Discovery of Tiancimycin Congeners from Streptomyces sp. CB03234-S

doi:10.6023/cjoc202111018

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (4): 1241-1247.DOI: 10.6023/cjoc202111018 Previous Articles Next Articles

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链霉菌CB03234-S中天赐霉素衍生物的发现

薛露^a^,^b, 张丽花^a^,^b, 张成玉^a, 赵鑫^a, 党伟帆^a, 王昭昕^a^,^b, 王春华^c, 所同川^c, 颜晓晖^a^,^b^,^*()

a 天津中医药大学中医药研究院天津 301617
b 北京大学天然药物及仿生药物国家重点实验室北京 100191
c 天津中医药大学中药制药工程学院天津 301617

收稿日期:2021-11-10 修回日期:2021-12-09 发布日期:2021-12-30
通讯作者: 颜晓晖
基金资助:
国家自然科学基金(81872779); 天然药物及仿生药物国家重点实验室开放基金(K202116)

Discovery of Tiancimycin Congeners from Streptomyces sp. CB03234-S

Lu Xue^a^,^b, Lihua Zhang^a^,^b, Chengyu Zhang^a, Xin Zhao^a, Weifan Dang^a, Zhaoxin Wang^a^,^b, Chunhua Wang^c, Tongchuan Suo^c, Xiaohui Yan^a^,^b()

a Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191
c College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617

Received:2021-11-10 Revised:2021-12-09 Published:2021-12-30
Contact: Xiaohui Yan
Supported by:
National Science Foundation of China(81872779); State Key Laboratory of Natural and Biomimetic Drugs(K202116)

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Abstract

Tiancimycins (TNMs) are anthraquinone-fused enediynes with phenomenal antitumor activity. By heterologous expression of two cytochrome P450 hydroxylase genes, dynE10 and dynOrf19, in the TNMs high-producing strain Streptomyces sp. CB03234-S, three TNM derivatives 1~3 were isolated. Their chemical structures were determined by one-dimensional and two-dimensional NMR, high resolution mass spectrometry and circular dichroism. TNM H (1) is the C-9-hydroxylated product of TNM D, TNM T1 (2) is a cycloaromatized product, and TNM T3 (3) is a known compound. Compound 1 exhibited strong antitumor activity against the four tested cancer cell lines, including HeLa, MB49, B16 and BIU87.

Key words: tiancimycins, anthraquinone-fused enediyne, cytochrome P450 hydroxylase, antitumor activity, heterologous expression

Cite this article

Lu Xue, Lihua Zhang, Chengyu Zhang, Xin Zhao, Weifan Dang, Zhaoxin Wang, Chunhua Wang, Tongchuan Suo, Xiaohui Yan. Discovery of Tiancimycin Congeners from Streptomyces sp. CB03234-S[J]. Chinese Journal of Organic Chemistry, 2022, 42(4): 1241-1247.

