Discovery of a New Polycyclic Tetramate Macrolactam Clifednamide K

doi:10.6023/cjoc202109042

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (4): 1224-1228.DOI: 10.6023/cjoc202109042 Previous Articles Next Articles

NOTES

新多环大环内酰胺Clifednamide K的发现

罗洁^a, 颜雅倩^a, 王浩鑫^b, 李瑶瑶^a^,^*()

a 山东大学药学院天然产物化学生物学教育部重点实验室济南 250012
b 山东大学微生物技术国家重点实验室山东青岛 266237

收稿日期:2021-09-26 修回日期:2021-12-24 发布日期:2022-01-11
通讯作者: 李瑶瑶
基金资助:
国家自然科学基金(81773598); 山东大学青年学者计划(2016WLJH31); 长江学者和创新团队发展计划(IRT_17R68)

Discovery of a New Polycyclic Tetramate Macrolactam Clifednamide K

Jie Luo^a, Yaqian Yan^a, Haoxin Wang^b, Yaoyao Li^a()

a Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012
b State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237

Received:2021-09-26 Revised:2021-12-24 Published:2022-01-11
Contact: Yaoyao Li
Supported by:
National Natural Science Foundation of China(81773598); Young Scholars Program of Shandong University(2016WLJH31); Program for Changjiang Scholars and Innovative Research Team in University(IRT_17R68)

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Abstract

The artificial hybrid polycyclic tetramate macrolactam (PoTeM) gene cluster was constructed through combinatory biosynthesis approach and two PoTeMs, preikarugamycin (1) and clifednamide K (2), were isolated from the recombinant strain SR111-cbmA-OX1-cftC. The chemical structures of 1 and 2 were determined to be the biosynthetic inermediate of ikarugamycin and a new 5/6 dicyclic PoTeM, respectively, by analysis of nuclear magnetic resonance spectroscopy (NMR) data and high resolution mass spectrometry (HRMS). The antibacterial activity of compounds 1 and 2 was tested by filter paper disc diffusion assay. The results showed that they were inactive at 20 μg/disc. The cytotoxicity of compounds 1 and 2 was evaluated by methyl thiazolyl tetrazolium (MTT) colorimetric method. Compound 1 showed potent antiproliferative activity against human liver (HepG-2) and breast cancer cell lines (MCF-7) with half maximal inhibitory concentration (IC₅₀) values of 3.34 and 2.72 μmol/L, respectively, while compound 2 showed no cytotoxicity for the tested cell lines.

Key words: natural product, biological activity, polycyclic tetramate macrolactam, heterologous expression

Cite this article

Jie Luo, Yaqian Yan, Haoxin Wang, Yaoyao Li. Discovery of a New Polycyclic Tetramate Macrolactam Clifednamide K[J]. Chinese Journal of Organic Chemistry, 2022, 42(4): 1224-1228.

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References 16

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Position	δ (J/Hz)		Position	δ (J/Hz)
Position	¹H NMR	¹³C NMR	Position	¹H NMR	¹³C NMR
1		166.6 (C)	18	7.97 (d, 15.0)	–
2	6.53 (d, 15.0)	126.3 (CH)	19		–
3	7.64 (dd, 15.0, 10.2)	138.9 (CH)	20		102.6 (C)
4	6.30 (dd, 15.0, 10.2)	132.0 (CH)	21		–
5	5.71 (dd, 15.0, 10.2)	141.0 (CH)	22
6	3.33 (br s)	46.0 (CH)	23	4.09~4.06 (m)	61.4 (CH)
7	5.58 (dt, 9.6, 3.6)	129.1 (CH)	24		197.3 (C)
8	6.00 (d, 9.6)	130.7 (CH)	25	2.22~2.13 (m)	28.0 (CH₂)
9	1.87~1.82 (m)	49.4 (CH)		2.07~1.99 (m)
10	1.58~1.51 (m)	47.1 (CH)	26	1.63~1.58 (m)	23.5 (CH₂)
11	2.56~2.51 (m)	41.4 (CH)		1.47~1.42 (m)
12	2.26~2.17 (m)	33.1 (CH₂)	27	4.14~4.09 (m)	39.0 (CH₂)
	1.42~1.37 (m)			2.86 (t, 12.0)
13	1.54~1.49 (m)	43.2 (CH)	28	8.47 (d, 8.4)
14	2.64~2.58 (m)	45.5 (CH)	29	1.70~1.60 (m)	21.6 (CH₂)
15	6.04 (dd, 16.0, 5.1)	142.5 (CH)	30	1.04 (t, 7.2)	14.0 (CH₃)
16	6.28 (dd, 16.0, 9.5)	133.8 (CH)	31	4.01 (dd, 10.2, 5.4)	63.5 (CH₂)
17	7.53 (dd, 15.0, 9.5)	141.8 (CH)		3.76 (dd, 10.2, 7.8)

Position	δ (J/Hz)		Position	δ (J/Hz)
Position	¹H NMR	¹³C NMR	Position	¹H NMR	¹³C NMR
1		166.6 (C)	18	7.97 (d, 15.0)	–
2	6.53 (d, 15.0)	126.3 (CH)	19		–
3	7.64 (dd, 15.0, 10.2)	138.9 (CH)	20		102.6 (C)
4	6.30 (dd, 15.0, 10.2)	132.0 (CH)	21		–
5	5.71 (dd, 15.0, 10.2)	141.0 (CH)	22
6	3.33 (br s)	46.0 (CH)	23	4.09~4.06 (m)	61.4 (CH)
7	5.58 (dt, 9.6, 3.6)	129.1 (CH)	24		197.3 (C)
8	6.00 (d, 9.6)	130.7 (CH)	25	2.22~2.13 (m)	28.0 (CH₂)
9	1.87~1.82 (m)	49.4 (CH)		2.07~1.99 (m)
10	1.58~1.51 (m)	47.1 (CH)	26	1.63~1.58 (m)	23.5 (CH₂)
11	2.56~2.51 (m)	41.4 (CH)		1.47~1.42 (m)
12	2.26~2.17 (m)	33.1 (CH₂)	27	4.14~4.09 (m)	39.0 (CH₂)
	1.42~1.37 (m)			2.86 (t, 12.0)
13	1.54~1.49 (m)	43.2 (CH)	28	8.47 (d, 8.4)
14	2.64~2.58 (m)	45.5 (CH)	29	1.70~1.60 (m)	21.6 (CH₂)
15	6.04 (dd, 16.0, 5.1)	142.5 (CH)	30	1.04 (t, 7.2)	14.0 (CH₃)
16	6.28 (dd, 16.0, 9.5)	133.8 (CH)	31	4.01 (dd, 10.2, 5.4)	63.5 (CH₂)
17	7.53 (dd, 15.0, 9.5)	141.8 (CH)		3.76 (dd, 10.2, 7.8)

Compd.	HepG-2	MCF-7
1	3.34±0.05	2.73±0.07
2	>20	>20
Doxorubicin	0.93±0.04	1.12±0.09

Compd.	HepG-2	MCF-7
1	3.34±0.05	2.73±0.07
2	>20	>20
Doxorubicin	0.93±0.04	1.12±0.09

新多环大环内酰胺Clifednamide K的发现

Discovery of a New Polycyclic Tetramate Macrolactam Clifednamide K

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