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1.
J Med Chem ; 67(3): 2019-2030, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38265364

RESUMO

As the primary enzyme responsible for the activatable conversion of Irinotecan (CPT-11) to SN-38, carboxylesterase 2 (CES2) is a significant predictive biomarker toward CPT-11-based treatments for pancreatic ductal adenocarcinoma (PDAC). High SN-38 levels from high CES2 activity lead to harmful effects, including life-threatening diarrhea. While alternate strategies have been explored, CES2 inhibition presents an effective strategy to directly alter the pharmacokinetics of CPT-11 conversion, ultimately controlling the amount of SN-38 produced. To address this, we conducted a high-throughput screening to discover 18 small-molecule CES2 inhibitors. The inhibitors are validated by dose-response and counter-screening and 16 of these inhibitors demonstrate selectivity for CES2. These 16 inhibitors inhibit CES2 in cells, indicating cell permeability, and they show inhibition of CPT-11 conversion with the purified enzyme. The top five inhibitors prohibited cell death mediated by CPT-11 when preincubated in PDAC cells. Three of these inhibitors displayed a tight-binding mechanism of action with a strong binding affinity.


Assuntos
Carboxilesterase , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Camptotecina/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Irinotecano/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Carboxilesterase/antagonistas & inibidores
2.
J Med Chem ; 65(13): 8855-8868, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35700557

RESUMO

Human carboxylesterase 2 (hCES2) converts anticancer prodrugs, such as irinotecan, into their active metabolites via phase I drug metabolism. Owing to interindividual variability, hCES2 serves as a predictive marker of patient response to hCES2-activated prodrug-based therapy, whereby a low intratumoral hCES2 activity leads to therapeutic resistance. Despite the ability to identify nonresponders, effective treatments for resistant patients are needed. Clinically approved photodynamic therapy is an attractive alternative for irinotecan-resistant patients. Here, we describe the application of our hCES2-selective small-molecule ratiometric fluorescent chemosensor, Benz-AP, as a single theranostic agent given its discovered functionality as a photosensitizer. Benz-AP produces singlet oxygen and induces photocytotoxicity in cancer cells in a strong negative correlation with hCES2 activity. Two-photon excitation of Benz-AP produces fluorescence, singlet oxygen, and photocytotoxicity in tumor spheroids. Overall, Benz-AP serves as a novel theranostic agent with selective photocytotoxicity in hCES2-prodrug resistant cancer cells, making Benz-AP a promising agent for in vivo applications.


Assuntos
Neoplasias , Fotoquimioterapia , Pró-Fármacos , Fluorescência , Humanos , Irinotecano/farmacologia , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Oxigênio Singlete
3.
ACS Med Chem Lett ; 12(8): 1295-1301, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34413959

RESUMO

Phenalenone is a synthetically accessible, highly efficient photosensitizer with a near-unity singlet oxygen quantum yield. Unfortunately, its UV absorption and lack of fluorescence has made it unsuitable for fluorescence-guided photodynamic therapy against cancer. In this work, we synthesized a series of phenalenone derivatives containing electron-donating groups to red-shift the absorption spectrum and bromine(s) to permit good singlet oxygen production via the heavy-atom effect. Of the derivatives synthesized, the phenalenone containing an amine at the 6-position with bromines at the 2- and 5-positions (OE19) exhibited the longest absorption wavelength (i.e., green) and produced both singlet oxygen and red fluorescence efficiently. OE19 induced photocytotoxicity with nanomolar potency in 2D cultured PANC-1 cancer cells as well as light-induced destruction of PANC-1 spheroids with minimal dark toxicity. Overall, OE19 opens up the possibility of employing phenalenone-based photosensitizers as theranostic agents for photodynamic cancer therapy.

4.
IUCrdata ; 6(Pt 6): x210654, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36337324

RESUMO

The title compound, C12H17I2O3P, was prepared in three steps from p-xylene. Heterodimers between nearly identical mol-ecules are connected via three hydrogen bonds from benzylic and ester methyl-ene groups to phospho-nate. The dimers form chains along the a-axis direction, stabilized by C-H⋯O bridges.

5.
Chemistry ; 26(12): 2713-2718, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31814180

RESUMO

Human NAD(P)H: Quinone Oxidoreductase 1 (hNQO1) is an attractive enzyme for cancer therapeutics due to its significant overexpression in tumors compared to healthy tissues. Its unique catalytic mechanism involving the two-electron reduction of quinone-based compounds has made it a useful target to exploit in the design of hNQO1 fluorescent chemosensors and hNQO1-activatable-prodrugs. In this work, hNQO1 is exploited for an optical therapeutic. The probe uses the photosensitizer, phenalenone, which is initially quenched via photo-induced electron transfer by the attached quinone. Native phenalenone is liberated in the presence of hNQO1 resulting in the production of cytotoxic singlet oxygen upon irradiation. hNQO1-mediated activation in A549 lung cancer cells containing high levels of hNQO1 induces a dose-dependent photo-cytotoxic response after irradiation. In contrast, no photo-cytotoxicity was observed in the normal lung cell line, MRC9. By targeting hNQO1, this scaffold can be used to enhance the cancer selectivity of photodynamic therapy.


