Substitution of a triazole for the central olefin in biologically active stilbenes

Stockdale, David P.; Beutler, John A.; Wiemer, David F.

doi:10.1016/j.bmcl.2022.128980

Cited by 3 publications

(7 citation statements)

References 35 publications

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“…159 Substitution of the alkene bond with 1,2,3-triazole or amide bonds has yielded analogues with good biological activities. 152,160,161 Among these, compounds 21b and 21a exhibit comparable biological activity against the glioblastoma-derived cell line SF295 (Figure 30B). 152 6.3.…”

Section: Triazoles and Bioisosterismmentioning

confidence: 97%

“…While this structure renders triazoles similar to olefins in certain aspects, their electronic structure and properties deviate significantly from typical olefins. 152,153 Microtubules, composed of αand β-tubulin heterodimers, have been identified as particularly promising targets for discovering anticancer agents, playing pivotal roles in cell shape maintenance, motility, and chromosome segregation. 154 Despite the clinical success of microtubule-targeting agents (MTAs), the emergence of resistance to MTAs has triggered a need for novel compounds with alternative mechanisms of action and improved chemical properties.…”

Section: Triazoles and Bioisosterismmentioning

confidence: 99%

“…Similarly, triazoles, composed of three nitrogen atoms, establish a π electron system within the ring, often termed a “cyclic olefin”. While this structure renders triazoles similar to olefins in certain aspects, their electronic structure and properties deviate significantly from typical olefins. , …”

Section: Triazoles and Bioisosterismmentioning

confidence: 99%

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Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

Guan,

Xing,

Wang

et al. 2024

J. Med. Chem.

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Triazole demonstrates distinctive physicochemical properties, characterized by weak basicity, various dipole moments, and significant dual hydrogen bond acceptor and donor capabilities. These features are poised to play a pivotal role in drug−target interactions. The inherent polarity of triazole contributes to its lower logP, suggesting the potential improvement in water solubility. The metabolic stability of triazole adds additional value to drug discovery. Moreover, the metal-binding capacity of the nitrogen atom lone pair electrons of triazole has broad applications in the development of metal chelators and antifungal agents. This Perspective aims to underscore the unique physicochemical attributes of triazole and its application. A comparative analysis involving triazole isomers and other heterocycles provides guiding insights for the subsequent design of triazoles, with the hope of offering valuable considerations for designing other heterocycles in medicinal chemistry. ■ SIGNIFICANCE AND IMPACT• Significance: Triazole rings, including 1,2,3-triazole and 1,2,4-triazole, are pivotal in drug design due to their unique physicochemical properties, serving as versatile alternatives to various aromatic rings and functional groups.• Impact: It emphasizes the influence of the physicochemical properties of triazoles while providing comparative data with other frequently employed pharmacophores in medicinal chemistry. • Innovation: This Perspective discusses the influence of diverse physicochemical properties of triazoles and their strategic application in drug design.

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Section: Triazoles and Bioisosterismmentioning

confidence: 97%

Section: Triazoles and Bioisosterismmentioning

confidence: 99%

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Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

Guan,

Xing,

Wang

et al. 2024

J. Med. Chem.

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“…Nevertheless, several analogs were developed by this approach to establish structure–activity relationships. These SARs were all based on the cytotoxicity of these compounds either on the 60 cell-lines assay of the NCI or on a more straightforward two-cell assay (one cell line sensitive to the SWs, another more resistant). , Both strategies have shown that the HHX moiety, one phenol on the D-ring, and the trans -stilbene motif are mandatory to keep the cytotoxic profile of SWs even if the latter can, to some extent, be replaced by an amide or triazole ring . On the contrary, some portions of the molecule are tolerant to modifications (the prenyl chain and one phenol on the D-ring, for example).…”

Section: Introductionmentioning

confidence: 99%

“…20,21 Both strategies have shown that the HHX moiety, one phenol on the D-ring, and the trans-stilbene motif are mandatory to keep the cytotoxic profile of SWs even if the latter can, to some extent, be replaced by an amide 22 or triazole ring. 23 On the contrary, some portions of the molecule are tolerant to modifications (the prenyl chain and one phenol on the D-ring, for example).…”

Section: ■ Introductionmentioning

confidence: 99%

Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein

Jézéquel,

Rampal,

Guimard

et al. 2023

J. Med. Chem.

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Schweinfurthins (SWs) are naturally occurring prenylated stilbenes with promising anticancer properties. They act through a novel mechanism of action similar to that of other families of natural compounds. Their known target, oxysterolbinding protein (OSBP), plays a crucial role in controlling the intracellular distribution of cholesterol. We synthesized 15 analogues of SWs and demonstrated for the first time that their cytotoxicity as well as that of natural derivatives correlates with their affinity for OSBP. Through this extensive SAR study, we selected one synthetic analogue obtained in one step from SW-G. Using its fluorescence properties, we showed that this compound recapitulates the effect of natural SW-G in cells and confirmed that it leads to cell death via the same mechanism. Finally, after pilot PK experiments, we provided the first evidence of its in vivo efficacy in combination with temozolomide in a patient-derived glioblastoma xenograft model.

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Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[b,f]oxepine Derivatives

et al. 2023

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Cancer is one of the most common causes of human death worldwide; thus, numerous therapies, including chemotherapy, have been and are being continuously developed. In cancer cells, an aberrant mitotic spindle—a microtubule-based structure necessary for the equal splitting of genetic material between daughter cells—leads to genetic instability, one of the hallmarks of cancer. Thus, the building block of microtubules, tubulin, which is a heterodimer formed from α- and β-tubulin proteins, is a useful target in anti-cancer research. The surface of tubulin forms several pockets, i.e., sites that can bind factors that affect microtubules’ stability. Colchicine pockets accommodate agents that induce microtubule depolymerization and, in contrast to factors that bind to other tubulin pockets, overcome multi-drug resistance. Therefore, colchicine-pocket-binding agents are of interest as anti-cancer drugs. Among the various colchicine-site-binding compounds, stilbenoids and their derivatives have been extensively studied. Herein, we report systematic studies on the antiproliferative activity of selected stilbenes and oxepine derivatives against two cancer cell lines—HCT116 and MCF-7—and two normal cell lines—HEK293 and HDF-A. The results of molecular modeling, antiproliferative activity, and immunofluorescence analyses revealed that compounds 1a, 1c, 1d, 1i, 2i, 2j, and 3h were the most cytotoxic and acted by interacting with tubulin heterodimers, leading to the disruption of the microtubular cytoskeleton.

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Substitution of a triazole for the central olefin in biologically active stilbenes

Cited by 3 publications

References 35 publications

Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein

Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[b,f]oxepine Derivatives

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