Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

Li, Feng; Yu, Shujia; Wang, Hai; Yang, Sheng-Wei; Li, Xue; Dai, Heping; Zhao, Liwen; Jiang, Cheng; Wang, Shaobin

doi:10.3390/molecules26113162

Cited by 9 publications

(2 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Table 2, most of the corresponding ( S )‐amines of 1‐indanone and their derivatives are potential active APIs in the treatment of various diseases, such as a broad range of cancers (MLN4924, ( S )‐ 2 o ), [26] obesity and type 2 diabetes (SR9230, ( S )‐ 2 p ), [27] advanced melanoma and bladder cancer (( S )‐ 2 e ), [28] prostate cancer (( S )‐ 2 h ), [29] CXCR3 disease (( S )‐ 2I ), [30] osteoarthritis (( S )‐ 2 g ), [31] Alzheimer's disease (AD) (( S )‐ 2 m ) [32] and autoimmune diseases (( S )‐ 2 k ) [33] (Scheme S2). Thus, to explore the substrate scope of the best design M9, a panel of 1‐indanone derivatives was investigated using purified M9 under IPA‐saturated conditions to determine TON.…”

Section: Resultsmentioning

confidence: 99%

Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps

Yang

Zhang

et al. 2022

Angewandte Chemie

View full text Add to dashboard Cite

ω‐Transaminases (ω‐TAs) show considerable potential for the synthesis of chiral amines. However, their low catalytic efficiency towards bulky substrates limits their application, and complicated catalytic mechanisms prevent precise enzyme design. Herein, we address this challenge using a mechanism‐guided computational enzyme design strategy by reprograming the transition and ground states in key reaction steps. The common features among the three high‐energy‐barrier steps responsible for the low catalytic efficiency were revealed using quantum mechanics (QM). Five key residues were simultaneously tailored to stabilize the rate‐limiting transition state with the aid of the Rosetta design. The 14 top‐ranked variants showed 16.9–143‐fold improved catalytic activity. The catalytic efficiency of the best variant, M9 (Q25F/M60W/W64F/I266A), was significantly increased, with a 1660‐fold increase in kcat/Km and a 1.5–26.8‐fold increase in turnover number (TON) towards various indanone derivatives.

show abstract

Section: Resultsmentioning

confidence: 99%

Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps

Yang

Zhang

et al. 2022

Angewandte Chemie

View full text Add to dashboard Cite

show abstract

“…The well‐established RT inhibitor, BFA, is known to have poor bioavailability in vivo, which has hindered its clinical use [187]. However, derivatives of BFA have shown anti‐cancer activity against a plethora of cancer types, with most recent work targeting cervical, breast and hepatocellular cancers, with improved bioavailability [188–192]. Other methods to circumvent this issue are centred on improvement to drug delivery, such as that by Zhang et al who are using nanomicelles to improve the delivery of BFA [193–196].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease

Bingham,

McCarthy,

Buckley

2024

Traffic

View full text Add to dashboard Cite

Retrograde trafficking (RT) orchestrates the intracellular movement of cargo from the plasma membrane, endosomes, Golgi or endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC) in an inward/ER‐directed manner. RT works as the opposing movement to anterograde trafficking (outward secretion), and the two work together to maintain cellular homeostasis. This is achieved through maintaining cell polarity, retrieving proteins responsible for anterograde trafficking and redirecting proteins that become mis‐localised. However, aberrant RT can alter the correct location of key proteins, and thus inhibit or indeed change their canonical function, potentially causing disease. This review highlights the recent advances in the understanding of how upregulation, downregulation or hijacking of RT impacts the localisation of key proteins in cancer and disease to drive progression. Cargoes impacted by aberrant RT are varied amongst maladies including neurodegenerative diseases, autoimmune diseases, bacterial and viral infections (including SARS‐CoV‐2), and cancer. As we explore the intricacies of RT, it becomes increasingly apparent that it holds significant potential as a target for future therapies to offer more effective interventions in a wide range of pathological conditions.

show abstract

Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps

Yang

Zhang

et al. 2022

Angew Chem Int Ed

View full text Add to dashboard Cite

ω-Transaminases (ω-TAs) show considerable potential for the synthesis of chiral amines. However, their low catalytic efficiency towards bulky substrates limits their application, and complicated catalytic mechanisms prevent precise enzyme design. Herein, we address this challenge using a mechanism-guided computational enzyme design strategy by reprograming the transition and ground states in key reaction steps. The common features among the three high-energy-barrier steps responsible for the low catalytic efficiency were revealed using quantum mechanics (QM). Five key residues were simultaneously tailored to stabilize the rate-limiting transition state with the aid of the Rosetta design. The 14 top-ranked variants showed 16.9-143fold improved catalytic activity. The catalytic efficiency of the best variant, M9 (Q25F/M60W/W64F/I266A), was significantly increased, with a 1660-fold increase in k cat / K m and a 1.5-26.8-fold increase in turnover number (TON) towards various indanone derivatives.

show abstract

Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

Cited by 9 publications

References 38 publications

Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps

Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps

Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease

Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps

Contact Info

Product

Resources

About