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Bioorg Med Chem Lett. 2017 Feb 15;27(4):1026-1030. doi: 10.1016/j.bmcl.2016.12.066. Epub 2016 Dec 29.

Microbial hydroxylation and glycosylation of pentacyclic triterpenes as inhibitors on tissue factor procoagulant activity.

Author information

1
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
2
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
3
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China. Electronic address: boyangyu59@163.com.
4
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: 1020071849@cpu.edu.cn.

Abstract

To discover new inhibitors on tissue factor procoagulant activity, 20 pentacyclic triterpenes were semi-synthetized through microbial transformation and assayed on the model of human THP-1 cells stimulated by lipopolysaccharide. In the biotransformation two types of reactions were observed, regio-selective hydroxylation and glycosylation. The bioassay results showed that most of tested compounds were significant effective on this model and two of the biotransformation products 23-hydroxy-28-O-β-d-glucopyranosyl betulinic acid (3d) and 28-O-β-d-glucopyranosyl oleanic acid (1a) exhibited most potential activities with the IC50 values of 0.028, 0.035nM respectively. The preliminary structure and activity relationship analysis revealed that the aglycones with single free hydroxyl group on the skeleton (1, 1j) were less effective than that with more free hydroxyl groups (1d, 1f, 2), mono-glycosylation can significantly enhance their inhibitory effects. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.

KEYWORDS:

Biotransformation; Pentacyclic triterpenes; Structure and activity relationship (SAR); Tissue factor

PMID:
28109788
DOI:
10.1016/j.bmcl.2016.12.066
[Indexed for MEDLINE]

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