Modulation of Cellular Apoptosis with Apoptotic Protease-Activating Factor 1 (Apaf-1) Inhibitors

Mondragón, Laura; Orzáez, Mar; Sanclimens, Glòria; Moure, Alejandra; Armiñán, Ana; Sepúlveda, Pilar; Messeguer, Àngel; Vicent, Marı́a J.; Pérez‐Payá, Enrique

doi:10.1021/jm701195j

Cited by 62 publications

(41 citation statements)

References 37 publications

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“…Peptoid 1 contains two dichlorophenylethylamino moieties that were found to be important for activity. 128,161 Noticeably, the activators of the Apaf-1 mediated apoptosome assembly, discussed above, reported by Nguyen and Wells 118 also contain a dichlorobenzylamino moiety. Likewise, a halophenyl moiety, in this case bearing a trifluoromethyl group, is also present in the diarylurea derivatives, identified by Lademann et al 158 as inhibitors of the formation of the apoptosome complex.…”

Section: Synthetic Inhibitors Of the Apaf-1-mediated Apoptosome Assemmentioning

confidence: 90%

“…Confirming this hypothesis, the conformationally restrained mimetic (2 in, 161 QM31 in, 75 now SVT016426; Table I) elicited improved anti-apoptotic activity in an other studied cellular models. 161 Furthermore, SVT016426 was shown to inhibit the release of cytochrome c from mitochondria and suppressed the Apaf-1-dependent intra-S-phase DNA damage checkpoint. 75 The molecular mechanism involved in the anti-apoptotic activity of SVT016326 is currently under study.…”

Section: Synthetic Inhibitors Of the Apaf-1-mediated Apoptosome Assemmentioning

confidence: 99%

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Molecules that modulate Apaf‐1 activity

Pérez‐Payá

Orzáez

Mondragón

et al. 2011

Medicinal Research Reviews

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Programmed cell death, apoptosis, is a highly regulated cellular pathway, responsible for the elimination of cells in the organism that are no longer needed or extensively damaged. Defects in the regulation of apoptosis could be at the molecular basis of different diseases, either when it is insufficient or excessive. The formation of the macromolecular complex, apoptosome, is a key event in this pathway, which has also been defined as the intrinsic apoptosis pathway. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated apoptotic protease-activating factor (Apaf-1), dATP, and procaspase-9. Recent studies have produced a wealth of information about the regulation and functions of Apaf-1, but additional studies aimed at elucidating its role as a signaling device at the crosstalk between different signaling pathways are needed to take advantage for the development of modulators of apoptosis pathways and possible therapeutic applications.

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Section: Synthetic Inhibitors Of the Apaf-1-mediated Apoptosome Assemmentioning

confidence: 90%

Section: Synthetic Inhibitors Of the Apaf-1-mediated Apoptosome Assemmentioning

confidence: 99%

Molecules that modulate Apaf‐1 activity

Pérez‐Payá

Orzáez

Mondragón

et al. 2011

Medicinal Research Reviews

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“…Other applications of polymer-drug nanoconjugates include rheumatoid arthritis (122), inflammation (123),regenerative medicine e.g. for wound healing (124), ischemia (125) and osteoporosis (126) etc.…”

Section: Polymer-drug Nanoconjugates Targeting Other Diseasesmentioning

confidence: 99%

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

Abioye

Chi-Tangyie²,

Kola-Mustapha³

et al. 2016

PNT

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Background: Over the last four decades, the use of water soluble polymers in rational formulation design has rapidly evolved into valuable drug delivery strategies to enhance the safety and therapeutic effectiveness of poorly soluble drugs, particularly anticancer drugs. Novel advances in polymer chemistry have provided new generations of well defined polymeric architectures for specific applications in polymer-drug conjugate design. However, total control of crucial parameters such as particle size, molecular weight distribution, polydispersity, localization of charges, hydrophilic-lipophilic balance and non site-specific coupling reactions during conjugation has been a serious challenge. Objective: This review briefly describes the current advances in polymer-drug nanoconjugate design and various challenges hindering their transformation into clinically useful medicines. Method: Existing literature was reviewed. Results: This review provides insights into the significant impact of covalent and non-covalent interactions between drug and polymer on drug loading (or conjugation) efficiency, conjugate stability, mechanism of drug release from the conjugate and biopharmaceutical properties of poorly soluble drugs. The utility values and application of Quality by Design principles in rational design, optimization and control of the Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) that underpin the safety, quality and efficacy of the nanoconjugates are also presented. Conclusion: It was apparent that better understanding of the physicochemical properties of the nanoconjugates as well as the drug-polymer interaction during conjugation process is essential to be able to control the biodistribution, pharmacokinetics, therapeutic activity and toxicity of the nanoconjugates which will in turn enhance the prospect of successful transformation of these promising nanoconjugates into clinically useful nanomedicines.

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“…In a process dependent on the hydrolysis of ATP or dATP to ADP or dADP respectively, the Apaf-1-cytochrome c heterodimers assemble into the apoptosome, which provides a platform for the activation of the initiator procaspase-9. Then, the activated caspase-9 cleaves and activates executioner caspases such as caspase-3 [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Within this project, we identified some active compounds after screening of a diversity-oriented chemical library of N-alkylglycine oligomers [4]. Then, geometrical restrictions were devised to increase the selectivity [2] by reducing the conformational freedom. A hit compound (1) was obtained [6], and structural studies of 1 showed the presence of cis/trans isomers of the tertiary amide bond exchanging at low rates ( Fig.…”

Section: Introductionmentioning

confidence: 99%