4-Hydroxyderricin Isolated from the Sap of Angelica keiskei Koidzumi: Evaluation of Its Inhibitory Activity towards Dipeptidyl Peptidase-IV

Diah Lia Aulifa,I Ketut Adnyana,Jutti Levita,Sukrasno Sukrasno

doi:10.3390/scipharm87040030

Diah Lia Aulifa, I Ketut Adnyana + Show 2 more

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https://doi.org/10.3390/scipharm87040030

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Abstract

Angelica keiskei sap is used as a blood-sugar reducer in Indonesia, however its molecular mechanism has not yet been explored. 4-hydroxyderricin (4-HD) is one of the major components extracted from A. keiskei sap. The aim of this work was to isolate 4-HD from the sap of A. keiskei planted in Lombok, Indonesia, and to study in silico and in vitro mechanisms against dipeptidyl peptidase-IV (DPP-IV). The dried sap was submitted to liquid–liquid extraction using solvents with different polarity. Further purification processing was conducted using gradient elution column chromatography. The isolated compound was a yellowish powder, m/z 339.2215 [M + H]+, which was confirmed as 4-HD. Sitagliptin, a DPP-IV inhibitor, was employed as the positive control for both the in silico and in vitro studies. It was indicated that 4-HD interacts with Glu206 and Phe357, important amino acid residues in the DPP-IV binding pocket. These interactions are similar to that of sitagliptin. The affinity of 4-HD (inhibition constant (Ki) = 3.99 μM) to DPP-IV is lower than that of sitagliptin (inhibition constant (Ki) = 0.17 μM). Furthermore, in vitro study showed that 4-HD inhibits DPP-IV (IC50 = 81.44 μM) weaker than for sitagliptin (IC50 = 0.87 μM). We concluded that 4- HD might have potential in inhibiting DPP-IV. However, by considering the polar interaction of sitagliptin with DPP-IV, a further structure modification of 4-HD, e.g., by introducing a polar moiety such as a hydroxyl group, might be needed to obtain stronger activity as a DPP-IV inhibitor.

Highlights

Diabetes mellitus (DM) is considered as a serious health problem due to its increasing prevalence in most developing countries [1], new antidiabetic drugs and therapies are always of interest to be explored [2]
More than one million Indonesians were diagnosed with DM in 2018 [4], whereas 451 million have been reported to suffer the same problem globally [1,3]
The yellow sap of Angelica keiskei was collected from Mount Rinjani, Lombok, Indonesia

Summary

Introduction

Diabetes mellitus (DM) is considered as a serious health problem due to its increasing prevalence in most developing countries [1], new antidiabetic drugs and therapies are always of interest to be explored [2]. More than one million Indonesians were diagnosed with DM in 2018 [4], whereas 451 million (age 18–99 years) have been reported to suffer the same problem globally [1,3]. Type 2 DM (T2DM) is characterized by insulin insensitivity, inhibition of insulin production, and eventually, pancreatic beta-cell failure. This leads to a decrease in glucose transport into the liver, muscle cells, and fat cells [5].

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