Assuntos
Antineoplásicos/química , NAD(P)H Desidrogenase (Quinona)/química , NAD/metabolismo , Fenalenos/química , Fármacos Fotossensibilizantes/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , NAD(P)H Desidrogenase (Quinona)/farmacologia , Fenalenos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Quinonas/metabolismo , Oxigênio Singlete/química
6.
Chem Sci ; 10(36): 8428-8437, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31803422

RESUMO

Irinotecan-based therapy is a common treatment for pancreatic cancer. To elicit its anticancer activity, the drug requires first the hydrolysis action of the enzyme human carboxylesterase 2 (hCES2). It has been established that pancreatic cancer patients have various levels of hCES2, whereby patients having low levels respond poorer to Irinotecan than patients with higher levels, suggesting that hCES2 can be used to predict response. However, current methods that measure hCES2 activity are inaccurate, complex or lengthy, thus being incompatible for use in a clinical setting. Here, we developed a small molecule ratiometric fluorescent chemosensor that accurately measures hCES2 activity in a single-step within complex mixtures. Our chemosensor is highly selective for hCES2 over hCES1, cell permeable and can measure hCES2 activity in pancreatic cancer patient-derived xenografts. Given the simplicity, accuracy and tissue compatibility of our assay, we anticipate our chemosensor can be used to predict patient response to Irinotecan-based therapy.

7.
Biochemistry ; 51(32): 6421-31, 2012 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-22803618

RESUMO

Photoswitchable distance constraints in the form of photoisomerizable chemical cross-links offer a general approach to the design of reversibly photocontrolled proteins. To apply these effectively, however, one must have guidelines for the choice of cross-linker structure and cross-linker attachment sites. Here we investigate the effects of varying cross-linker structure on the photocontrol of folding of the Fyn SH3 domain, a well-studied model protein. We develop a theoretical framework based on an explicit-chain model of protein folding, modified to include detailed model linkers, that allows prediction of the effect of a given linker on the free energy of folding of a protein. Using this framework, we were able to quantitatively explain the experimental result that a longer, but somewhat flexible, cross-linker is less destabilizing to the folded state than a shorter more rigid cross-linker. The models also suggest how misfolded states may be generated by cross-linking, providing a rationale for altered dynamics seen in nuclear magnetic resonance analyses of these proteins. The theoretical framework is readily portable to any protein of known folded state structure and thus can be used to guide the design of photoswitchable proteins generally.


Assuntos
Proteínas Proto-Oncogênicas c-fyn/química , Alcinos/síntese química , Alcinos/química , Compostos Azo/síntese química , Compostos Azo/química , Reagentes de Ligações Cruzadas/química , Espectroscopia de Ressonância Magnética , Modelos Químicos , Modelos Moleculares , Fotólise , Conformação Proteica , Dobramento de Proteína , Ácidos Sulfanílicos/síntese química , Ácidos Sulfanílicos/química , Domínios de Homologia de src
8.
Angew Chem Int Ed Engl ; 48(8): 1484-6, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19148911

RESUMO

Longer switching wavelengths and good photochemical yields and stabilities of the cis isomers in reducing aqueous environments are achieved by introducing 2,2'-aminoalkyl substituents into 4,4'-diamido-substituted azobenzenes. The products are thus suitable for photocontrol of biomolecular structures in intracellular environments, such as switching between two peptide configurations (see picture).


Assuntos
Compostos Azo/química , Compostos Azo/síntese química , Compostos Azo/efeitos da radiação , Dicroísmo Circular , Peptídeos/química , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Estereoisomerismo
9.
Org Biomol Chem ; 6(23): 4323-32, 2008 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-19005591

RESUMO

Azobenzene derivatives can be used to reversibly photo-regulate conformation and activity when introduced as intramolecular bridges in peptides and proteins. Here we report the design, synthesis, and characterization of an azobenzene derivative that absorbs between 400-450 nm in aqueous solution to produce the cis isomer, and relaxes back to the trans isomer with a half-life of a few seconds at room temperature. In the trans form, the linker can span a distance of approximately 25 A, so that it can bridge Cys residues spaced i, i + 15 in an alpha-helix. Switching of the azobenzene cross-linker from trans to cis causes a decrease in the helix content of peptides where the linker is attached via Cys residues spaced at i, i + 15 and i, i + 14 positions, no change in helix content with Cys residues spaced i, i + 11 and an increase in helix content in a peptide with Cys residues spaced at i, i + 7. In the presence of 10 mM reduced glutathione, the azobenzene cross-linker continued to photo-switch after 24 hours. This cross-linker design thus expands the possibilities for fast photo-control of peptide and protein structure in biochemical systems.


