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A New Analogue of Echinomycin and a New Cyclic Dipeptide from a Marine-Derived Streptomyces sp. LS298.

Zhen X, Gong T, Liu F, Zhang PC, Zhou WQ, Li Y, Zhu P - Mar Drugs (2015)

Bottom Line: Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time.Compound 1 exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with the minimum inhibitory concentration (MIC) values ranged from 16 to 64 μg/mL.Moreover, it displayed remarkable anti-tumor activities; the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 μM.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Xicheng District, Beijing 100050, China. zhenxin@imm.ac.cn.

ABSTRACT
Quinomycin G (1), a new analogue of echinomycin, together with a new cyclic dipeptide, cyclo-(l-Pro-4-OH-l-Leu) (2), as well as three known antibiotic compounds tirandamycin A (3), tirandamycin B (4) and staurosporine (5), were isolated from Streptomyces sp. LS298 obtained from a marine sponge Gelliodes carnosa. The planar and absolute configurations of compounds 1 and 2 were established by MS, NMR spectral data analysis and Marfey's method. Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time. Antibacterial and anti-tumor activities of compound 1 were measured against 15 drug-sensitive/resistant strains and 12 tumor cell lines. Compound 1 exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with the minimum inhibitory concentration (MIC) values ranged from 16 to 64 μg/mL. Moreover, it displayed remarkable anti-tumor activities; the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 μM.

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Key HMBC and ROESY correlations of compound 1.
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marinedrugs-13-06947-f002: Key HMBC and ROESY correlations of compound 1.

Mentions: Quinomycin G (1) was obtained as an amorphous yellow powder, a molecular formula of C51H64N12O12S2 was determined by HRESIMS (m/z 1101.4288 [M + H]+, calcd for C51H65N12O12S2, 1101.4286), requiring 26 degrees of unsaturation. The chemical structure of 1 was adumbrated as an echinomycin analogue by the close similarity of its molecular formula and ultraviolet spectral properties (λmax (log ε) 245.2 nm (2.6), 325.8 nm (1.9), respectively) to those of echinomycin [10]. The 1H NMR spectrum of 1 (Table 1) displayed four NH resonances (δH: 10.67 (1H, s), 9.20 (1H, d, J = 9.5 Hz), 9.01 (1H, d, J = 9.5 Hz), 7.83 (1H, overlap)); 12 aromatic protons signals (δH: 9.68 (1H, s), 9.63 (1H, s), 8.27 (1H, d, J = 8.0 Hz), 8.20 (3H, d, J = 8.0 Hz), 7.95–7.97 (2H, overlap), 7.84–7.89 (2H, overlap), 6.90 (1H, brs), 6.11 (1H, brs)); two methylene resonances (δH: 5.02 (1H, dd, J = 11.5, 3.0 Hz), 4.67 (1H, d, J = 11.5 Hz); 3.47 (1H, dd, J = 16.0, 5.0 Hz), 2.54 (1H, d, J = 16.0 Hz)); ten methine signals (δH: 6.03 (1H, d, J = 4.0 Hz), 5.70 (1H, s), 5.37 (1H, d, J = 9.0 Hz), 5.28 (1H, m), 4.85 (1H, m), 4.47 (1H, d, J = 11.0 Hz), 3.74 (1H, d, J = 2.0 Hz), 3.42 (1H, d, J = 10.5 Hz), 2.49 (1H, m), 2.27 (1H, m)); 11 methyl signals in the upfield region, including four N-Me groups (δH: 3.37 (3H, s), 3.15 (3H, s), 3.02 (3H, s), 2.97 (3H, s)), one S-Me group (δH: 2.07 (3H, s)). 51 carbons were observed in the 13C NMR spectrum of compound 1 (Table 1), including ten ester/amide carbonyls (δC: 172.2 (2C), 171.5, 169.9 (2C), 169.8, 168.3, 163.6, 163.2, 161.9) and 18 sp2 carbon signals (δC: 143.9 (2C), 143.7, 143.5, 143.4, 142.4, 140.3 (2C), 133.0, 132.4, 131.9, 131.6, 131.0, 130.0 (2C), 129.4 (2C), 104.3). Comprehensive analysis of the 1H-1H COSY (Supplementary Materials Figure S8) and HSQC of compound 1, indicated that compound 1 was comprised of two quinoxalines and eight amino acid moieties (two N-Me-Val, two Ala, two N-Me-Cys, one Ser, and one Dehydroxy-Ser) (Figure 2). The connections between amino acids moieties were confirmed by an HMBC experiment. The HMBCs ((H-α (δH: 4.85 (1H, m) of Ala′ to the C=O (δC: 163.2) of Dehydroxy-Ser; N-CH3 (δH: 3.37 (3H, s) of N-Me-Cys′ to the C=O (δC: 172.2) of Ala′; N-CH3 (δH: 3.02 (3H, s) of N-Me-Val′ to the C=O (δC: 171.5) of N-Me-Cys′; H-β (δH: 4.67 (1H, d, J = 11.5 Hz) of Ser to the C=O (δC: 169.9) of N-Me-Val′; NH (δH: 9.20 (1H, d, J = 9.5 Hz) of Ala to the C=O (δC: 169.9) of Ser; N-CH3 (δH: 3.15 (3H, s) of N-Me-Cys to the C=O (δC: 172.2) of Ala; N-CH3 (δH: 2.97 (3H, s) of N-Me-Val to C=O (δC: 168.3) of N-Me-Cys)), indicated that the connections were Dehydroxy-Ser-Ala′-N-Me-Cys′-N-Me-Val′-Ser-Ala-N-Me-Cys-N-Me-Val. Above all evidence, compound 1 was structurally similar to echinomycin. The only difference between them was the presence of a double bond (δH: 6.90 (1H, brs), 6.11 (1H, brs); δC: (133.0, 104.3)) in compound 1. In the HMBC spectrum, the methylene protons (δH: 6.90 (1H, brs), 6.11 (1H, brs)) to C=O (δC: 163.2), confirmed that the double bond originated from the Ser. On the basis of the above information, all protons and carbon resonances were assigned and the planar structure of compound 1 was established. Because the planar differences in the structures of compound 1 and echinomycin cause the changes on spatial configurations, the NMR spectral data, especially 1H NMR spectral data of compound 1 were different with that of echinomycin. The appearance of double bond of Dehydroxy-Ser may make the quinoxaline, amide, alkene, and carbonyl groups form a large conjugate plane (Supplementary Materials Figure S9). The CH3 of the Ala′ positioned in the shielding area, so its 1H NMR spectral data upfielded to δH: 0.19.


