Synthesis and Cytotoxic Activity of Novel C-23-Modified Asiatic Acid Derivatives

Yi-Hong Lu,Ming-Cang Chen,Xiao-Ting Tian,Yang Xie,Fang Liu,Cheng-Gang Huang,Zhou Xu

doi:10.3390/molecules25163709

Abstract

We selectively oxidized the C-23 hydroxyl group in an asiatic acid (AA) derivative and then, for the first time with AA, modification of the C-23 carboxyl group was conducted to synthesize a series of new AA derivatives. The evaluation of their cytotoxic activities against two human cancer cell lines (SKOV-3 and HCT116) using the MTT assay in vitro revealed a distinctive structure activity relationship (SAR) associated with the intramolecular hydrogen bonding of the amide moiety at C-23. According to the established SAR, the cytotoxic activities of four promising compounds were then evaluated against MCF-7, A549, A2780, HepG2 and HL-60 cancer cell lines. Compound 10 had the best cytotoxic activity among all tested derivatives in the HL-60 cell line, giving IC50 = 0.47 μM, while showing no cytotoxic effect against human normal cells (HUVEC).

Highlights

NNaattuurraallpprroodduucctstsaraerea ma amjoarjosrousrocuerocef leoafdlecaodmcpoomunpdosufnodrsnfeowr tnheewraptheeurtaicpaeguetnictsa[g1e,2n]t.sIn[1r,2ec].enInt yrecaersn,ttryietearrpse, ntroiitdersp, aesnoindeso, fatshoenlaergoefstthcelalsasregseostf nclaatsusreasl porfondautcutrsa, lhpavroedbuecetns,frheaqvueenbtelyenrefpreoqrtueednftolyr trheepiorrrtemd aforkratbhleirbiroeamctairvkitaibelseinbcioluadctiinvgitiaenstiicnacnlucedrinegffeacntsti;ciannpcearrteicffuelcatrs,;triniteprapretnicouildara,ctirdiste, rspuecnhoaids oalceiadns,osliuccahciads o[3li]c, aasciiadti(cOaAci)d[3(A], Aas)ia(Fticguacreid1()A[4A,5)](aFnigdumrea1s)li[n4i,c5]acaindd(MmaAs)li[n6i,c7]a,chidav(eMrAec)e[i6v,e7d], ihnacvrearseecdeiavtetednitniocnre.ased attention.Figure 1
To protect the C-3 and C-23 hydroxyl groups, asiatic acid (AA) as the starting material was reacted with 2,2-dimethoxypropane to selectively form a six-membered ketal ring in the initial framework, affording crude product compound 1 in high yield
We reported a highly selective oxidation method on the C-23 hydroxyl group in an AA derivative, and for the first time with AA derivatives, the C-23 carboxyl group was modified to synthesize a series of novel AA derivatives

Summary

Introduction

NNaattuurraallpprroodduucctstsaraerea ma amjoarjosrousrocuerocef leoafdlecaodmcpoomunpdosufnodrsnfeowr tnheewraptheeurtaicpaeguetnictsa[g1e,2n]t.sIn[1r,2ec].enInt yrecaersn,ttryietearrpse, ntroiitdersp, aesnoindeso, fatshoenlaergoefstthcelalsasregseostf nclaatsusreasl porfondautcutrsa, lhpavroedbuecetns,frheaqvueenbtelyenrefpreoqrtueednftolyr trheepiorrrtemd aforkratbhleirbiroeamctairvkitaibelseinbcioluadctiinvgitiaenstiicnacnlucedrinegffeacntsti;ciannpcearrteicffuelcatrs,;triniteprapretnicouildara,ctirdiste, rspuecnhoaids oalceiadns,osliuccahciads (oOleAan) o[3li]c, aasciiadti(cOaAci)d[3(A], Aas)ia(Fticguacreid1()A[4A,5)](aFnigdumrea1s)li[n4i,c5]acaindd(MmaAs)li[n6i,c7]a,chidav(eMrAec)e[i6v,e7d], ihnacvrearseecdeiavtetednitniocnre.ased attention. Referring to other triterpenoid acids with a similar structure, an di-O-acetylated benzylamide maslinic acid derivative, named EM2 (Figure 1), exhibited rather low EC50 values (EC50 = 0.5 μM) against human ovarian cancer cells (A2780) [20,27] Another natural triterpenoid acid, gypsogenin (Figure 1), is extracted from Gypsophila [28], and contains a natural C-23 aldehyde group, which inhibited several cancer cell lines [29]. Heller et al conducted oxidation on the C-23 aldehyde group to synthesize 23-carboxyl and 23-methylester gypsogenin derivatives, which showed inhibition against several cancer cell lines [30]. A 23-oicacid-28amide gypsogenin derivative gave IC50 = 2.2 μM for HepG-2 cell line [31] Taking into account these good results, in this paper we introduced benzyl amine to form amide bonds at C-28, and conducted rather highly selective oxidation at the C-23 hydroxyl group to transform 23-hydroxy into aldehyde and further into carboxyl functionalities. According to the structure activity relationship (SAR) established on the cytotoxic activities against SKOV-3 and HCT-116 cells, the cytotoxic activities of four promising compounds were evaluated against additional cancer cell lines (MCF-7, A549, A2780, HepG2 and HL-60)

Chemistry

Materials

In-Vitro Cytotoxicity of Human Cancer Cell Lines

In-Vitro Cytotoxicity of Human Normal Cell Line

Conclusions