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Fig. & Tab. 6

References 13

[1]	Yan, X. Nat. Prod. Rep. 2021, 39, 703. doi: 10.1039/D1NP00054C
[2]	Yan, X.; Ge, H.; Huang, T.; Hindra; Yang, D.; Teng, Q.; Crnovčić, I.; Li, X.; Rudolf, J. D.; Lohman, J. R.; Gansemans, Y.; Zhu, X.; Huang, Y.; Zhao, L. X.; Jiang, Y.; Van Nieuwerburgh, F.; Rader, C.; Duan, Y.; Shen, B. mBio 2016, 7, e02104.
[3]	Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D.; Clardy, J. J. Antibiot. (Tokyo) 1989, 42, 1449. pmid: 2793600
[4]	Davies, J.; Wang, H.; Taylor, T.; Warabi, K.; Huang, X. H.; Andersen, R. J. Org. Lett. 2005, 7, 5233. doi: 10.1021/ol052081f
[5]	Yan, X.; Chen, J. J.; Adhikari, A.; Yang, D.; Crnovcic, I.; Wang, N.; Chang, C. Y.; Rader, C.; Shen, B. Org. Lett. 2017, 19, 6192. doi: 10.1021/acs.orglett.7b03120
[6]	Igarashi, M.; Sawa, R.; Umekita, M.; Hatano, M.; Arisaka, R.; Hayashi, C.; Ishizaki, Y.; Suzuki, M.; Kato, C. J. Antibiot. (Tokyo) 2021, 74, 291. doi: 10.1038/s41429-020-00402-1
[7]	Poudel, Y. B.; Rao, C.; Kotapati, S.; Deshpande, M.; Thevanayagam, L.; Pan, C.; Cardarelli, J.; Chowdari, N.; Kaspady, M.; Samikannu, R.; Kuppusamy, P.; Saravanakumar, P.; Arunachalam, P. N.; Deshpande, S.; Rangan, V.; Rampulla, R.; Mathur, A.; Vite, G. D.; Gangwar, S. Bioorg. Med. Chem. Lett. 2020, 30, 126782. doi: 10.1016/j.bmcl.2019.126782
[8]	Nicolaou, K. C.; Rigol, S.; Pitsinos, E. N.; Das, D.; Lu, Y.; Rout, S.; Schammel, A. W.; Holte, D.; Lin, B.; Gu, C.; Sarvaiya, H.; Trinidad, J.; Barbour, N.; Valdiosera, A. M.; Sandoval, J.; Lee, C.; Aujay, M.; Fernando, H.; Dhar, A.; Karsunky, H.; Taylor, N.; Pysz, M.; Gavrilyuk, J. Proc. Natl. Acad. Sci. U. S. A. 2021, 118, e2107042118. doi: 10.1073/pnas.2107042118
[9]	Annaval, T.; Teijaro, C. N.; Adhikari, A.; Yan, X.; Chen, J. J.; Crnovcic, I.; Yang, D.; Shen, B. ACS. Chem. Biol. 2021, 16, 1172. doi: 10.1021/acschembio.1c00365
[10]	Cohen, D. R.; Townsend, C. A. Nat. Chem. 2018, 10, 231. doi: 10.1038/nchem.2876
[11]	Gao, Q.; Thorson, J. S. FEMS Microbiol. Lett. 2008, 282, 105. doi: 10.1111/j.1574-6968.2008.01112.x
[12]	Yan, X.; Chen, J. J.; Adhikari, A.; Teijaro, C. N.; Ge, H.; Crnovcic, I.; Chang, C. Y.; Annaval, T.; Yang, D.; Rader, C.; Shen, B. Org. Lett. 2018, 20, 5918. doi: 10.1021/acs.orglett.8b02584
[13]	Zhuang, Z.; Jiang, C.; Zhang, F.; Huang, R.; Yi, L.; Huang, Y.; Yan, X.; Duan, Y.; Zhu, X. Biotechnol. Bioeng. 2019, 116, 1304. doi: 10.1002/bit.26944

Position	1
Position	δ_C, type	δ_H (J in Hz)	δ_C, type	δ_H (J in Hz)
1-NH		9.70 (d, 5.04)		10.39 (d, 5.46)
2	144.7, C		143.5, C
3	110.2, C		106.8, C
4	186.4, C		186.6, C
5	113.0, C		113.5, C
6	148.3, C		147.7, C
7	157.5, C		157.2, C
8	105.6, CH	s, 6.74	105.6, CH	s, 6.85
9	159.0, C		158.6, C
10	105.9, C		105.9, C
11	186.2, C		184.8, C
12	112.3, C		111.8, C
13	154.3, C		154.8, C
14	131.5, CH	s, 8.45	132.2, CH	s, 7.22
15	135.6, C		134.7, C
16	66.9, C		46.7, CH	3.55 (dd, 5.22, 2.46)
17	62.8, CH	5.96 (d, 5.16)	68.9, CH	5.39 (dd, 5.22, 5.82)
18	102.9, C		135.9, C
19	91.5, C		126.3, CH	7.40 (d, 7.68)
20	124.3, CH	6.09 (d, 9.96)	126.7, CH	7.15 (td, 7.68, 1.38)
21	123.3, CH	6.00 (d, 9.96)	127.8, CH	7.21 (t, 7.68)
22	89.3, C		127.4, CH	7.37 (dd, 7.68, 1.38)
23	97.7, C		138.0, C
24	44.5, CH	5.22 (d, 5.04)	52.4, CH	5.28 (dd, 5.46, 2.46)
25	78.7, C		80.3, C
26	75.6, C		77.7, C
27	24.9, CH₃	s, 1.48	15.8, CH₃	s, 1.33
28	74.4, CH	4.26 (d, 6.90)	73.7, CH	4.72 (d, 6.54)
29	172.6, C		173.3, C
30	51.7, CH₃	s, 3.66
6-OH		br s, 13.58
7-OCH₃	56.8, CH₃	3.90, s	56.7, CH₃	s, 3.91
9-OH		12.51, br s
13-OH		12.40, br s
17-OH		6.57 (d, 5.16)		5.99 (d, 5.82)
26-OH		s, 5.53		s, 5.48
28-OH		5.67 (d, 6.90)		6.35 (d, 6.54)