A New Analogue of Echinomycin and a New Cyclic Dipeptide from a Marine-Derived Streptomyces sp. LS298.

Zhen X, Gong T, Liu F, Zhang PC, Zhou WQ, Li Y, Zhu P - Mar Drugs (2015)

Key HMBC and ROESY correlations of compound 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663560&req=5

marinedrugs-13-06947-f002: Key HMBC and ROESY correlations of compound 1.
Mentions: Quinomycin G (1) was obtained as an amorphous yellow powder, a molecular formula of C51H64N12O12S2 was determined by HRESIMS (m/z 1101.4288 [M + H]+, calcd for C51H65N12O12S2, 1101.4286), requiring 26 degrees of unsaturation. The chemical structure of 1 was adumbrated as an echinomycin analogue by the close similarity of its molecular formula and ultraviolet spectral properties (λmax (log ε) 245.2 nm (2.6), 325.8 nm (1.9), respectively) to those of echinomycin [10]. The 1H NMR spectrum of 1 (Table 1) displayed four NH resonances (δH: 10.67 (1H, s), 9.20 (1H, d, J = 9.5 Hz), 9.01 (1H, d, J = 9.5 Hz), 7.83 (1H, overlap)); 12 aromatic protons signals (δH: 9.68 (1H, s), 9.63 (1H, s), 8.27 (1H, d, J = 8.0 Hz), 8.20 (3H, d, J = 8.0 Hz), 7.95–7.97 (2H, overlap), 7.84–7.89 (2H, overlap), 6.90 (1H, brs), 6.11 (1H, brs)); two methylene resonances (δH: 5.02 (1H, dd, J = 11.5, 3.0 Hz), 4.67 (1H, d, J = 11.5 Hz); 3.47 (1H, dd, J = 16.0, 5.0 Hz), 2.54 (1H, d, J = 16.0 Hz)); ten methine signals (δH: 6.03 (1H, d, J = 4.0 Hz), 5.70 (1H, s), 5.37 (1H, d, J = 9.0 Hz), 5.28 (1H, m), 4.85 (1H, m), 4.47 (1H, d, J = 11.0 Hz), 3.74 (1H, d, J = 2.0 Hz), 3.42 (1H, d, J = 10.5 Hz), 2.49 (1H, m), 2.27 (1H, m)); 11 methyl signals in the upfield region, including four N-Me groups (δH: 3.37 (3H, s), 3.15 (3H, s), 3.02 (3H, s), 2.97 (3H, s)), one S-Me group (δH: 2.07 (3H, s)). 51 carbons were observed in the 13C NMR spectrum of compound 1 (Table 1), including ten ester/amide carbonyls (δC: 172.2 (2C), 171.5, 169.9 (2C), 169.8, 168.3, 163.6, 163.2, 161.9) and 18 sp2 carbon signals (δC: 143.9 (2C), 143.7, 143.5, 143.4, 142.4, 140.3 (2C), 133.0, 132.4, 131.9, 131.6, 131.0, 130.0 (2C), 129.4 (2C), 104.3). Comprehensive analysis of the 1H-1H COSY (Supplementary Materials Figure S8) and HSQC of compound 1, indicated that compound 1 was comprised of two quinoxalines and eight amino acid moieties (two N-Me-Val, two Ala, two N-Me-Cys, one Ser, and one Dehydroxy-Ser) (Figure 2). The connections between amino acids moieties were confirmed by an HMBC experiment. The HMBCs ((H-α (δH: 4.85 (1H, m) of Ala′ to the C=O (δC: 163.2) of Dehydroxy-Ser; N-CH3 (δH: 3.37 (3H, s) of N-Me-Cys′ to the C=O (δC: 172.2) of Ala′; N-CH3 (δH: 3.02 (3H, s) of N-Me-Val′ to the C=O (δC: 171.5) of N-Me-Cys′; H-β (δH: 4.67 (1H, d, J = 11.5 Hz) of Ser to the C=O (δC: 169.9) of N-Me-Val′; NH (δH: 9.20 (1H, d, J = 9.5 Hz) of Ala to the C=O (δC: 169.9) of Ser; N-CH3 (δH: 3.15 (3H, s) of N-Me-Cys to the C=O (δC: 172.2) of Ala; N-CH3 (δH: 2.97 (3H, s) of N-Me-Val to C=O (δC: 168.3) of N-Me-Cys)), indicated that the connections were Dehydroxy-Ser-Ala′-N-Me-Cys′-N-Me-Val′-Ser-Ala-N-Me-Cys-N-Me-Val. Above all evidence, compound 1 was structurally similar to echinomycin. The only difference between them was the presence of a double bond (δH: 6.90 (1H, brs), 6.11 (1H, brs); δC: (133.0, 104.3)) in compound 1. In the HMBC spectrum, the methylene protons (δH: 6.90 (1H, brs), 6.11 (1H, brs)) to C=O (δC: 163.2), confirmed that the double bond originated from the Ser. On the basis of the above information, all protons and carbon resonances were assigned and the planar structure of compound 1 was established. Because the planar differences in the structures of compound 1 and echinomycin cause the changes on spatial configurations, the NMR spectral data, especially 1H NMR spectral data of compound 1 were different with that of echinomycin. The appearance of double bond of Dehydroxy-Ser may make the quinoxaline, amide, alkene, and carbonyl groups form a large conjugate plane (Supplementary Materials Figure S9). The CH3 of the Ala′ positioned in the shielding area, so its 1H NMR spectral data upfielded to δH: 0.19.

Bottom Line: Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time.Compound 1 exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with the minimum inhibitory concentration (MIC) values ranged from 16 to 64 μg/mL.Moreover, it displayed remarkable anti-tumor activities; the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 μM.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Xicheng District, Beijing 100050, China. zhenxin@imm.ac.cn.

ABSTRACT
Quinomycin G (1), a new analogue of echinomycin, together with a new cyclic dipeptide, cyclo-(l-Pro-4-OH-l-Leu) (2), as well as three known antibiotic compounds tirandamycin A (3), tirandamycin B (4) and staurosporine (5), were isolated from Streptomyces sp. LS298 obtained from a marine sponge Gelliodes carnosa. The planar and absolute configurations of compounds 1 and 2 were established by MS, NMR spectral data analysis and Marfey's method. Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time. Antibacterial and anti-tumor activities of compound 1 were measured against 15 drug-sensitive/resistant strains and 12 tumor cell lines. Compound 1 exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with the minimum inhibitory concentration (MIC) values ranged from 16 to 64 μg/mL. Moreover, it displayed remarkable anti-tumor activities; the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 μM.

Show MeSH
Related in: MedlinePlus