Bioactive Diterpenoid Containing a Reversible “Spring-Loaded” (E,Z)-dieneone…

20 Янв 2015 | Author: | No comments yet »
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Abstract

Three new briarane briareolate esters L #x02013; N (1 3) have been isolated a gorgonian Briareum asbestinum . esters L (1) and M (2) are the first natural possessing a 10-membered macrocyclic with a ( E,Z )-dieneone and exhibit inhibition activity against human embryonic stem (BG02) and a pancreatic cancer line (BxPC-3). Briareolate L (1), was found to contain a ( E,Z )-dieneone Michael acceptor that can form a reversible bond to model sulfur-based

The marine gorgonian of the genus is an abundant source of highly diterpenoids belonging to the eunicellin, cembrane, and briarane classes and numerous biological activities cytotoxicity, anti-microbial, anti-inflammatory, immunomodulatory, antifouling, and ichthotoxicity). 1 The esters are a small group of briarane diterpenoids isolated Briareum asbestinum off the coast of that contain a C-19 ester instead of the #x003b3;-lactone 2 ,3 ,4 In the course of screening pre-fractionated and extracts of marine invertebrates to compounds that impact embryonic stem cell growth using a 96-well real-time cell electronic (RT-CES) system, activity was for the extract of the gorgonian Briareum . Further purification of the active led to the isolation of three new briarane briareolate ester L #x02013; N ( 1 3 ), together with three briareolate esters B ( 5 ), C ( 6 ) and G ( 4 ). In this we report the isolation, biological and possible mechanism of bioactivity.

The of 1 was determined by a detailed analysis of the NMR ( Figure 1 ). The HSQC experiment the assignment of all the protons to the corresponding atoms. The 1 H#x02013; 1 H COSY and experiments allowed the gross of 1 to be determined and revealed that 1 had the planar structure as the C-19 ester briarane diterpenoid ester G ( 4 ). However, the signals of 1 . at H 6.21 (br s) and #x003b4; H 7.68 (br s) more downfield when with the analogous signals of ester G 4 [H-6 (#x003b4; H and H-7 (#x003b4; H 6.62)] 4 suggesting a in the geometry of the double bonds.

Selected 2D NMR correlations for 1 .

From the 2D data, it was found that H-7 NOE correlations with H-2 and H-10 and H-7 on the inside of the 10-membered ring and the geometry of the C-7#x02013;C-8 double to be assigned as E. In addition, NOE correlations from H-6 to H-17, and H 3 -16 established the of the C-5#x02013;C-6 double bond as Z. The configuration of C-1, C-2, C-11, C-12, and C-14 was from coupling patterns in the 1 H NMR and NOE correlations observed in a ROESY (see Figure S1, Supporting ). The configuration at C-17 could not be determined due to limited NOE data, a correlation from H-6 to H-17 is with the assignment of the Me-18 -orientated as observed in all previously briareolate esters. 2 ,3 ,4

Briareolate M ( 2 ) was isolated as a colorless oil. The of briareolate ester M ( 2 ) showed an [M + Na] + ion at m/z corresponding to the molecular formula C 33 H 50 O 9 . 98 units higher than of 1 . The 1 H NMR spectrum of 2 was similar to that of ester L ( 1 ), except that [#x003b4; H 4.82, br q (3.0)] was downfield by 1.05 ppm ( Table 1 ) as with that of 1 . In the 13 C NMR spectrum, the of C-12 (#x003b4; C 73.0) was downfield by 2.5 ppm and those of C-11 C 33.2) and C-13 (#x003b4; C were shifted upfield by 2.7 and 3.6 respectively, in comparison with of 1 . This suggested that the group of 1 . was replaced by a hexanoate at C-12 in 2 . The presence of the hexanoate was confirmed by the NMR data [#x003b4; H (3H, t, J = 7.0 Hz), ca. 1.33 overlapped), 1.62 (2H, 2.28 (2H, m), #x003b4; C (q), 22.4, 24.9, and 34.7 (each t), 173.1

1 H NMR Data (500 MHz) for Esters 1 #x02013; 3

The relative of briareolate ester M ( 2 ) was assumed to be the as that of 1 due to the similarity of proton#x02013;proton constants and 1 H and 13 C chemical shifts. briareolate ester M was assigned as 2 .

ester N ( 3 ) was isolated as a colorless The molecular formula of briareolate N ( 3 ), C 33 H 50 O 9 . that was determined from the of the [M + Na] + ion at m/z 613.3350 and required 9 degrees of Initial analysis of the NMR suggested briareolate ester N ( 3 ) had the same skeleton as briareolate ester B ( 5) . that the hydroxy group at was replaced by a hexanoate group. The 1 H and 13 C NMR of 3 were similar to that of 5 . that H-12 (#x003b4; H m) was shifted downfield by 1.27 ppm as with that of 5 . 2 In addition, in the 13 C NMR resonances of C-12 (#x003b4; C were shifted downfield by 1.8 ppm and of C-11 (#x003b4; C 32.3) and (#x003b4; C 31.4) were upfield by 1.2 and 2.2 ppm, respectively, in with those of 5 . An HMBC observed from H-12 H 5.13) to the ester carbonyl at #x003b4; C 172.9 allowed of the hexanoate group at the C-12 The similarity of proton#x02013;proton coupling and 1 H and 13 C chemical shifts together a ROESY spectrum of 3 showed the relative configuration as 5 at all eight centers. Thus, briareolate N was assigned as 3 .

