Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer

Salvino, Joseph M.; Srikanth, Yellamelli V.V.; Lou, Rongliang; Oyer, Halley M.; Chen, Nan; Kim, Felix J.

doi:10.1016/j.bmcl.2017.03.030

Cited by 4 publications

(3 citation statements)

References 29 publications

(34 reference statements)

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“…A aplicação da radiação de micro-ondas em reações orgânicas apresenta destaque na literatura, visto que seu uso em sínteses orgânicas demostra que em uma menor quantidade de tempo, com presença ou ausência de solventes, é possível melhorar rendimentos e até mesmo realizar sínteses que antes não eram possíveis. 40,41 Com esse enfoque, melhor rendimento, menor tempo reacional e, principalmente o respeito ao sexto protocolo da química verde: Eficiência energética, esta proposta metodológica foi desenvolvida em reator de micro-ondas, sem agentes tiofílicos, sem solventes, sem refluxo, com este objetivo.…”

Section: Metodologia C -Reação De Guanilação Da Tioureia 8 Sem Agente...unclassified

Uso De Reator De Micro-Ondas Para Guanilação De Tioureias

Andrade,

dos Santos,

Barbosa

et al. 2024

Química Orgânica: Conceitos, Fundamentos E Avanços

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Com o crescimento abrangente de novos fármacos, os compostos nitrogenados que possuem grupos funcionais guanidínicos, ocupam bastante espaço devido ao seu amplo espectro de atividades biológicas e farmacológicas. Em nosso grupo de pesquisa (LaBSIMCO), a aplicação de tioureias para à síntese de guanidinas e seus derivados sintéticos, é um dos alvos que norteiam nossas pesquisas científicas. Neste contexto, a síntese de guanidinas funcionalizadas, apesar de bastante descrita na literatura, objetivou este trabalho, a partir do estudo e aplicação de nova metodologia sintética com vislumbre para o desenvolvimento de reações “mais limpas” e que direcionassem para a aplicação da química verde. Principalmente, por não empregar agentes tiofílicos (que em sua grande maioria são metais com alto grau de toxicidade), como são descritos na literatura, para a obtenção de guanidinas. Nesta nova proposta de metodologia empregou-se o iodo molecular com agente tiofílico por apresentar baixa toxicidade e a água como solvente sem o uso de metal. Os produtos obtidos foram caracterizados por análise espectroscópica de Ressonância Magnética Nuclear (RMN) de Hidrogênio 1H e Carbono 13C (uni e bidimensionais). As reações na qual foram empregadas o iodo foram promovidas sob refluxo a 80ºC e a reação com a água em banho ultrassônico por 48 horas, onde a reação utilizou iodo molecular como agente de dessulfurização apresentou um rendimento de 20,88% e com a água 23,36%. Este trabalho teve como objetivo, aplicar duas novas metodologias de síntese para o desenvolvimento desta substancia voltada a química verde. Porém com os resultados obtidos, constatou-se que a metodologia com iodo molecular como agente guanilante, sem a presença de metais pesados, apresentou maior rendimento, mas que as reações ainda necessitam de algumas adaptações para obter melhores rendimentos.

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Section: Metodologia C -Reação De Guanilação Da Tioureia 8 Sem Agente...unclassified

Uso De Reator De Micro-Ondas Para Guanilação De Tioureias

Andrade,

dos Santos,

Barbosa

et al. 2024

Química Orgânica: Conceitos, Fundamentos E Avanços

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“…The active site of these target proteins comprises one or more acidic amino acids. Recent studies have shown that guanidine-based drugs specifically bind to acidic residues present at the active site of an enzyme via hydrogen-bond interactions. − Crystal structures of the avian flu neuraminidase inhibitor zanamivir show the inhibitor molecule bridging the active site residues Asp152 and Glu229 . Understanding the pH-dependent binding of guanidine-based drug molecules to proteins can aid in designing better drugs.…”

