Lactone Analogues Research Articles

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

Identification of novel Nrf2-activating neuroprotective agents: Elucidation of structural congeners of (-)-galiellalactone and congener-based novel Nrf2 activators

Herein, (-)-galiellalactone 1 congeners responsible for the nuclear factor erythroid 2-related factor 2 (Nrf2)-activating neuroprotective effects were elucidated. Additionally, novel congener-based Nrf2 activators were identified using a drug repositioning strategy. (-)-Galiellalactone, which comprises a tricyclic lactone skeleton, significantly activates antioxidant response element (ARE)-mediated transcription in neuroblastoma SH-SY5Y cells. Interestingly, two cyclohexene-truncated [3.3] bicyclic lactone analogs, which possess an exocyclic α-methylene-γ-butyrolactone moiety, exhibited higher Nrf2/ARE transcriptional activities than the parent (-)-galiellalactone. We confirmed that the cyclohexene moiety embedding the [3.3] bicyclic lactone congener does not play the essential role of (-)-galiellalactone for Nrf2/ARE activation. Nrf2/ARE activation by novel analogs resulted in the upregulation of downstream antioxidative and phase II detoxifying enzymes, heme oxygenase-1, and NAD(P)H quinone oxidoreductase 1, which are closely related to the cytoprotective effects on neurodegenerative diseases. (-)-Galiellalactone and its [3.3] bicyclic variants 3l and 3p increased the expression of antioxidant genes and exhibited neuroprotective effects against 6-hydroxydopamine-mediated neurotoxicity in the neuroblastoma SH-SY5Y cell line.

Synthesis and biological evaluation of natural Lachnophyllum methyl ester, Lachnophyllum lactone and their synthetic analogs.

(2Z)-Lachnophyllum methyl ester and (4Z)-Lachnophyllum lactone were recently identified as major components in essential oils and extracts of Conyza bonariensis from Togo. Extended biological evaluation of these acetylenic compounds was however hampered by the reduced amounts isolated. A synthetic route was designed providing access to larger quantities of these two natural products as well as to original non-natural analogs with the prospect of exploring for the first time the structure-activity relationships in this series. Using LC/MS analysis, synthetic samples allowed confirming the presence of the two previously isolated natural products in plant extracts obtained by the accelerated solvent extraction technique. The nematocidal activity of the synthesized compounds confirmed the potency of the natural products, which remain the most active among all analogs tested. The synthesized compounds were also assessed against Leishmania infantum axenic amastigotes and the Mycobacterium tuberculosis H37Rv pathogenic strain. (2Z)-Lachnophyllum methyl ester, (4Z)-Lachnophyllum lactone and lactone analogs exhibited the strongest antileishmanial potency. As expected, a longer alkyl chain was necessary to observe significant antimycobacterial activity. The lactone analog bearing a C10 lipophilic appendage displayed the highest antimycobacterial potency. The notable activities of lactones, naturally occurring or analogs, either nematicidal, antileishmanial or antimycobacterial, were compared to their cytotoxicity for mammalian cells and revealed moderate selectivity index values. In this regard, the innocuous (2Z)-Lachnophyllum methyl ester and its analogs open up more promising perspectives for the discovery of bioactive agents to protect both agricultural crops and human health.

Degradable Linear and Bottlebrush Thioester-Functional Copolymers through Atom-Transfer Radical Ring-Opening Copolymerization of a Thionolactone

Polymers with tailored architectures and degradability were prepared through thiocarbonyl addition ring-opening (TARO) atom-transfer radical polymerization (ATRP) using dibenzo[c,e]oxepin-5(7H)-thione (DOT), Cu(I)Br, and tris[2-(dimethylamino)ethyl]amine (Me6TREN) as the thionolactone, catalyst, and ligand, respectively, in combination with a selection of acrylic comonomers. Although copolymers with selectively degradable backbone thioesters and low dispersities (1.10 ≤ D̵ ≤ 1.26) were achieved using DMSO, acetonitrile, or toluene as the solvent, the Cu(I)-catalyzed dethionation of DOT to its (oxo)lactone analogue limited the achievable copolymer DOT content. Using anhydrous polymerization conditions minimized the side reaction and provided degradable copolymers with a higher (≤32 mol %) thioester content. Water-soluble molecular brushes were prepared by grafting poly(ethylene glycol) methyl ether acrylate–DOT copolymers from a pre-made multi-ATRP initiator. Due to copolymerization kinetics, the thioesters were installed close to the junctions and enabled the fast (<1 min) cleavage of the arms from the core to give water-soluble products using 10 mM oxone.

