Inhibitory Effect of Chlorogenic Acid Analogues Comprising Pyridine and Pyrimidine on α-MSH-Stimulated Melanogenesis and Stability of Acyl Analogues in Methanol.

Jaeuk Sim,Jae-Kyung Jung,Hee-Soon Lee,Eun-Yeong Kim,Srinu Lanka,Kiho Lee,Chhabi Lal Chaudhary,Soon-Sil Hyun,Young-Hee Lee,Seung-Yong Seo,Chan-Hyun Jung,Young-Soo Kim,Mayavan Viji,Jeong-Woong Jo,Manjunatha Vishwanath

doi:10.3390/ph14111176

Jaeuk Sim, Jae-Kyung Jung + Show 13 more

Open Access

https://doi.org/10.3390/ph14111176

Copy DOI

Abstract

In continuation of studies for α-MSH stimulated melanogenesis inhibitors, we have evaluated the design, synthesis, and activity of a new series of chlorogenic acid (CGA) analogues comprising pyridine, pyrimidine, and diacyl derivatives. Among nineteen synthesized compounds, most of them (fifteen) exhibited better inhibitions of melanin formation in B16 melanoma cells. The results illustrated that a pyridine analogue 6f and a diacyl derivative 13a of CGA showed superior inhibition profiles (IC50: 2.5 ± 0.7 μM and 1.1 ± 0.1 μM, respectively) of α-MSH activities than positive controls, kojic acid and arbutin (IC50: 54 ± 1.5 μM and 380 ± 9.5 μM, respectively). The SAR studies showed that both –CF3 and –Cl groups exhibited better inhibition at the meta position on benzylamine than their ortho and para positions. In addition, the stability of diacyl analogues of CGA in methanol monitored by HPLC for 28 days indicated the steric bulkiness of acyl substituents as a key factor in their stability.

Highlights

Melanin, produced by the melanocytes through the complex melanogenesis process, plays a significant role in determining the color of human skin, eye, and hair [1,2,3,4,5].Melanocytes are known to be stimulated by various factors including UV radiation, melanocyte-stimulating hormone (α-MSH), a phosphodiesterase inhibitor, such as theophylline
Considering the importance of skincare products, as a part of our continuous work in the way to the preparation of potent chlorogenic acid (CGA) analogues targeting α-MSH-stimulated melanogenesis inhibition [63,64], we have reported the design and synthesis of dimethoxy phenyl analogues of CGA comprising of pyridine, pyrimidine, and cyclohexyl caffeamide skeletons (Figure 1) along with their inhibitory activities against melanin formation
Pyridine (6a–g), pyrimidine (10a–f), and cyclohexyl ester (13a–d, 15 and 17) analogues of CGA in hand, we evaluated their inhibitory activity of melanin formation in B16 melanoma cells under stimulus of α-MSH, and the IC50 values are summarized in Table 1

Summary

Introduction

Melanin, produced by the melanocytes through the complex melanogenesis process, plays a significant role in determining the color of human skin, eye, and hair [1,2,3,4,5].Melanocytes are known to be stimulated by various factors including UV radiation, melanocyte-stimulating hormone (α-MSH), a phosphodiesterase inhibitor, such as theophylline. Melanin, produced by the melanocytes through the complex melanogenesis process, plays a significant role in determining the color of human skin, eye, and hair [1,2,3,4,5]. Tyrosinase (EC.1.14.18.1) is the main rate-limiting enzyme that controls the biosynthesis of melanin production by the conversion of L-tyrosine to dopaquinone via L-dopa using monophenolase and diphenolase activities [6,7,8,9]. An excess secretion of melanin from melanocytes due to prolonged exposure to sunlight leads to dermatologic disorders such as melasma [10], freckles [11], post-inflammatory melanoderma [12], solar lentigines [13], vitiligo [14], and even cancer [15].

Objectives

Methods

Results

Conclusion