Structural Development of Benzhydrol-Type 1'-Acetoxychavicol Acetate (ACA) Analogs as Human Leukemia Cell-Growth Inhibitors Based on Quantitative Structure-Activity Relationship (QSAR) Analysis

Abstract

1Ј-Acetoxychavicol acetate (ACA: 1, Fig. 1) was first isolated from the rhizomes and seeds of Zingiberaceae plants, including Languas garanga and Alpinia garanga, which have been used as a ginger substitute and a stomach medicine in Southeast Asia.1) Recent studies have revealed that ACA (1) exhibits antitumor activities against a wide variety of cancers [2][3][4][5][6] and anti-tumor-promoting activities towards estrogen-related endometrial carcinogenesis, 4) azoxymethaneinduced colonic aberrant crypt foci, 5) phorbol ester-induced skin tumor promotion. 6) Moreover, ACA (1) has been reported to elicit a variety of biological activities, including antioxidant, anti-inflammatory, and anti-human immunodeficiency virus (HIV) activity, 7-9) induction of nitric oxide (NO) synthase gene expression, 8) and inhibition of interferon-b production. 10) We (Kizaki's group) have recently reported that ACA (1) induces the apoptosis of myeloid leukemia cells in vitro and in vivo through inhibition of NFkB-related functions, 11,12) suggesting ACA (1) is a candidate therapeutic agent for the treatment of myeloid leukemia. ACA (1) induces cell apoptosis through two different pathways in myeloid leukemia cells, i.e., through generation of reactive oxygen species (ROS) and through activation of the Fas-pathway.11) ACA (1) also inhibited the cellular growth of myeloma cells in association with the down-regulation of NF-kB activity, affecting both the caspase 8 and 9 pathways. 13)Azuma et al. recently reported structure-activity relationship studies of ACA (1) for apoptotic activity towards human leukemia HL-60 cells, 14) showing that (i) the two acetyl groups and the unsaturated double bond between the Cb and Cg positions of ACA (1) are essential for the activity, and (ii) the configuration at the a-position of ACA (1) does not affect the activity. Based on these results, we synthesized several ACA (1) analogs and examined their cell-growth-inhibitory activity using human leukemia HL-60 cells. Compound 2 (Fig. 1), a benzhydrol diacetate derivative, possessed moderate HL-60 cell-growth-inhibitory activity with an IC 50 value of 3.5 mM, i.e., it is slightly less potent than ACA (1, IC 50 ϭ2.0 mM). This led us to plan detailed structure-activity relationship studies of benzhydrol analogs developed from 2 as a lead compound.Here we describe structural development of benzhydroltype potent HL-60 cell-growth inhibitors, guided by quantitative structure-activity relationship (QSAR) analysis.Chemistry The synthesis of compound 2 and its analogs is outlined in Charts 1-3. Briefly, the hydroxyl group of 4-hydroxybenzaldehyde (9) was protected with tert-butyldimethylchlorosilane (TBS-Cl), followed by treatment with appropriate Grignard or aryllithium reagents (generated from aryl bromide by treatment with n-butyllithium) to afford the intermediates 11a-d. Deprotection of the TBS group was performed with tetra-n-butylammonium fluoride (TBAF), and then acetylation with acetic anhydride afforded 3a-d. On the other hand, protection of the hydroxyl ...

TM‐233, a novel analog of 1′‐acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities

“…a, lower panel) is a novel benzhydrol‐type analog of ACA (1′‐acetoxychavicol acetate) (Fig. a, upper panel), which we had previously developed and which was dissolved in DMSO at a stock concentration of 10 mM. Interleukin‐6 (IL‐6) was purchased from Wako Pure Chemical Industries (Osaka, Japan).…”

“…With the aim of discovering more potent NF‐κB inhibitors, we subsequently developed several ACA analogs based on quantitative structure–activity relationship (QSAR) analysis. We and other groups have reported QSAR studies of ACA for apoptotic activity towards human leukemia HL‐60 cells, showing that the two acetyl groups and the unsaturated double bond between the Cβ and Cγ positions of ACA are essential for its activity, and synthesized novel constructs that differ at the Cβ and Cγ positions of ACA . TM‐233 is a novel benzhydrol‐type analog of ACA that exhibits greater growth inhibition of HL‐60 leukemia cells.…”

Structure–activity relationships of benzhydrol derivatives based on 1′-acetoxychavicol acetate (ACA) and their inhibitory activities on multiple myeloma cell growth via inactivation of the NF-κB pathway

“…The inhibitory activity of compound 18, which had a 9-anthracenyl group instead of a phenyl (B) ring, was the most potent (IC 50 = 0.12 lM). 17 …”

“…According to the same method used for reduction of carbonyl group of 4, starting from 6 (1.56 g, 5.01 mmol) which was prepared as previously reported, 17 7 (1.38 g, 87%) was obtained as colorless oil. 1 …”

“…We previously demonstrated that ACA derivative 1 consisted of a benzhydrol skeleton and retained moderate HL-60 cell-growth-inhibitory activity with an IC 50 value of 3.5 lM. 17 We also performed a quantitative SAR analysis on benzhydrol derivatives, and revealed that the enantiomers of ACA derivatives showed the same cell-growth-inhibitory activity toward HL-60 cells, and the introduction of bulky and hydrophobic groups to the phenyl (B) ring enhanced its inhibitory effects on the growth of HL-60 cells. However, it currently remains unclear whether ACA derivatives suppress the growth of myeloid leukemia cells by inhibiting the NF-jB pathway.…”