Acyl Homoserine Lactone Analogs as Potential Inhibitors of Quorum Sensing

Gram negative bacteria are difficult to treat and are becoming increasingly resistant to conventional antibiotics. Pseudomonas aeruginosa is one such bacterium that causes opportunistic infections in hospital settings and has been recognized by the CDC and WHO as a looming threat to public health due to few treatment options and the rise of antibiotic resistance. A promising strategy to combat antibiotic resistance is to focus on virulence, rather than growth. In an antivirulence approach, the goal is to compromise the bacterium’s pathogenicity so that it is easier for the host’s immune system to clear the infection. Many Gram negative bacteria like P. aeruginosa and Chromobacterium violaceum use a LuxIR quorum sensing system to control virulence, where the LuxI synthase makes an acyl homoserine lactone signal that is detected by the LuxR transcriptional regulator, leading to the upregulation of virulence genes. One way to block virulence is to disrupt the production of the quorum sensing signaling molecules. In this study we have designed, synthesized and structurally characterized a series of potential small molecule inhibitors of the CviI synthase from C. violaceum as a model system for the more complex P. aeruginosa system. CviI converts a hexanoyl‐acyl carrier protein (hexanoyl‐ACP) and S‐adenosylmethionine (SAM) to a C6‐homoserine lactone (C6‐HSL). The potential inhibitors were designed to mimic the structural moieties of the acyl‐ACP starting material and the C6‐HSL product. The appropriate chain length should give specificity for the CviI synthase over other LuxI homologs. By varying the head group, the hope is to find an inhibitor that maximizes the affinity for the acyl‐ACP binding pocket, inhibiting the enzyme from making the C6‐HSL signal. An advantage of our methodology is that the synthesis only requires one step, which enables a quick production of a library to elucidate structure‐activity relationships. In future experiments, these compounds will be assayed in C. violaceum to determine if they possess anti‐quorum sensing and, specifically, anti‐CviI activity. The information gained could serve as a guide for future quorum sensing inhibitor development for P. aeruginosa and other Gram negative pathogens.

Antitumor properties of novel sesquiterpene lactone analogs as NFκB inhibitors that bind to the IKKβ ubiquitin-like domain (ULD).

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKβ subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and invitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k). Screening of these MMB carbamates identified analogs with potent growth inhibition properties against a panel of 60 human cancer cell lines (71% of the molecules screened had GI50 values<2μM). Two analogs, the benzyl carbamate 7b and the phenethyl carbamate7k, were the most active compounds. Lead compound 7b inhibited cell proliferation in M9 ENL AML cells, and in TMD-231, OV-MD-231 and SUM149 breast cancer cell lines. Interestingly, mechanistic studies showed that 7b did not inhibit p65 phosphorylation in M9 ENL AML and OV-MD-231cells, but did inhibit phophorylation of both p65 and IκBα in SUM149cells. 7b also reduced NFκB binding to DNA in both OV-MD-231 and SUM149cells. Molecular docking studies indicated that 7b and 7k are both predicted to interact with the ubiquitin-like domain (ULD) of the IKKβ subunit. These data suggest that in SUM149cells, 7b is likely acting as an allosteric inhibitor of IKKβ, whereas in M9 ENL AML and OV-MD-231cells 7b is able to inhibit an event after IκB/p65/p50 phosphorylation by IKKβ that leads to inhibition of NFκB activation and reduction in NFκB-DNA binding. Analog 7b was by far the most potent compound in either carbamate series, and was considered an important lead compound for further optimization and development as an anticancer agent.

Synthesis of new 1,4‐ and 1,5‐disubstituted N‐ethyl acetate and N‐α‐butyro‐γ‐lactone alkylimidazole derivatives as N‐acylhomoserine lactone analogs

AbstractNew alkylimidazoles functionalized with a homoserine lactone or an alkyloxycarbonyl moiety have been synthesized as N‐acylhomoserine lactones (AHLs) analogs. The 1,4‐disubstituted imidazole derivatives were prepared by alkylation of 4(5)‐alkylimidazoles with α‐bromo‐γ‐butyrolactone or ethyl α‐bromoacetate. An alternative route was preferred for the synthesis of their 1,5‐disubstituted counterparts based on the use of a N1‐protected alkylimidazole, its alkylation to an N3‐imidazolyl‐α‐acetate and deprotection to the desired 1,5‐disubstituted esters and subsequent alkylation of the acetate moiety with cyclic ethylene sulfate followed by acid‐catalyzed cyclization. The ability to modulate bacterial quorum sensing of all new compounds was compared to that of previously reported AHL analogs in which the amide bond is replaced by a heterocyclic group.

