Fermentation Optimization of the Caerulomycin H and the Synthesis of Cyanogriside K

doi:10.6023/cjoc202204035

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (9): 2840-2849.DOI: 10.6023/cjoc202204035 Previous Articles Next Articles

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浅蓝霉素H的发酵优化与浅蓝苷K的化学合成

罗云^a, 高谕康^a, 燕鹏程^a, 朱伟明^a^,^b^,^c^,^*()

a 中国海洋大学医药学院海洋药物教育部重点实验室山东青岛 266003
b 中国科学院上海有机化学研究所天然产物有机合成化学重点实验室上海 200032
c 青岛海洋科学与技术试点国家实验室海洋药物与生物制品功能实验室山东青岛 266237

收稿日期:2022-04-14 修回日期:2022-06-06 发布日期:2022-06-16
通讯作者: 朱伟明
基金资助:
国家自然科学基金委员会-山东省人民政府联合基金(U1906213); 天然产物有机合成化学院重点实验室开放基金(SIOC-2021-7)

Fermentation Optimization of the Caerulomycin H and the Synthesis of Cyanogriside K

Yun Luo^a, Yukang Gao^a, Pengcheng Yan^a, Weiming Zhu^a^,^b^,^c()

a Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
c Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong 266237

Received:2022-04-14 Revised:2022-06-06 Published:2022-06-16
Contact: Weiming Zhu
Supported by:
National Natural Science Foundation of China-Shandong Union Foundation(U1906213); Open Fund Projects from Key Laboratory of Synthetic Chemistry of Natural Substances(SIOC-2021-7)

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Abstract

Caerulomycin H (2) and its 4-yl α-L-rhamnopyranoside [cyanogriside K (1)] are two microbial natural products from marine-derived Actinoalloteichus cyanogriseus WH1-2216-6. Cyanogriside K (1) shows good antiproliferative activity against tumor cells, whereas the yield is very low and the synthesis has not been reported. Thus, enough caerulomycin H (2) was first obtained by optimazing the fermentation condition of the mutant strain CRM05 of A. cyanogriseus WH1-2216-6. The yield of caerulomycin H (2) reached 272 mg/L (increased by 5 times) in the optimal solid medium consisted of corn pellets (80 g) and liqiud medium 5# for actinomycetes (100 mL). Then cyanogriside K (1) was synthesized with 25.6% total yield from caerulomycin H (2) by six steps reactions including deoximation, rhamnosylation, oximation and deacetylation. The structure of cyanogriside K (1) was identified by NMR, HRESIMS and specific rotation data. It is the same compound as the reported natural product. Furthermore, cyanogriside K (1) showed good bioactivity against the proliferation of the tumor cell lines PATU8988T, 786-O, 5673, DU145, A-375, FaDu and SF126, with the half maximal inhibitory concentration (IC₅₀) values ranging from 1.07 μmol/L to 1.78 μmol/L.

Key words: caerulomycin H, fermentation optimization, rhamnosylation, cyanogriside K, antiproliferation

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Yun Luo, Yukang Gao, Pengcheng Yan, Weiming Zhu. Fermentation Optimization of the Caerulomycin H and the Synthesis of Cyanogriside K[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2840-2849.

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Concentrstion/(mg•mL^–1)	Peak area
0.005	868
0.025	5053
0.05	10067
0.10	20158
0.20	40907
0.40	80590
0.50	101588
0.75	152430
1.00	203151

Concentrstion/(mg•mL^–1)	Peak area
0.005	868
0.025	5053
0.05	10067
0.10	20158
0.20	40907
0.40	80590
0.50	101588
0.75	152430
1.00	203151

培养方法	发酵时间/d	发酵量	浅蓝霉素H产量
发酵1	15	300 mL	42.4 mg/L
发酵2	170	540 g	139.3 mg/kg
发酵3	170	540 g	72.9 mg/kg
发酵4	15	300 mL	71.1 mg/L
发酵5	17	180 g	166.1 mg/kg
	23	180 g	272.2 mg/kg
	32	180 g	176.6 mg/kg

