Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

Wang, Ruxuan; Zhang, Rentao; Yang, Haoran; Xue, Nina; Chen, Xiaoguang; Yu, Xiaoming

doi:10.1016/j.cclet.2022.05.043

Cited by 5 publications

(3 citation statements)

References 22 publications

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“…The

worth, which represents the composite focus causing a 50% decrease in cellular feasibility, was resolute using Eq. 2 ( Mohamadi et al, 2017 ; Wang et al, 2020 ; Wang R et al, 2023 ; Wang Y et al, 2023 ; Xu et al, 2023 ):

…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: In vitro BSA-binding, antimicrobial, and antitumor activity against human cancer cell lines of two lanthanide (III) complexes

et al. 2023

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The investigation involved examining the binding of two lanthanide complexes, specifically those containing Holmium (Ho) and Dysprosium (Dy), with a ligand called 1, 10-phenanthroline (phen), and bovine serum albumin (BSA). The evaluation was carried out utilizing fluorescence measurements, Förster theory, and docking studies. The findings indicated that both the Ho-complex and Dy-complex possessed a significant ability to quench the emission of the protein. Furthermore, the primary mechanism of interaction was identified as a static process. The Kb values indicate a strong tendency of these complexes for binding with BSA. The Kb values show the strangely high affinity of BSA to complexes and the following order for binding affinity: Ho-complex > Dy-complex. The thermodynamic parameters were found to be negative, affirming that the main forces driving the interaction between BSA and the lanthanide complexes are van der Waals engagement and hydrogen bonds. Additionally, the investigation included the examination of competition site markers, and molecular docking proposed that the engagement sites of the Ho-complex and Dy-complex with BSA were predominantly located in site 3 (specifically, subdomain IB). Moreover, the Ho-complex and Dy-complex were specifically chosen for their potential anticancer and antimicrobial properties. Consequently, these complexes could present promising prospects as novel candidates for anti-tumor and antibacterial applications.

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“…The

…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: In vitro BSA-binding, antimicrobial, and antitumor activity against human cancer cell lines of two lanthanide (III) complexes

et al. 2023

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“…As an excellent PTA in this nano-system, aza-BODIPY displays strong NIR absorbance and near-infrared second window (NIR II) emission, which enables it to have a high photothermal conversion in PTT (as shown in Scheme 1 b) [ 48 , 49 , 50 , 51 , 52 ]. In addition, geldanamycin can specifically bind to the HSP90 through the amine group to inhibit the overexpression of the protein and improve the heat sensitivity of cancer cells [ 40 , 53 , 54 , 55 ]. Additionally, the anticancer process of BDPII-gel@TSL NPs was turned on through the irradiation of 808 nm with a low power density (0.5 W cm −2 ), where the photothermal effect of BDPII in NPs was excited to generate a mild temperature (42 °C) and induce a phase transition of TSL to positive release the geldanamycin and BDPII, activating the chemo–photothermal dual synergistic therapy.…”

Section: Introductionmentioning

confidence: 99%

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells

Peng,

Jiang,

et al. 2023

Pharmaceutics

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Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but often suffers from unsatisfactory efficacy in view of the occurrence of drug resistance, suboptimal drug delivery and release profile. As a result, the combinatory of chemotherapy and mild PTT would integrate their advantages and overcome the shortcomings. Herein, we synthesized an NIR-activatable and mild-temperature-sensitive nanoplatform (BDPII-gel@TSL) composed of temperature-sensitive liposomes (TSL), heat shock protein 90 (HSP90) inhibitor (geldanamycin) and photothermal agent (BDPII), for dual chemotherapy and mild PTT in cancer cells. BDPII, constructed with donor-acceptor moieties, acts as an excellent near-infrared (NIR) photothermal agent (PTA) with a high photothermal conversion efficiency (80.75%). BDPII-containing TSLs efficiently produce a mild hyperthermia effect (42 °C) under laser irradiation (808 nm, 0.5 W cm−2). Importantly, the phase transformation of TSL leads to burst release of geldanamycin from BDPII-gel@TSL, and this contributes to down-regulation of the overexpression of HSP90, ensuring efficient inhibition of cancer cell growth. This research provides a dual-sensitive synergistic therapeutic strategy for cancer cell treatment.

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“…Initially, considering Hsp90 as a potential therapeutic target was challenging due to its essential role in the cytoplasm for normal cell viability and growth [14]. However, the discovery of geldanamycin (GA) and its powerful anticancer effects through Hsp90 inhibition [15,16] generated considerable interest and research in this area. As a result, a wide range of Hsp90 inhibitors have been identified and synthesized; it has been documented that benzoquinone ansamycins, a category of naturally derived antibiotics, exhibit inhibitory effects on the functioning of Hsp90 [17].…”

Section: Introductionmentioning

confidence: 99%

Marine-Derived Compounds as Potential Inhibitors of Hsp90 for Anticancer and Antimicrobial Drug Development: A Comprehensive In Silico Study

Ouassaf,

Bourougaa,

Al-Mijalli

et al. 2023

Molecules

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Marine compounds constitute a diverse and invaluable resource for the discovery of bioactive substances with promising applications in the pharmaceutical development of anti-inflammatory and antibacterial agents. In this study, a comprehensive methodology was employed, encompassing pharmacophore modeling, virtual screening, in silico ADMET assessment (encompassing aspects of absorption, distribution, metabolism, excretion, and toxicity), and molecular dynamics simulations. These methods were applied to identify new inhibitors targeting the Hsp90 protein (heat shock protein 90), commencing with a diverse assembly of compounds sourced from marine origins. During the virtual screening phase, an extensive exploration was conducted on a dataset comprising 31,488 compounds sourced from the CMNPD database, characterized by a wide array of molecular structures. The principal objective was the development of structure-based pharmacophore models, a valuable approach when the pool of known ligands is limited. The pharmacophore model DDRRR was successfully constructed within the active sites of the Hsp90 crystal structure. Subsequent docking studies led to the identification of six compounds (CMNPD 22591, 9335, 10015, 360799, 15115, and 20988) demonstrating substantial binding affinities, each with values below −8.3 kcal/mol. In the realm of in silico ADMET predictions, five of these compounds exhibited favorable pharmacokinetic properties. Furthermore, molecular dynamics simulations and total binding energy calculations using MM-PBSA indicated that these marine-derived compounds formed exceptionally stable complexes with the Hsp90 receptor over a 100-nanosecond simulation period. These findings underscore the considerable potential of these novel marine compounds as promising candidates for anticancer and antimicrobial drug development.

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Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

Cited by 5 publications

References 22 publications

RETRACTED: In vitro BSA-binding, antimicrobial, and antitumor activity against human cancer cell lines of two lanthanide (III) complexes

RETRACTED: In vitro BSA-binding, antimicrobial, and antitumor activity against human cancer cell lines of two lanthanide (III) complexes

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells

Marine-Derived Compounds as Potential Inhibitors of Hsp90 for Anticancer and Antimicrobial Drug Development: A Comprehensive In Silico Study

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