(+)-Dehydroabietylamine derivatives target triple-negative breast cancer

Ling, Taotao; Tran, My Kim; González, Miguel A.; Gautam, Lekh Nath S.; Connelly, Michele; Wood, Rachael K.; Fatima, Iram; Miranda-Carboni, Gustavo A.; Rivas, Fátima

doi:10.1016/j.ejmech.2015.07.034

Cited by 28 publications

(19 citation statements)

References 31 publications

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“…Recently, dehydroabietylamine (L 0 ), which is one of the most vital modified products of rosin, has attracted considerable attention due to the broad spectrum of biological properties (Singh et al, 2014;Lin et al, 2015;Auxiliadora et al, 2016;Bahekar et al, 2016;Fei et al, 2016;Liu et al, 2016;Wang et al, 2016;Huang et al, 2017;Liu et al, 2017). In general, a focus of research on dehydroabietylamine derivatives with their anticancer, antibacterial, antifungal, and cytotoxic activities has been paid their attention in forest chemistry too.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents

Zhao

Sun

et al. 2020

Drug Delivery

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Several dehydroabietylamine derivatives containing heterocyclic moieties such as thiophene and pyrazine ring were successfully synthesized. The antiproliferative activities of these thiophene-based Schiffbases, thiophene amides, and pyrazine amides were investigated in vitro against Hela (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver), and HUVEC (umbilical vein) cells by MTT assay. The toxicity of L 1 ÀL 10 (IC 50 ¼ 5.92À >100 lM) was lower than L 0 (1.27 lM) and DOX (4.40 lM) in every case. Compound L 1 had higher anti-HepG2 (0.66 lM), anti-MCF-7 (5.33 lM), and anti-A549 (2.11 lM) and compound L 3 had higher anti-HepG2 (1.63 lM) and anti-MCF-7 (2.65 lM) activities. Both of these compounds were recognized with high efficiency in apoptosis induction in HepG2 cells and intercalated binding modes with DNA. Moreover, with average IC 50 values of 0.66 and 5.98 lM, L 1 was nine times more effective at suppressing cultured HepG2 cells viability than normal cells (SI ¼ 9). The relative tumor proliferation rate (T/C) was 38.6%, the tumor inhibition rate was up to 61.2%, which indicated that L 1 had no significant toxicity but high anti-HepG2 activity in vivo. Thus, it may be a potential antiproliferation drug with nontoxic side effects.

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Section: Introductionmentioning

confidence: 99%

Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents

Zhao

Sun

et al. 2020

Drug Delivery

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“…Natural product sources continue to provide front-line pharmacotherapy for millions of people worldwide [ 33 ] and our group has previously leveraged this approach to identify natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells (i.e. abietanes) [ 9 ]. Several studies have documented the anti-cancer activity of Jatrophone (JA), a macrocyclic diterpene compound isolated from the Jatropha isabelli , on UT51 glioma cells, NCI-ADR/RES drug-resistant ovarian cancer cells and K562 myelogenous leukemia cell model, illustrating anti-proliferative properties [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…As part of our collaborative efforts to identify new chemical entities against cancer using a high throughput NP fractionation system for a Hit-to-Lead drug discovery platform, we conducted a phenotypic cell-based screen using a small library of natural product fractions and pure natural products (12K entities) using an established CellTiterGlo cell viability assay [ 9 , 10 ]. The library included fractions and pure natural products from terrestrial plants from the American continent with recorded ethnopharmacological properties [ 9 ]. Several hits were identified against leukemia cellular models and also against Raji Non-Hodgkin Lymphoma.…”

Section: Introductionmentioning

confidence: 99%

The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer

et al. 2017

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Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/β-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and β-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) β-catenin protein levels, but not total β-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/β-catenin signaling pathway.

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“…The bis(3‐azido propanamide) 2,6‐AQ derivative ( 2 ) was prepared similarly, as the 2,6‐diaminoanthraquinone was directly reacted with 3‐azidopropanoyl chloride prepared from 3‐bromopropanoic acid [22] . The amino acid or dipeptide propargylamide derivatives were obtained by liquid phase coupling procedures known in the literature from the mono‐ or di‐BOC‐protected amino acids glycine, phenylalanine, lysine and ornithine [23–26] . Eventually, the final compounds 3 – 9 were obtained through the CuAAC reaction between the central scaffolds and the side chains which was performed using a catalytic amount a pre‐formed Cu(I) catalyst, obtained by reduction in water of Cu(II)SO 4 with sodium ascorbate.…”

Section: Resultsmentioning

confidence: 99%

Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

et al. 2021

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Guanine‐rich sequences are known to fold into G‐quadruplex (G4) arrangements, which are present in oncogenes and in the telomeric regions of chromosomes. In particular, G4s represent an obstacle to functioning of telomerase, an enzyme overexpressed in cancer cells causing their immortalization. Therefore, G4 stabilization using small molecules represents an appealing strategy for the medicinal chemist. Ligands based on an anthraquinone scaffold, to which peptidic side chains were attached by an amide bond, were previously reported. We envisioned improving this ligand concept leveraging the click chemistry approach, which, besides representing a flexible, high yielding synthetic strategy, allows an elongation of the side chains and an increase of π–π stacking and H‐bond interactions with the nucleobases through the triazole ring. Compounds were tested for their ability to interact with G4 DNA with a multiple analytical approach, demonstrating an elevated aptitude to stabilize the G4 and high selectivity over double stranded DNA.

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(+)-Dehydroabietylamine derivatives target triple-negative breast cancer

Cited by 28 publications

References 31 publications

Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents

Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents

The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer

Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

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