Assuntos
Reagentes de Ligações Cruzadas/farmacologia , Peptídeos/química , Absorção , Sequência de Aminoácidos , Compostos Azo/química , Cor , Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/metabolismo , Desenho de Fármacos , Glutationa/metabolismo , Concentração de Íons de Hidrogênio , Isomerismo , Cinética , Dados de Sequência Molecular , Peptídeos/metabolismo , Fotoquímica , Conformação Proteica/efeitos dos fármacos , Solventes/química , Espectrofotometria Ultravioleta , Compostos de Sulfidrila/química , Temperatura , Fatores de Tempo
10.
Chembiochem ; 9(13): 2147-54, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18729291

RESUMO

Azobenzene-based photoswitchable compounds can be use to photocontrol a variety of biochemical systems. In some cases, their effectiveness may be limited by the size of the conformational change that the switch undergoes. To produce an azobenzene photoswitch that undergoes a large end-to-end distance change upon isomerization, we synthesized 3,3'-diazene-1,2-diylbis{6-[2-sulfonato-4-(chloroacetylamino)phenylethynyl]benzene sulfonic acid} (DDPBA). This long, rigid, water-soluble, thiol-reactive cross-linker undergoes an end-to-end distance change of approximately 13 A upon isomerization. DDPBA was successfully cross-linked to peptides through cysteine side chains. The photoswitch undergoes trans-to-cis photoisomerization maximally when irradiated at 400 nm, although the efficiency of production of the cis isomer is lower than for simpler azobenzenes. Under steady-state illumination conditions, the percentage of cis form produced increases as temperature increases; approximately 56 % cis is obtained at 60 degrees C. Thermal relaxation occurs with a half-life of approximately 75 min at room temperature. When DDPBA was attached to an alpha-helical peptide with two cysteine residues at i and i+14 positions, an increase in helix content was observed after photoirradiation. When cross-linked to another peptide with two cysteine residues spaced at i and i+21 positions, a decrease in helix content after trans-to-cis isomerization was observed. Due to the small percentage of cis form produced under the experimental conditions, the CD signal changes were small. However, the large structural change upon photoisomerization provided by this cross-linker can potentially be used to photoswitch other biochemical systems.


Assuntos
Compostos Azo/síntese química , Compostos Azo/farmacologia , Benzenossulfonatos/síntese química , Benzenossulfonatos/farmacologia , Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/farmacologia , Luz , Peptídeos/química , Sequência de Aminoácidos , Compostos Azo/química , Compostos Azo/metabolismo , Benzenossulfonatos/química , Benzenossulfonatos/metabolismo , Dicroísmo Circular , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/metabolismo , Desenho de Fármacos , Isomerismo , Dados de Sequência Molecular , Peptídeos/metabolismo , Fotoquímica , Conformação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Solventes/química , Espectrofotometria Ultravioleta
12.
Bioconjug Chem ; 17(3): 670-6, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16704204

RESUMO

Azobenzene derivatives can be used to reversibly photoregulate secondary structure when introduced as intramolecular bridges in peptides and proteins. Here we report the design, synthesis, and characterization of a disubstituted N,N-dialkyl azobenzene derivative that absorbs near 480 nm in aqueous solution and relaxes with a half-life of approximately 50 ms at room temperature. The wavelength of maximum absorbance and the rate of thermal relaxation are solvent-dependent. An increase in the percentage of organic solvent leads, in general, to a blue shift in the absorbance maximum and a slowing of the relaxation rate. In accordance with the design, the thermal relaxation of the azobenzene cross-linker from cis to trans causes an increase in the helix content of one peptide where the linker is attached via cysteine residues spaced at i, i + 11 positions and a decrease in helix content of another peptide with cysteine residues spaced at i, i + 7. This cross-linker design thus expands the possibilities for fast photocontrol of peptide and protein structure.


Assuntos
Reagentes de Ligações Cruzadas/química , Peptídeos/química , Cor , Reagentes de Ligações Cruzadas/síntese química , Concentração de Íons de Hidrogênio , Isomerismo , Cinética , Dados de Sequência Molecular , Fotoquímica , Estrutura Secundária de Proteína , Solventes , Análise Espectral , Fatores de Tempo
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