Heterocyclic Chemistry Applied to the Design of N-Acyl Homoserine Lactone Analogues as Bacterial Quorum Sensing Signals Mimics.

N-acyl homoserine lactones (AHLs) are small signaling molecules used by many Gram-negative bacteria for coordinating their behavior as a function of their population density. This process, based on the biosynthesis and the sensing of such molecular signals, and referred to as Quorum Sensing (QS), regulates various gene expressions, including growth, virulence, biofilms formation, and toxin production. Considering the role of QS in bacterial pathogenicity, its modulation appears as a possible complementary approach in antibacterial strategies. Analogues and mimics of AHLs are therefore biologically relevant targets, including several families in which heterocyclic chemistry provides a strategic contribution in the molecular design and the synthetic approach. AHLs consist of three main sections, the homoserine lactone ring, the central amide group, and the side chain, which can vary in length and level of oxygenation. The purpose of this review is to summarize the contribution of heterocyclic chemistry in the design of AHLs analogues, insisting on the way heterocyclic building blocks can serve as replacements of the lactone moiety, as a bioisostere for the amide group, or as an additional pattern appended to the side chain. A few non-AHL-related heterocyclic compounds with AHL-like QS activity are also mentioned.

Synthetic homoserine lactone analogues as antagonists of bacterial quorum sensing.

Quorum sensing (QS) is a density-dependent form of cell-cell communication that triggers the functional coordination of cooperative behaviors such as the production of virulence factors and biofilm formation. Quorum quenching (QQ) refers to all processes involved in the disruption of QS and is regarded as a promising strategy for treating bacterial infections. Herein, four compounds with closely related chemical structures to homoserine γ-lactone were synthesized and fully characterized. The compounds are termed TGK-series compounds. These compounds were subsequently tested in their QS inhibition activity using an E. coli Top 10 QS biosensor strain, a GFP QS reporter, that probes the capacity of bacteria to detect their cognate autoinducer N-(3-oxohexanoyl)-homoserine lactone (3OC6HSL) substrate by means of a single intracellular protein LuxR. All TGK-series compounds were found to significantly inhibit the ability of bacteria to produce GFP but without exerting toxicity when applied at a concentration of 50µM. In parallel, the interaction of TGK-series compounds with LuxR were studied by molecular docking simulations. These studies revealed that TGK-series compounds bound to the natural substrate N-(3-oxo-octanoyl)-l-homoserine lactone (OOHL) binding site and that the binding ability of the compounds with the TraR protein (a surrogate of LuxR) was even more favorable in comparison with the natural substrate. It was also uncovered that TGK-series compounds form stronger hydrophobic interactions with the TraR protein than 3OC6HSL does, thus providing a rationale for the enhancement of the QQ activity of the synthetic TGK-series compounds. This study will serve to guide future works aimed to design promising novel QS inhibitor candidates on a rational basis.

Synthesis and olfactory evaluation of optically active β-alkyl substituted γ-lactones and whiskey lactone analogues

Optically active β-alkyl substituted γ-lactones and whiskey lactone analogues were synthesized, and the odor properties were evaluated. During the preparation of the chiral intermediates, we found good reaction conditions for the highly enantioselective esterification of 3-arylmethyl-2-methyl-1-propanols to kinetically resolve them. The results of the olfactory evaluations of the synthesized lactones revealed that the alkyl groups on the γ-lactone rings played an important role for the odor profiles.

Synthesis and Biological Evaluation of Novel L-Homoserine Lactone Analogs as Quorum Sensing Inhibitors of Pseudomonas aeruginosa.

In this study, we synthesized four series of novel L-homoserine lactone analogs and evaluated their in vitro quorum sensing (QS) inhibitory activity against two biomonitor strains, Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Studies of the structure-activity relationships of the set of L-homoserine lactone analogs indicated that phenylurea-containing N-dithiocarbamated homoserine lactones are more potent than (Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone (C30), a positive control for biofilm formation. In particular, compared with C30, QS inhibitor 11f significantly reduced the production of virulence factors (pyocyanin, elastase and rhamnolipid), swarming motility, the formation of biofilm and the mRNA level of QS-related genes regulated by the QS system of PAO1. These results reveal 11f as a potential lead compound for developing novel antibacterial quorum sensing inhibitors.

