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Studies of the Antitumor Constituents of Secondary Metabolites Produced by Deep-Sea Microorganisms

Author: LiDeHai
Tutor: GuQianQun
School: Ocean University of China
Course: Medicinal Chemistry
Keywords: deep-sea microorganisms secondary metabolites antitumor activity bioassay-guided fractionation
CLC: R914
Type: PhD thesis
Year: 2007
Downloads: 788
Quote: 2
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Deep-sea microorganisms have been considered an important source of bioactive leading compounds, due to their unique living environment. A study on seven strains of deep-sea microorganisms and one shallow-sea actinomycete, was carried out to investigate the potential anti-tumor compounds. Studies include screening for microbial strains with antitumor acitvities, fermentation studies, bioassay-guided fractionation, structural elucidation, and preliminary evaluation for anti-tumor activities of pure compounds.Using MTT or SRB methods, thirty four active deep-sea strains and seven shallow-sea strains were screened out of two hundred twenty six strains microorganisms isolated from deep-sea samples, and thirty four strains from shallow-sea, on the bioassay of tsFT210 or K562 cell lines. Seven strains deep-sea microorganisms (3 bacteria, 1 actinomycete and 3 fungi) and one strain shallow-sea actinomycete were chosen based on the result of re-screening combining with HPLC and TLC chemical analysis. After choosing appropriate fermentation condition, eight active strains were fermented, respectively. The whole broths were extracted with ethyl acetate to give ferment extracts, which were subjected to silica gel column chromatography, Sephadex LH-20 and HPLC by bioassay-guided fractionation, respectively. One hundred seven compounds were isolated from the eight active strains. Twenty five compounds (1-25) were isolated from fungus FL30r (Phialocephala sp.), sixteen compounds (26-41) from fungus YH11-2 (Aspergillus Sydowi), twenty nine compounds (42-70) from actinomycete 11014 (Streptoverticillium luteoverticillatum), ten compounds (47-49, 71-77) from bacterium 39 (Bacillus sp.), eight compounds (46-48, 78-82) from bacterium 133 (Pseudomonas sp.), nine compounds (46-49, 78, 83-86) from bacterium 168 (Pseudomonas sp.), four compounds (39, 87-89) from an unidentified actinomycete YuCH and six compounds (90-95) from fungus F23-2 (Penicillium sp.).By means of modern spectral analysis (UV, IR, NMR, MS, CD) and physico-chemical properties, the structures (see Fig. 1) of ninety five pure compounds were respectively determined. Among them there are thirteen new compounds, including four novel Sorbicillin timers (1-4), which were deduced the relative structure by NOESY spectrum and proposed the absolute stereochemistry by analysis their biosynthesis route; three new Bisorbicillinoids (5-7); one new Sorbicillinoids (13); one new bisbenezylγ-butenolide (21); one new Sesquiterpenoids (22); one newγ-Pyrone analog (26); one new Chromone derivate (27) and one novel Phenazine derivative (71) with [4, 2, 2] ring structure. Additionally, two compounds (72,78) were isolated from nature source for the first time.In addition, the chemical structure types of compounds are involved in polyketone [8-12 (Bisorbicillinoids), 14-20 (Sorbicillinoids), 28-31 (Citrinin derivates)], Steroides (23-25, 32-36, 89, 93-94), Triterpenoids (37), Esters (42-45, 78, 38, 39, 66, 76-77, 80), Benzene derivates (40, 59-62, 64, 79, 86, 95), Alkaloids (63, 73-75, 83-85, 46-58, 88, 91-92, 68-70, 81-82, 87, 90),γ-Pyrone (67), etc.These compounds were evaluated for their cytotoxicities against several cancer cell lines such as HL-60, P388, K562, etc, by the MTT or SRB method. The results indicated that all of the new compounds showed cytotoxicities in certain extent. Among them, Trisorbicillinoids A (1) showed significant bioactivities against HL60 and P388 (IC50 = 3.14 and 9.10μM respectively), Trisorbicillinoids B-D (2, 3, 4) have weak cytotoxicities against P388 and K562 cells. The IC50 values of new compounds 6, 7, 26 were 8.9, 10.5 and 8.5 on HL60 respectively. Compounds 13, 21, 22 and 27 have strong cytotoxicites with IC50 values 0.1, 0.2, 0.16 and 8.9μM respectively on P388. Compounds 13 and 22 also showed activities on K562 cells (IC50 = 4.8 and 0.05μM respectively). Comound 71 has the inhibition rate 78.3% on concentration 50μM. In addition, the antitumor activities in vitro of known compounds 16, 17, 18, 20, 24, 28, 29, 30, 36, 40, 42-45, 72, 78, 80 and 85 were reported for the first time.Summarily, this work obtained thirty four important active strains from deep-sea microorganisms and ninety five compounds from eight active strains (7 stains from deep-sea and 1 strain from shallow-sea). Among them, thirteen compounds were identified new. Thirty two compounds with antitumor activities in vitro were discovered for the first time (they are thirteen new compounds and nineteen known ones). Studies mentioned above provided novel structures for searching leading antitumor compounds and strain resources of great value for further study and development of deep-sea microorganism.

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