scholarly journals Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

2018 ◽  
Author(s):  
Joanna Zawacka-Pankau ◽  
Vera V. Grinkevich ◽  
Mikhail Burmakin ◽  
Aparna Vema ◽  
Karin Fawkner ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Small Molecules ◽  
Anticancer Therapy ◽  
Mechanisms Of Action ◽  
Allosteric Modulation ◽  
Structural Element ◽  
Allosteric Mechanism ◽  
Anti Cancer ◽  
P53 Activation ◽  
Pharmacological Potential

AbstractGiven the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

scholarly journals Novel Allosteric Mechanism of P53 Activation by Small Molecules for Targeted Anticancer Therapy

2018 ◽  
Author(s):  
Joanna Zawacka-Pankau ◽  
Vera V. Grinkevich ◽  
Mikhail Burmakin ◽  
Aparna Vema ◽  
Karin Ridderstråle ◽  
...  
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
Allosteric Mechanism ◽  
P53 Activation

Anticancer Properties of Essential Oils: An Overview

2018 ◽  
Vol 18 (10) ◽  
pp. 957-966 ◽  
Author(s):  
Milene Aparecida Andrade ◽  
Mariana Aparecida Braga ◽  
Pedro Henrique Souza Cesar ◽  
Marcus Vinicius Cardoso Trento ◽  
Mariana Araújo Espósito ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Essential Oils ◽  
Public Health Problem ◽  
Mechanisms Of Action ◽  
Low Molecular Weight ◽  
Anticancer Properties ◽  
Anti Cancer ◽  
Different Types ◽  
Antitumor Properties ◽  
Pharmaceutical Properties

Background: Essential oils are complex mixtures of low molecular weight compounds extracted from plants. Their main constituents are terpenes and phenylpropanoids, which are responsible for their biological and pharmaceutical properties, such as insecticidal, parasiticidal, antimicrobial, antioxidant, anti-inflammatory, analgesic, antinociceptive, anticarcinogenic, and antitumor properties. Cancer is a complex genetic disease considered as a serious public health problem worldwide, accounting for more than 8 million deaths annually. Objective: The activities of prevention and treatment of different types of cancer and the medicinal potential of essential oils are addressed in this review. Conclusion: Several studies have demonstrated anti-carcinogenic and antitumor activity for many essential oils obtained from various plant species. They may be used as a substitution to or in addition to conventional anti-cancer therapy. Although many studies report possible mechanisms of action for essential oils compounds, more studies are necessary in order to apply them safely and appropriately in cancer therapy.

Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

2019 ◽  
Vol 16 (11) ◽  
pp. 1194-1201 ◽  
Author(s):  
Farhad Saravani ◽  
Ebrahim Saeedian Moghadam ◽  
Hafezeh Salehabadi ◽  
Seyednasser Ostad ◽  
Morteza Pirali Hamedani ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Cytotoxic Activity ◽  
Binding Site ◽  
Cell Line ◽  
Cell Lines ◽  
Tubulin Polymerization ◽  
Adenocarcinoma Cell Line ◽  
Adenocarcinoma Cell ◽  
Colchicine Binding Site ◽  
Anti Cancer

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

scholarly journals Minimal mechanistic component of proteasome activation and prevention of impairment by pathological oligomers

2021 ◽  
Author(s):  
Janelle Chuah ◽  
Tifffany Thibaudeau ◽  
David Smith
Keyword(s):  
Small Molecules ◽  
Conformational Changes ◽  
Bound State ◽  
Proof Of Concept ◽  
Α Subunit ◽  
Gate Opening ◽  
Allosteric Mechanism ◽  
Dependent Mechanism ◽  
Degradation Of Peptides