Position	1
Position	δ_C, type	δ_H (J in Hz)	δ_C, type	δ_H (J in Hz)
1-NH		9.70 (d, 5.04)		10.39 (d, 5.46)
2	144.7, C		143.5, C
3	110.2, C		106.8, C
4	186.4, C		186.6, C
5	113.0, C		113.5, C
6	148.3, C		147.7, C
7	157.5, C		157.2, C
8	105.6, CH	s, 6.74	105.6, CH	s, 6.85
9	159.0, C		158.6, C
10	105.9, C		105.9, C
11	186.2, C		184.8, C
12	112.3, C		111.8, C
13	154.3, C		154.8, C
14	131.5, CH	s, 8.45	132.2, CH	s, 7.22
15	135.6, C		134.7, C
16	66.9, C		46.7, CH	3.55 (dd, 5.22, 2.46)
17	62.8, CH	5.96 (d, 5.16)	68.9, CH	5.39 (dd, 5.22, 5.82)
18	102.9, C		135.9, C
19	91.5, C		126.3, CH	7.40 (d, 7.68)
20	124.3, CH	6.09 (d, 9.96)	126.7, CH	7.15 (td, 7.68, 1.38)
21	123.3, CH	6.00 (d, 9.96)	127.8, CH	7.21 (t, 7.68)
22	89.3, C		127.4, CH	7.37 (dd, 7.68, 1.38)
23	97.7, C		138.0, C
24	44.5, CH	5.22 (d, 5.04)	52.4, CH	5.28 (dd, 5.46, 2.46)
25	78.7, C		80.3, C
26	75.6, C		77.7, C
27	24.9, CH₃	s, 1.48	15.8, CH₃	s, 1.33
28	74.4, CH	4.26 (d, 6.90)	73.7, CH	4.72 (d, 6.54)
29	172.6, C		173.3, C
30	51.7, CH₃	s, 3.66
6-OH		br s, 13.58
7-OCH₃	56.8, CH₃	3.90, s	56.7, CH₃	s, 3.91
9-OH		12.51, br s
13-OH		12.40, br s
17-OH		6.57 (d, 5.16)		5.99 (d, 5.82)
26-OH		s, 5.53		s, 5.48
28-OH		5.67 (d, 6.90)		6.35 (d, 6.54)

细胞株	HeLa	MB49	B16	BIU87
天赐霉素A	4.48±0.22	0.38±0.03	0.48±0.11	1.16±0.13
天赐霉素D	16.6±2.3	2.80±0.27	9.18±0.54	1.10±0.26
化合物 1	4.34±0.28	0.82±0.21	5.44±0.71	1.11±0.23

细胞株	HeLa	MB49	B16	BIU87
天赐霉素A	4.48±0.22	0.38±0.03	0.48±0.11	1.16±0.13
天赐霉素D	16.6±2.3	2.80±0.27	9.18±0.54	1.10±0.26
化合物 1	4.34±0.28	0.82±0.21	5.44±0.71	1.11±0.23

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链霉菌CB03234-S中天赐霉素衍生物的发现

Discovery of Tiancimycin Congeners from Streptomyces sp. CB03234-S

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