培养方法	发酵时间/d	发酵量	浅蓝霉素H产量
发酵1	15	300 mL	42.4 mg/L
发酵2	170	540 g	139.3 mg/kg
发酵3	170	540 g	72.9 mg/kg
发酵4	15	300 mL	71.1 mg/L
发酵5	17	180 g	166.1 mg/kg
	23	180 g	272.2 mg/kg
	32	180 g	176.6 mg/kg

Entry	R	Reagent	Solvent^a	Temperature and time	Ref.	Yield^b/%
1	Br	Ag₂CO₃	MeCN	80 ℃, 1+3 h^c	[11a~11d]	68.4
2		Ag₂CO₃	Toluene	105 ℃, 3 h	[11a~11d]	7
3		Cs₂CO₃	MeCN	25 ℃, 24 h	[11e]	11
4		Bu₄NBr, NaOH	CHCl₃/H₂O (V∶V=1∶1)	40 ℃	[12a]	—^d
5		Bu₄NBr, K₂CO₃	CHCl₃/H₂O (V∶V=1∶1)	40 ℃	[12b]	—
6	OAc	FeCl₃•6H₂O	CH₂Cl₂	25 ℃	[13a, 13b]	—
7	OAc	BF₃•OEt₂	CH₂Cl₂	25 ℃	[13c]	—
8		NIS, TfOH	CH₂Cl₂	–78 ℃	[14a~14c]
9		NIS, TMSOTf	CH₂Cl₂	–35 ℃	[14d]	—
10		BF₃•OEt₂	CH₂Cl₂	25 ℃	[15a~15c]	—

浅蓝霉素H的发酵优化与浅蓝苷K的化学合成

Fermentation Optimization of the Caerulomycin H and the Synthesis of Cyanogriside K

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Position	Natural 1 (J in Hz)^[6]		Synthetic 1 (J in Hz)
Position	δ_C	δ_H	δ_C	δ_H
2	157.0 (C)		157.0 (C)
3	108.3 (CH)	8.00(d, J=1.9 H)	108.3 (CH)	8.00 (d, J=2.3)
4	163.6 (C)		163.6 (C)
5	107.2 (CH)	7.45 (d, J=1.9)	107.2 (CH)	7.45 (d, J=2.3)
6	153.6 (C)		153.6 (C)
7	148.7 (CH)	8.15 (s)	148.7 (CH)	8.15 (s)
2'	154.4 (C)		154.4 (C)
3'	120.7 (CH)	8.38 (d, J=7.9)	120.7 (CH)	8.38 (d, J=7.7)
4'	137.7 (CH)	7.96 (t, J=7.9)	137.4 (CH)	7.96 (td, J=7.7, 1.7)
5'	124.6 (CH)	7.48 (dd, J=7.9, 4.0)	124.6 (CH)	7.48 (ddd, J=7.7, 5.0 1.2)
6'	149.3 (CH)	8.69 (d, J=4.1)	149.3 (CH)	8.69 (dt, J=5.1, 1.2)
1''	98.1 (CH)	5.63 (d, J=1.9)	98.1 (CH)	5.63 (d, J=1.9)
2''	70.1 (CH)	3.88 (t, J=4.2)	70.1 (CH)	3.88 (dd, J=3.2, 1.9)
3''	70.3 (CH)	3.67 (dt, J=5.2, 4.2)	70.3 (CH)	3.67 (dd, J=9.0, 3.2)
4''	71.6 (CH)	3.17 (d, J=5.2)	71.6 (CH)	3.16 (s)
5''	69.8 (CH)	3.43 (dq, J=5.2, 6.1)	69.8 (CH)	3.43 (dd, J=9.0, 6.1)
6''	17.9 (CH₃)	1.11 (d, J=6.1)	17.9 (CH₃)	1.11 (d, J=6.1)

Compd.	A549	MKN-45	HCT-116	HeLa	K562	SF126	PA-1	768-O	5637	DU145	CAL-62	PATU8988T	HOS	A-375	A-673	FaDu	GBC-SD
1	7.32	3.61	3.53	2.47	9.29	1.78	5.79	1.68	1.08	1.14	2.90	1.07	2.45	1.52	2.82	1.15	2.28
Dox	1.10	1.25	0.94	0.41	0.41	0.78	0.63	0.59	0.24	0.44	0.41	0.33	0.92	0.20	0.23	0.21	5.34