In addition to isolating three new esters the previously reported briareolate ester G ( 4 ) was isolated and from identical spectroscopic (MS, IR, UV, optical rotation, 1 H and 13 C NMR 4 In the original publication the geometry of the double bond was not determined due to In the ROESY experiment of 4 . the olefinic H-6 exhibited NOE correlations to both H-7 and the methyl H 3 -16 and allowed assignment of the of the C-7#x02013;C-8 double bond as Z . NOE from H-7 to H-17 placed H-7 on the of the 10-membered ring confirmed the Z of the C-5#x02013;C-6 double bond. NOE correlations confirmed the relative of the compound with that of the reported compound 4 .

hESCs are a cell type isolated the inner cell mass of blastocysts. 5 ,6 The advent of defined and controlled differentiation has enabled of hESCs to discover molecules impact growth, differentiation or in undifferentiated and differentiating populations. The growth inhibitory activities of 1 — 6 were evaluated hESCs (BG02) and a pancreatic cell line (BxPC-3) a RT-CES system. 7 Briareolate L ( 1 ) showed the greatest growth against both the BG02 and cells with EC 50 values of 2.4 and 9.3 respectively (see Figure S2, Information ). Briareolate ester G ( 4 ) did not any cytotoxic effects against the or the BxPC-3 cells at 20 #x000b5;M Figure S3, Supporting Information ). 2 showed reduced cytotoxic against the BG02 cells an EC 50 value of 8.0 #x000b5;M and only cytostatic effects at 13.0 and #x000b5;M against the BxPC-3 No inhibitory activity was found for 3 . 5 . and 6 at 40 #x000b5;M.

The screening results raised the why briareolate G ( 4 ), which differs in the geometry of the double bond C-7#x02013;C-8, was not biologically active. The significant spectral differences between 1 and 4 were the chemical of the protons and carbons of the dienone. In the downfield shift of the olefinic H-7 at #x003b4; H 6.62 (#x003b4; C in 4 to #x003b4; H 7.64 (#x003b4; C the upfield shift of the carbons of the double bond [#x003b4; C (C-5), #x003b4; C 123.5 for 4 ; and #x003b4; C 140.2 (C-5), C 116.4 (C-6) for 1 ], and the upfield of the olefinic methyl group H 3 -16 #x003b4; H 2.17 (#x003b4; C in 4 to #x003b4; H 1.73 (#x003b4; C

The chemical shift differences that the C-5#x02013;C-6 double in 1 is less conjugated with the double bond compared to 4 and the ( E,Z )-dienone is twisted out of plane due to of the 10-membered macrocycle. The observation of a UV absorption maxima at 284 nm for 1 compared to 288 nm for 4 is with less conjugation. suggested that 1 could be or cocked for nucleophilic attack at the and electrophilic C-7 position in order to ring strain energy in the To the best of our knowledge, this is the example of a 10-membered macrocyclic containing an ( E,Z )-dieneone and could be a explanation for the difference in biological of compounds 1 and 4 .

To explore the #x0201c;spring-loaded#x0201d; acceptor hypothesis solutions of 1 and 4 reacted with a series of nucleophiles (eq 1). Briareolate ester L ( 1 ) was to react with the sulfur-based thiophenol at room temperature at in methanol- d 4 to afford the enol 1,4 product ( 7a ) quickly (#x0003c; 5 quantitatively ( 1 H NMR analysis; see Figure S4 Information ) and stereoselectively (1D NOESY; see S5, Supporting Information ). In addition 1 was to react with the amino derivative cysteine methyl in the presence of DMAP over to afford the keto 1,4 addition ( 7b . Nu = L-Cys-OMe; see Figure S6, Supporting ).

Although the 1,4 addition products stable enough to obtain NMR datasets the adducts formed found to be labile towards on HPLC (C18 and PRP-1) and not be purified chromatographically without reversal ( 7 #x02192; 1 ). All attempted of oxygen- and nitrogen-based nucleophiles phenol, aniline, N -Boc methyl ester, N -Boc methyl ester, L-histidine ester HCl, and N -benzoyl-L-arginine ester) with and without failed to produce any detectable 1,4 products in reactions with 1 . ester G ( 4 ) did not react with any of the tested and indicated that the or #x0201c;spring-loaded#x0201d; ( E,Z )-dienone is required for addition reactions to occur.

To understand the reactivity of the compounds, the molecular structures and energies of 1 and 4 calculated using density theory in Gaussian 09 8 employing the functional and 6-31G(d) basis set ( 2 for 1 ; and see Figure S7 for 4 ). The ( Z,Z )-dieneone isomer 4 was to be more stable than the ( E,Z isomer 1 with calculated energies of -1654.75577047 and -1654.69805219 Ha, This corresponds to an energy of 36.22 kcal/mol.

Optimized molecular structure of L ( 1) .

The energies of the two isomers were calculated in methanol and water at the same level of theory the CPCM solvent model. In cases the ( Z,Z )-dieneone 4 was found to be the stable isomer with differences of 29.75 and 29.58 in methanol and water, respectively. solutions of 1 in benzene or methanol found to be thermally stable 60#x000b0;C), direct irradiation W Hg lamp) for five days led to photoisomerization (see Figure S8, Information ) to give 4 that had NMR and optical rotation data and is in with the calculated stability of the ( Z,Z


Recently there has been a interest in Michael acceptors in compounds that can undergo reactions with thiols bardoxolone methyl (RTA402). 9 ,10 methyl is a synthetic homotriterpenoid induces Nrf2 (NF-E2-related 2), a transcription factor of the antioxidant and is currently in late-stage clinical for chronic kidney disease. 11 the identification of novel structural capable of reversible thiol reactions such as in 1 and 2 could utility in the drug discovery

Toyota E'z
Toyota E'z
Toyota E'z
Toyota E'z

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