Inhibition of melanin production by sesquiterpene lactones from Saussurea lappa and their analogues

This research is aimed towards the discovery of a novel skin whitening agent from sesquiterpene lactones. We screened nine sesquiterpene lactones from Saussurea lappa root extracts, costunolide (1), α-, β-, γ-cyclocostunolides (2, 3, 4), santamarine (5), reynosin (6), arbuscirin A (7), dehydrocostus lactone (8), and 11β, 13-dehydrocostus lactone (9), for their melanin inhibitory activity in B16 melanoma cells. This study was focused on the inhibition of the extracellular melanin content. The screening results revealed that only α-cyclocostunolide (2) showed notable inhibition of the melanin production, particularly the extracellular melanin content, with an IC50 value of 5.75 μM. In addition, structure-activity relationship (SAR) of 12 sesquiterpene lactone analogues with reference to their melanin inhibitory activity was also investigated. However, none of the analogues were found to show any significant melanin inhibitory activity. To the best of our knowledge the above study is the first SAR investigation involving the melanin inhibitory activity of sesquiterpene lactones. It established that eudesmanolide-type lactone having a double bond between C3 and C4 showed the most efficient melanin inhibition. Additionally, the presence of a hydroxyl, ketone or ester moiety as the C1-substituent markedly decreased the melanin inhibitory activity. Thus, these findings suggest that α-cyclocostunolide (2) might be useful in the therapy of skin disorders.

Optimization of P2Y12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties.

P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.

Synthesis of new chalcone-based homoserine lactones and their antiproliferative activity evaluation

Three series of new homoserine lactone analogs were efficiently synthesized starting from methionine and further evaluated for their antiproliferative activity against different cancer cell lines. Among these compounds, some of the chalcone containing compounds 6a-n showed acceptable antiproliferative activity against prostate cancer cells DU145 and PC-3 with the IC50 values less than 10 μM. Compounds 6c, 6e and 6h inhibited growth of DU145 and PC-3 cells at low micromolar levels with the IC50 values ranging from 3.0 to 5.0 μM, much more potent than natural OdDHL. Compound 6e concentration-dependently inhibited colony formation and cell migration of DU145 cells. A synergistic effect on the growth inhibition and the apoptosis of DU145 cells was observed when compound 6e was used in combination with TRAIL. OdDHL or 6e treatment concentration-dependently activated TRAIL death receptor DR5 which may account for the observed synergistic effect of 6e or OdDHL with TRAIL on the growth inhibition and cell apoptosis. Compound 6e also inhibited migration of DU145 cells in a time- and concentration-dependent manner. The data suggest that quorum sensing molecules OdDHL and 6e may improve the sensitivity of DU145 cells toward TRAIL via activating DR5, compound 6e may be used as a potential lead compound for developing new TRAIL receptor agonists.

A comparative study of non-native N-acyl l-homoserine lactone analogs in two Pseudomonas aeruginosa quorum sensing receptors that share a common native ligand yet inversely regulate virulence

Certain bacteria can coordinate group behaviors via a chemical communication system known as quorum sensing (QS). Gram-negative bacteria typically use N-acyl l-homoserine lactone (AHL) signals and their cognate intracellular LuxR-type receptors for QS. The opportunistic pathogen Pseudomonas aeruginosa has a relatively complex QS circuit in which two of its LuxR-type receptors, LasR and QscR, are activated by the same natural signal, N-(3-oxo)-dodecanoyl l-homoserine lactone. Intriguingly, once active, LasR activates virulence pathways in P. aeruginosa, while activated QscR can inactivate LasR and thus repress virulence. We have a limited understanding of the structural features of AHLs that engender either agonistic activity in both receptors or receptor-selective activity. Compounds with the latter activity profile could prove especially useful tools to tease out the roles of these two receptors in virulence regulation. A small collection of AHL analogs was assembled and screened in cell-based reporter assays for activity in both LasR and QscR. We identified several structural motifs that bias ligand activation towards each of the two receptors. These findings will inform the development of new synthetic ligands for LasR and QscR with improved potencies and selectivities.

Arylnaphthalene lactone analogues: synthesis and development as excellent biological candidates for future drug discovery.

Arylnaphthalene lactones are natural products extracted from a wide range of different parts of plants. The progressing interest in the synthesis of these compounds is due to their significant biological activities, which have made them potential candidates in drug discovery and development. This review mainly covers recent developments in the synthesis and biological applications of arylnaphthalene lactone analogs.

Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death.

Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC50) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells. Intriguingly, the effects of both compounds were blockaded by pretreatment with ROS scavengers, N-acetylcysteine and reduced glutathione, and protein synthesis inhibitor, cycloheximide. Further, knockdown of MEK upstream regulator RAF1 and autophagosomal marker LC3, and co-treatment with JNK or ERK1/2 inhibitor resulted in the most significant attenuation of DETD-35-induced morphological and molecular or biochemical changes in cancer cells, while the inhibitory effect of DET was not influenced by MAPK inhibitor treatment. Therefore, DETD-35 exerted both ER stress-mediated paraptosis and apoptosis, which may explain its superior activity to DET against TNBC cells. Although the chemotherapeutic drug paclitaxel induced vacuole-like structures in MDA-MB-231 cells, no paraptotic cell death features were detected. This study provides a strategy for combating TNBC through sesquiterpene lactone analogs by induction of oxidative and ER stresses that cause paraptosis-like cell death.

Strain identification and quorum sensing inhibition characterization of marine-derived Rhizobium sp. NAO1.

A novel strategy for combating pathogens is through the ongoing development and use of anti-quorum sensing (QS) treatments such as therapeutic bacteria or their anti-QS substances. Relatively little is known about the bacteria that inhabit the open ocean and of their potential anti-pathogenic attributes; thus, in an initiative to identify these types of therapeutic bacteria, planktonic microbes from the North Atlantic Ocean were collected, isolated, cultured and screened for anti-QS activity. Screening analysis identified one such strain, Rhizobium sp. NAO1. Extracts of Rhizobium sp. NAO1 were identified via ultra-performance liquid chromatography (UPLC) analysis. They were shown to contain N-acyl homoserine lactone (AHL)-based QS analogues (in particular, the N-butyryl homoserine lactone (C4-AHL) analogue) and could disrupt biofilm formation by Pseudomonas aeruginosa PAO1. QS inhibition was confirmed using confocal scanning laser microscopy and growth curves, and it was shown to occur in a dose-dependent manner without affecting bacterial growth. Secondary metabolites of Rhizobium sp. NAO1 inhibited PAO1 pathogenicity by downregulating AHL-mediated virulence factors such as elastase activity and siderophore production. Furthermore, as a result of biofilm structure damage, the secondary metabolite products of Rhizobium sp. NAO1 significantly increased the sensitivity of PAO1 to aminoglycoside antibiotics. Our results demonstrated that Rhizobium sp. strain NAO1 has the ability to disrupt P. aeruginosa PAO1 biofilm architecture, in addition to attenuating P. aeruginosa PAO1 virulence factor production and pathogenicity. Therefore, the newly identified ocean-derived Rhizobium sp. NAO1 has the potential to serve as a QS inhibitor and may be a new microbial resource for drug development.

Pd-Catalyzed Site-Selective Mono-allylic Substitution and Bis-arylation by Directed Allylic C-H Activation: Synthesis of anti-γ-(Aryl,Styryl)-β-hydroxy Acids and Highly Substituted Tetrahydrofurans.

An efficient palladium-catalyzed site-selective arylation of γ-vinyl-γ-lactone by aryl boronic acid has been developed. γ-Vinyl-γ-lactone 1a has been contemplated as allyl electrophile donor for allylic arylation via π-allyl palladium intermediate using 1.5 equiv of aryl boronic acid 2. Using 3.0 equiv of the latter resulted in mono-arylation by allylic substitution and subsequent site-selective second arylation by directed allylic C-H activation giving stereoselectively anti-γ-(aryl,styryl)-β-hydroxy acids. Presence of O2 was crucial for the second arylation via Pd(II) catalysis. Thus, a good synergy of dual catalysis by Pd(0) and Pd(II) was observed. This methodology has been elaborated to synthesize highly substituted tetrahydrofurans including aryl-Hagen's gland lactone analogues via intramolecular iodoetherification.

Novel sesquiterpene lactone analogues as potent anti-breast cancer agents

Triple-negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti-TNBC agent has been a challenge in oncology. In this study, fifty-eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD-35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA-MB-231, without inhibiting normal mammary cells M10. DETD-35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA-MB-231 cells in a concentration-dependent manner. Comparative study of DETD-35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time-dependent G2/M cell-cycle arrest, while DETD-35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD-35 was evaluated using a lung metastatic MDA-MB-231 xenograft mouse model. DETD-35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX-2 in SCID mice. DETD-35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD-35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.