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Syntheses and Structure–Activity Relationships in Growth Inhibition Activity against Human Cancer Cell Lines of 12 Substituted Berberine Derivatives

Wang, Bo, Deng, An-Jun, Li, Zhi-Hong, Wang, Nan, Qin, Hai-Lin·2020·Molecules
DOI 10.3390/molecules25081871PMC PMC7221678
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Abstract

In this study, quaternary berberine chloride is used as a lead compound to design and synthesize a series of berberine-12-amine derivatives to evaluate the growth inhibition activity against human cancer cell lines. Forty-two compounds of several series were obtained. The quaternary berberine-12-N,N-di-n-alkylamine chlorides showed the targeted activities with the IC50 values of most active compounds being dozens of times those of the positive control. A significant structure–activity relationship (SAR) was observed. The activities of quaternary berberine-12-N,N-di-n-alkylamine chlorides are significantly stronger than those of the reduced counterparts. In the range of about 6-8 carbon atoms, the activities increase with the elongation of n-alkyl carbon chain of 12-N,N-di-n-alkylamino, and when the carbon atom numbers are more than 6-8, the activities decrease with the elongation of n-alkyl carbon chain. The activities of the tertiary amine structure are significantly higher than that of the secondary amine structure.

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Figure 1 Structure of quaternary berberine chloride (QBC) (1).
Figure 1 Structure of quaternary berberine chloride (QBC) (1).CC BY · PubMed Central
Scheme 1 Syntheses of compounds 2, 3, and 4a–m. Reagents and conditions: (a) NaNO2, concentrated HNO3, AcOH, 50°C, 1h; (b) SnCl2·2H2O, concentrated HCl, EtOH, reflux, 30min; (c) RCOCl, pyridine, CH2Cl2, room temperature (rt), 12h. R= a: p-trifluoromethylphenyl; b: Me; c: isopropyl; d: p-bromophenyl; e: phenyl; f: p-fluorophenyl; g: p-methylphenyl; h: m-methylphenyl; i: Et; j: n-Bu; k: p-methoxyphenyl; l: p-nitrophenyl; m: t-Bu.
Scheme 1 Syntheses of compounds 2, 3, and 4a–m. Reagents and conditions: (a) NaNO2, concentrated HNO3, AcOH, 50°C, 1h; (b) SnCl2·2H2O, concentrated HCl, EtOH, reflux, 30min; (c) RCOCl, pyridine, CH2Cl2, room temperature (rt), 12h. R= a: p-trifluoromethylphenyl; b: Me; c: isopropyl; d: p-bromophenyl; e: phenyl; f: p-fluorophenyl; g: p-methylphenyl; h: m-methylphenyl; i: Et; j: n-Bu; k: p-methoxyphenyl; l: p-nitrophenyl; m: t-Bu.CC BY · PubMed Central
Scheme 2 Syntheses of compounds 5, 6a–l, and 7a–l. Reagents and conditions: (a) NaBH4, NiCl2·6H2O, THF/CH3OH, 66 °C, 20 min; (b) RCHO, NaBH(OCOCH3)3, AcOH, CH2Cl2, rt, 1h; (c) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2, 2N HCl, rt, 2h. R = a–l: CnH2n + 1 (n = 0–11).
Scheme 2 Syntheses of compounds 5, 6a–l, and 7a–l. Reagents and conditions: (a) NaBH4, NiCl2·6H2O, THF/CH3OH, 66 °C, 20 min; (b) RCHO, NaBH(OCOCH3)3, AcOH, CH2Cl2, rt, 1h; (c) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2, 2N HCl, rt, 2h. R = a–l: CnH2n + 1 (n = 0–11).CC BY · PubMed Central
Scheme 3 Syntheses of compounds 8 and 9. Reagents and conditions: (a) RCHO, NaBH(OCOCH3)3, AcOH, CH2Cl2, rt, 1h; (b) I2, absolute EtOH, reflux, 24h.
Scheme 3 Syntheses of compounds 8 and 9. Reagents and conditions: (a) RCHO, NaBH(OCOCH3)3, AcOH, CH2Cl2, rt, 1h; (b) I2, absolute EtOH, reflux, 24h.CC BY · PubMed Central
Figure 2 Effects of the active compounds inhibiting HCT-8 growth (n = 3).
Figure 2 Effects of the active compounds inhibiting HCT-8 growth (n = 3).CC BY · PubMed Central
Figure 3 Effects of the active compounds inhibiting Bel7402 growth (n = 3).
Figure 3 Effects of the active compounds inhibiting Bel7402 growth (n = 3).CC BY · PubMed Central
Figure 4 Effects of the active compounds inhibiting Hela growth (n = 3).
Figure 4 Effects of the active compounds inhibiting Hela growth (n = 3).CC BY · PubMed Central
Figure 5 Effects of the active compounds inhibiting A549 growth (n = 3).
Figure 5 Effects of the active compounds inhibiting A549 growth (n = 3).CC BY · PubMed Central
Figure 6 Effects of the active compounds inhibiting BGC-823 growth (n = 3).
Figure 6 Effects of the active compounds inhibiting BGC-823 growth (n = 3).CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Wang, B., Deng, A.-J., Li, Z.-H., Wang, N., & Qin, H.-L.
Venue
Molecules
Publisher
MDPI AG
Published
2020-04-18
Volume
25
Issue
8
Pages
1871
ISSN
1420-3049
DOI
10.3390/molecules25081871
PMC
PMC7221678
Cited by
23
References
1
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Mega-Project for Innovative Drugs (2019ZX09735002)
  • Drug Innovation Major Project (2018ZX09711001-005006)
  • the CAMS Initiation Fund for Innovative Medicine (2016-I2M-1-010)

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