), 6.51d (H-14), 6.70d (H-15); δ 128.9d, 130.6s, 137.7d, 146.4d], methyne (the δ 3.75dd of a band chlorine; δ 72.4d) and three methyl [δ 0.94s (H-13), 1.03s (H-11), 1.10s (H-12); δ 16.6q, 20.8q, 28.9q].4 structure is compared with 9 and 13 data through COSY, HMQC and HMBC data conclusive evidence and with these data 4Its three-dimensional relatively chemical based is intersected peak (H-3/H-2 α, H-3/H-5, H-3/H in NOESY 3-12, H-5/H 3-12, H 3-11/H 3-13) and the similarity of the situation of NMR data and 13 4At last, coupling constant J 14,15(13.0Hz) and between between H-9 and the H-14 and the NOEs between H-7 β and H-15 shown this two E geometric configuration that replaces two keys.
Because compound 5 decomposes during in being stored in the NMR pipe, so we fail to record mass-spectrometric data.Can derive possible molecular formula C by the NMR data 16H 23NCl 25 1H NMR spectrum is made up of following signal: two outer methene protons [δ 5.19 and 5.23s (H-15)], four vinyl proton [δ 5.09t (H-10), 5.16t (H-6), 6.62d (H-2), and 6.87d (H-1)], four methylene radical [δ 1.99t (H-8), 2.07q (H-9), 2.23q (H-5), 2.28t (H-4)] and three vinyl methyl [δ 1.61s (H-13), 1.61s (H-14), 1.69s (H-12)].Remove NCCl 2Outside the characteristic signal of δ 124.2s, 13C NMR data confirm to exist above-mentioned functional group with the HMQC experiment.With comparing of these data and 6, infer that 5 have methylene radical (C-1) and the chloro methyne (C-2) in trans double bond (J=13.1Hz) replacement 6.
Determine the absolute stereo chemistry of reticulidin A (10) by modified Mosher ' s method 7.When the NMR spectrum of record 10 MTPA derivative, monitoring H-1 β (+0.087), H 3-11 (+0.016) and H-9 (+0.048) on the occasion of (Δ δ S-R), and at H-3 (0.021), H 3-12 (0.008) and H 3-12 (0.006) are detected and are negative value.Therefore, 10 absolute configuration through confirm as (2R, 3R, 5S, 10S).When handling with MTPA, DCC and DMAP, reticulidin B (8) does not form the MTPA ester, infers that this is because due to the steric hindrance of hydroxyl.But result from 10 and their imporosity relation can infer that 8-12 is chemical with as above the description to structure is consistent with 2 and 3 absolute stereo.
Aldehyde 2 and 3 may be the katabolic product of corresponding dichloro carbonization imines.But, can not get rid of their possibilities as the biosynthesizing precursor.We do not have certain evidence to determine their biosynthesizing relation to this.
Bibliography and note (1) Tanaka, J.; Higa, T.J.Nat.Prod.1999,62,1339-1340. (2) Wratten, S.J.; Faulkner, D.J.J.Am.Chem.Soc.1977,99,7367-7368. (3) Wratten, S.J.; Faulkner, D.J.; Van Engen, D.; Clardy, J.Tetrahedron Lett.1978,1391-1394. (4) Wratten, S.J.; Faulkner, D.J.Tetrahedron Lett.1978,1395-1396. (5) Hirota, H.; Okino, T.; Yoshimura, E.; Fusetani, N.Tetrahedron 1998,54,13971-13980. (6) Simpson, J.S.; Raniga, P.; Garson, M.J.Tetrahedron Lett.1997,38,7947-7950. (7) Ohtani, I.; Kusumi, T.; Kashrman, Y.; Kakisawa, H.J.Am.Chem.Soc.1991,113,4092-4096.

Claims (2)

1. compound that is selected from following formula: compound (1)-(4):
Figure A0180944400021
2. medicinal compositions, said composition contains compound and the pharmaceutically acceptable carrier or the thinner of claim 1.
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