Abstract Impairment of proteasomal function has been implicated in neurodegenerative diseases, justifying the need to understand how the proteasome is activated for protein degradation. Here, using biochemical and structural (cryo-EM) strategies in both archaeal and mammalian proteasomes, we further determine the HbYX(-motif)-dependent mechanism of proteasomal activation used by multiple proteasome-activating complexes including the 19S Particle. We identify multiple proteasome α subunit residues involved in HbYX-dependent activation, a point mutation that activates the proteasome by partially mimicking a HbYX-bound state, and conformational changes involved in gate-opening with a 2.0A structure. Through an iterative process of peptide synthesis, we successfully design a HbYX-like dipeptide mimetic as a robust tool to elucidate how the motif autonomously activates the proteasome. The mimetic induces near complete gate-opening at saturating concentration, activating mammalian proteasomal degradation of peptides and proteins. Findings using our peptide mimetic suggest the HbYX-dependent mechanism requires cooperative binding in at least two intersubunit pockets of the α ring. Collectively, the results presented here unambiguously demonstrate the lone role of the HbYX tyrosine in the allosteric mechanism of proteasome activation and offer proof of concept for the robust potential of HbYX-like small molecules to activate the proteasome.

scholarly journals Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

2018 ◽  
Vol 1 (2) ◽  
pp. e00020 ◽  
Author(s):  
A.S. Latysheva ◽  
A.Yu. Misharin
Keyword(s):  
Synthetic Analogs ◽  
Anti Cancer ◽  
Novel Targets ◽  
Pharmacological Potential ◽  
Efficiency Data

This review deals with studies of researches of novel CYP17A1 steroidal inhibitors and relative compounds published over the last ten years. The review contains six chapters in which novel targets of well-known CYP17A1 inhibirors (abiraterone and galeterone), anti-cancer and anti-proliferative activities of them major metabolites and new synthetic analogs, and in addition another nitrogen-containing androstane and pregnane derivatives are considered. In the review 354 structures of novel steroid derivatives and them anti-cancer efficiency data are considered. Analysis of the literature data allows us to consider steroidal inhibitors of CYP17A1 as multi-target anti-cancer agents with high pharmacological potential.

Search for New Linear Musks Devoid of a 2,2-Dimethyl-1,4-dioxa­butane Unit: Synthesis and Olfactory Properties of 5-Substituted (3E)-Hex-3-enoates on the Way to Carba-Helvetolide and Carba-Serenolide

Synthesis ◽  
2017 ◽  
Vol 49 (11) ◽  
pp. 2443-2460 ◽  
Author(s):  
Kim Nguyen ◽  
Pascal Sutter ◽  
Philip Kraft
Keyword(s):  
Double Bond ◽  
Molecular Modeling ◽  
Malonic Acid ◽  
Crucial Role ◽  
Cost Driver ◽  
Receptor Interaction ◽  
Knoevenagel Reaction ◽  
Structural Element ◽  
Birch Reduction ◽  
Polar Interactions

Since the nucleophilic opening of isobutylene oxide competes with the formation of polyethers, the 2,2-dimethyl-1,4-dioxabutane moiety constitutes the most important cost driver in the synthesis of linear musks. Therefore, musk motifs devoid of this structural element would be highly attractive. Based on molecular modeling considerations, 5-methyl-substituted (3E)-configured alk-3-enoic esters accessible by deconjugative Knoevenagel reaction with malonic acid in the presence of piperidinium acetate with citronellal and Florhydral as substrates, were synthesized but showed disappointing olfactory properties, as did inverted ester motifs or dimethyl carbinols. Moving closer to carba-Serenolide structures, isobutyronitrile was added to m-isopropenylcumene. DIBAL-H with subsequent alanate reduction provided 4-(3-isopropylphenyl)-2,2-dimethylpentan-1-ol, which was either directly esterified, or esterified after Birch reduction and full hydrogenation. While these target structures were all odorless, (2E)-4-(3,3-dimethylcyclohexyl)pent-2-en-1-yl cyclopropanecarboxylate turned out to be a decent musk odorant (4.1 ng/L air). This proved the concept of an (E)-configured double bond in the middle of anticipated horseshoe-shaped conformers, but casted doubt on the non-importance of the ether oxygens in Helvetolide and Serenolide. Therefore, carba-Helvetolide and carba-Serenolide were synthesized from 3,3-dimethylcyclohexanone, and indeed turned out to be completely odorless. So polar interactions play a crucial role in the receptor interaction of these linear musks beyond merely favoring horseshoe-shaped conformers.

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