Section: Introductionmentioning

confidence: 99%

pH Regulates Ligand Binding to an Enzyme Active Site by Modulating Intermediate Populations

et al. 2022

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Understanding the mechanism of ligands binding to their protein targets and the influence of various factors governing the binding thermodynamics is essential for rational drug design. The solution pH is one of the critical factors that can influence ligand binding to a protein cavity, especially in enzymes whose function is sensitive to the pH. Using computer simulations, we studied the pH effect on the binding of a guanidinium ion (Gdm+) to the active site of hen egg-white lysozyme (HEWL). HEWL serves as a model system for enzymes with two acidic residues in the active site and ligands with Gdm+ moieties, which can bind to the active sites of such enzymes and are present in several approved drugs treating various disorders. The computed free energy surface (FES) shows that Gdm+ binds to the HEWL active site using two dominant binding pathways populating multiple intermediates. We show that the residues close to the active site that can anchor the ligand could play a critical role in ligand binding. Using a Markov state model, we quantified the lifetimes and kinetic pathways connecting the different states in the FES. The protonation and deprotonation of the acidic residues in the active site in response to the pH change strongly influence the Gdm+ binding. There is a sharp jump in the ligand-binding rate constant when the pH approaches the largest pK a of the acidic residue present in the active site. The simulations reveal that, at most, three Gdm+ can bind at the active site, with the Gdm+ bound in the cavity of the active site acting as a scaffold for the other two Gdm+ ions binding. These results can aid in providing greater insights into designing novel molecules containing Gdm+ moieties that can have high binding affinities to inhibit the function of enzymes with acidic residues in their active site.

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“…Recent studies have shown that guanidine-based drugs specifically bind to acidic residues present at the active site of an enzyme via hydrogen-bonded interactions. 40–42 Crystal structures of the avian flu neuraminidase inhibitor zanamivir show the inhibitor molecule bridging the active site residues Asp152 and Glu229. 43…”

Section: Introductionmentioning

confidence: 99%

pH Effect on Ligand Binding to an Enzyme Active Site

Singh

Muttathukattil

Singh

et al. 2022

Preprint

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Understanding the mechanism of ligands binding to their protein targets and the influence of various factors governing the binding thermodynamics is essential for rational drug design. The solution pH is one of the critical factors that can influence ligand binding to a protein cavity, especially in enzymes whose function is sensitive to the pH. Using computer simulations, we studied the pH effect on the binding of a guanidinium ion (Gdm+) to the active site of hen-egg white lysozyme (HEWL). HEWL serves as a model system for enzymes with two acidic residues in the active site and ligands with Gdm+ moieties, which can bind to the active sites of such enzymes and are present in several approved drugs treating various disorders. The computed free energy surface (FES) shows that Gdm+ binds to the HEWL active site using two dominant binding pathways populating multiple intermediates. We show that the residues close to the active site that can anchor the ligand could play a critical role in ligand binding. Using a Markov state model, we quantified the lifetimes and kinetic pathways connecting the different states in the FES. The protonation and deprotonation of the acidic residues in the active site in response to the pH change strongly influence the Gdm+ binding. There is a sharp jump in the ligand-binding rate constant when the pH approaches the largest pKa of the acidic residue present in the active site. The simulations reveal that, at most, three Gdm+ can bind at the active site, with the Gdm+ bound in the cavity of the active site acting as a scaffold for the other two Gdm+ ions binding. This result implies the possibility of designing single large molecules containing multiple Gdm+ moieties that can have high binding affinities to inhibit the function of enzymes with two acidic residues in their active site.

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Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer

Cited by 4 publications

References 29 publications

Uso De Reator De Micro-Ondas Para Guanilação De Tioureias

Uso De Reator De Micro-Ondas Para Guanilação De Tioureias

pH Regulates Ligand Binding to an Enzyme Active Site by Modulating Intermediate Populations

pH Effect on Ligand Binding to an Enzyme Active Site

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