苯并咪唑并氮杂糖的结构修饰及其β-葡萄糖苷酶抑制活性

doi:10.6023/cjoc202105003

摘要/Abstract

源于D-核糖的苯并咪唑并氮杂糖1和2具有良好的β-葡萄糖糖苷酶抑制活性, 对其苯环部位结构修饰, 通过Mitsunobu反应合成了30个新型苯环不同位置上含单取代基的苯并咪唑并氮杂糖稠合三环衍生物11a~11g, 12a~12g, 13a~13h和14a~14h. 测试了新合成化合物对β-葡萄糖糖苷酶(杏仁)的抑制活性. 结果显示, 化合物13e和13f与14f的混合物对β-葡萄糖糖苷酶(杏仁)表现出优越的酶抑制活性, IC₅₀值分别为0.49和0.25 μmol/L, 活性高于阳性对照米格列醇的酶抑制活性. 构效分析表明, 稠合三环氮杂糖中的六元氮杂糖环形式有利于此类苯并咪唑并氮杂糖三环衍生物的β-葡萄糖苷酶抑制活性. 苯环上3'或4'位连有给电基团, 如甲基、甲氧基等, 将极大地促进化合物的酶抑制活性.

关键词: 稠合三环氮杂糖, Mitsunobu反应, β-葡萄糖苷酶抑制剂, 苯并咪唑

The benzimidazole-fused tricyclic iminosugars 1 and 2 derived from D-ribose inhibited β-glucosidase significantly. On the basis of the structural modification on the phenyl ring of 1 and 2, thirty novel tricyclic iminosugars 11a~11g, 12a~12g, 13a~13h and 14a~14h bearing mono-substituent on the different positions on phenyl ring were synthesized through Mitsunobu reaction. The inhibitory activities of newly synthesized compounds were tested against β-glucosidase (almonds). The results showed that compound 13e and the mixture of 13f and 14f exhibited significantly β-glucosidase inhibitory activities with IC₅₀ values of 0.49 and 0.25 μmol/L, respectively, higher than that of the positive control, miglitol. The analysis of structure activity relationship (SAR) suggested that six-membered iminosugar ring in such fused tricyclic iminosugars was on the benefit of the compounds against β-glucosidase. The electron donor group on the 3' or 4' positions on the phenyl ring, such as methyl or methoxyl, would greatly promote the β-glucosidase inhibitory activities of the inhibitors.

Key words: fused tricyclic iminosugar, Mitsunobu reaction, β-glucosidase inhibitors, benzimidazole

引用此文

李丰兴, 卢昕, 刘旭, 苏路路, 李小六, 陈华. 苯并咪唑并氮杂糖的结构修饰及其β-葡萄糖苷酶抑制活性[J]. 有机化学, 2021, 41(9): 3643-3651.

Fengxing Li, Xin Lu, Xu Liu, Lulu Su, Xiaoliu Li, Hua Chen. Structural Modification of Benzimidazole-Iminosugars and Their Inhibitory Activities against β-Glycosidases[J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3643-3651.

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	Compd.	δ_C
	Compd.	a^a (R=F)	b^a (R=Cl)	c^a (R=Br)	d^a (R=CF₃)	e^a (R=OCH₃)	f^a (R=CH₃)	g^b (R=Cl)	h^b (R=CH₃)
C-4 (五元环)	11	61.5	61.6	61.1	61.2	61.2	60.9; 61.0^c	73.4	—^d
C-4 (五元环)	12	61.3	61.5	61.1	61.9	60.4	60.9; 61.0^c	73.4	—^d
C-5 (六元环)	13	44.4	44.4	44.4	44.5	44.5	44.3^c	44.7	44.5
C-5 (六元环)	14	44.4	44.4	43.9	44.5	44.4	44.3^c	47.1	47.0

	Compd.	δ_C
	Compd.	a^a (R=F)	b^a (R=Cl)	c^a (R=Br)	d^a (R=CF₃)	e^a (R=OCH₃)	f^a (R=CH₃)	g^b (R=Cl)	h^b (R=CH₃)
C-4 (五元环)	11	61.5	61.6	61.1	61.2	61.2	60.9; 61.0^c	73.4	—^d
C-4 (五元环)	12	61.3	61.5	61.1	61.9	60.4	60.9; 61.0^c	73.4	—^d
C-5 (六元环)	13	44.4	44.4	44.4	44.5	44.5	44.3^c	44.7	44.5
C-5 (六元环)	14	44.4	44.4	43.9	44.5	44.4	44.3^c	47.1	47.0

Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)	Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)
11a	3'-F	1.8	N.T.^b	13a	3'-F	92.4	2.46±0.23
12a	4'-F	13.4	N.T.	14a	4'-F	59.7	N.T.
11b	3'-Cl	—^a	N.T.	13b	3'-Cl	—	N.T.
12b	4'-Cl	—	N.T.	14b	4'-Cl	45.5	N.T.
11c	3'-Br	—	N.T.	13c	3'-Br	89.9	3.24±0.26
12c	4'-Br	—	N.T.	14c	4'-Br	88.5	3.34±0.49
11d	3'-CF₃	—	N.T.	13d	3'-CF₃	47.3	N.T.
12d	4'-CF₃	0.6	N.T.	14d	4'-CF₃	30.1	N.T.
11e	3'-OCH₃	52.0	N.T.	13e	3'-OCH₃	99.0	0.49±0.01
12e	4'-OCH₃	48.0	N.T.	14e	4'-OCH₃	79.1	N.T.
11f and 12f	3'-CH₃-4'-CH₃	58.7	N.T.	13f and 14f	3'-CH₃-4'-CH₃	96.9	0.25±0.01
11g	2'-Cl	—	N.T.	13g	2'-Cl	—	N.T.
12g	5'-Cl	—	N.T.	14g	5'-Cl	—	N.T.
13h	2'-CH₃	—	N.T.	14h	5'-CH₃	—	N.T.
2	H	91.7	2.85±0.24	Miglitol		99.4	0.63±0.14

Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)	Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)
11a	3'-F	1.8	N.T.^b	13a	3'-F	92.4	2.46±0.23
12a	4'-F	13.4	N.T.	14a	4'-F	59.7	N.T.
11b	3'-Cl	—^a	N.T.	13b	3'-Cl	—	N.T.
12b	4'-Cl	—	N.T.	14b	4'-Cl	45.5	N.T.
11c	3'-Br	—	N.T.	13c	3'-Br	89.9	3.24±0.26
12c	4'-Br	—	N.T.	14c	4'-Br	88.5	3.34±0.49
11d	3'-CF₃	—	N.T.	13d	3'-CF₃	47.3	N.T.
12d	4'-CF₃	0.6	N.T.	14d	4'-CF₃	30.1	N.T.
11e	3'-OCH₃	52.0	N.T.	13e	3'-OCH₃	99.0	0.49±0.01
12e	4'-OCH₃	48.0	N.T.	14e	4'-OCH₃	79.1	N.T.
11f and 12f	3'-CH₃-4'-CH₃	58.7	N.T.	13f and 14f	3'-CH₃-4'-CH₃	96.9	0.25±0.01
11g	2'-Cl	—	N.T.	13g	2'-Cl	—	N.T.
12g	5'-Cl	—	N.T.	14g	5'-Cl	—	N.T.
13h	2'-CH₃	—	N.T.	14h	5'-CH₃	—	N.T.
2	H	91.7	2.85±0.24	Miglitol		99.4	0.63±0.14