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1.
Org Lett ; 26(15): 3103-3108, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38588485

RESUMO

Here we present a novel strategy for the synthesis of enantiomerically enriched tetrahydronaphthalen-1-ols. The reaction proceeds via an alkylation (via hydrogen borrowing) and ammonium formate-mediated asymmetric transfer hydrogenation (via dynamic kinetic resolution), giving alkylated tetralols in high yields and good enantio- and diastereoselectivity across a diverse range of both alcohol and tetralone substrates. Additionally, these products were successfully derivatized to several complex molecules, demonstrating the utility of the tetrahydronaphthalen-1-ol.

2.
Magn Reson Chem ; 62(3): 198-207, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38258438

RESUMO

This study presents a straightforward solution to the challenge of elucidating the structures of nitrogen containing compounds undergoing isomerization. When spectral line broadening occurs related to isomerization, be it prototropic tautomerism or bond rotations, this poses a significant obstacle to structural elucidation. By adding acids, we demonstrate a simple approach to overcome this issue and effectively sharpen NMR signals for acid stable prototropic tautomers as well as the conformational isomers containing a morpholine or piperazine ring.

3.
Angew Chem Int Ed Engl ; 62(9): e202211794, 2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36524997

RESUMO

A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions. Our investigation includes preparations of novel, bench-stable Ni(COD)(L) complexes (COD=1,5-cyclooctadiene), in which L=quinone, cyclopentadienone, thiophene-S-oxide, and fulvene. Characterization by NMR, IR, single-crystal X-ray diffraction, cyclic voltammetry, thermogravimetric analysis, and natural bond orbital analysis sheds light on the structure, bonding, and properties of these complexes. Applications in an assortment of nickel-catalyzed reactions underscore the complementary nature of the different pre-catalysts within this toolkit.

4.
ACS Catal ; 12(2): 1150-1160, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36386561

RESUMO

A highly efficient and enantioselective asymmetric hydrogenation catalyzed by Ru-DTBM-segphos is reported for a broad range of pyridine-pyrroline tri-substituted alkenes. Kinetic, spectroscopic, and computational studies suggest that addition of H2 is rate-determining and that alkene insertion is the enantio-determining step. These studies also reveal an intriguing Ru-catalyzed H/D exchange process that is facilitated by the substrate at room temperature and low pressure where hydrogenation activity is suppressed. These studies lead to a mechanistic proposal that further defines the roles of hydrogen gas, Ru-H species, and protic solvents in this catalytic system.

5.
J Org Chem ; 87(4): 1934-1940, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-34232659

RESUMO

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.


Assuntos
Proteínas de Membrana , Indicadores e Reagentes , Proteínas de Membrana/química
6.
ACS Catal ; 12(10): 5961-5969, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-37727697

RESUMO

The mechanism of asymmetric hydrogenation of 2-pyridyl alkenes catalyzed by chiral Rh-phosphine complexes at ambient temperature is examined using kinetic, spectroscopic, and computational tools. The reaction proceeds with reversible substrate binding followed by rate-determining addition of hydrogen. Substrate binding occurs only through the pyridine nitrogen in contrast to other substrate classes exhibiting stronger substrate direction. The lack of influence of hydrogen pressure on the product enantiomeric excess suggests that a pre-equilibrium in substrate binding is maintained across the pressure range investigated. An off-cycle Rh-hydride species is implicated in the mild catalyst deactivation observed. In contrast to Ru-phosphine-catalyzed reactions of the same substrate class, the stereochemical outcome in this system correlates generally with the relative stability of the E and Z rotamers of the substrate.

7.
J Org Chem ; 86(15): 10380-10396, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34255510

RESUMO

As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.


Assuntos
Benchmarking , Preparações Farmacêuticas , Catálise , Paládio
8.
Org Lett ; 21(2): 529-534, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30620608

RESUMO

Six fungal metabolites, of which five were new, including one (1) with a dioxa[4.3.3]propellane ring system, were discovered, identified, and structurally elucidated from Neosetophoma sp. (strain MSX50044); these compounds are similar to the bis-tropolone, eupenifeldin. Three of the meroterpenoids are potent cytotoxic agents against breast, ovarian, mesothelioma, and lung cancer cells with nanomolar IC50 values while not inducing mitochondrial toxicity at 12.5 µM.


Assuntos
Antineoplásicos/farmacologia , Ascomicetos/metabolismo , Terpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ascomicetos/química , Humanos , Estrutura Molecular , Terpenos/química , Terpenos/isolamento & purificação
9.
J Org Chem ; 82(19): 10715-10721, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28809492

RESUMO

An addition of organozinc nucleophiles to N-acyl activated quinolines and isoquinolines is described. Simple transmetalation with the corresponding Grignard reagents using ZnCl2 forms organozinc compounds which are functional group tolerant and stable to reactive acyl chloride reagents for extended periods. A wide variety of substrates which include reactive electron-withdrawing groups are well tolerated to form 2-substituted dihydroquinolines and dihydroisoquinolines. This methodology has been applied toward an improved synthetic route of uncialamycin and its analogs.

10.
J Org Chem ; 82(8): 4044-4049, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28394130

RESUMO

The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CH3CN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids. Through investigation of the kinetics of this transformation, a mechanism was revealed involving a novel initiation pathway and a self-propagation cycle. The initiation pathway involves activation of hydroxamic acid by nitriles and subsequent Lossen rearrangement to generate the corresponding isocyanate. The isocyanate functions as a "pseudo-catalyst" for this system, leading to generation of product through a second Lossen rearrangement and regeneration of a new isocyanate molecule. Thorough mechanistic understanding allowed for this highly efficient process to be implemented on a 55 kg scale in 95.5% isolated yield.

11.
J Org Chem ; 82(9): 4958-4963, 2017 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-28406018

RESUMO

A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.


Assuntos
Fármacos Anti-HIV/síntese química , Triterpenos/química , Fármacos Anti-HIV/farmacologia , Catálise , Ciclização , Estrutura Molecular , Oxirredução , Análise Espectral/métodos , Estereoisomerismo , Triterpenos/síntese química , Triterpenos/farmacologia
12.
J Nat Prod ; 79(10): 2758-2761, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27684353

RESUMO

Three major degradation products resulted from the exposure of betulonaldehyde (1) to air in solution at room temperature. From HRMS and NMR data, the products, which were isolated by preparative supercritical fluid chromatography (SFC), were identified as betulonic acid (2) and C-17 hydroperoxide epimers 3 (ß-OOH) and 4 (α-OOH). For 3 and 4, the H-18 multiplet pattern of the isolated products established the configuration at C-17.


Assuntos
Ácido Oleanólico/análogos & derivados , Triterpenos/química , Acetona/química , Ar , Cromatografia Líquida de Alta Pressão , Cromatografia com Fluido Supercrítico , Peróxido de Hidrogênio/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Ácido Oleanólico/química , Estereoisomerismo
13.
J Antibiot (Tokyo) ; 65(11): 559-64, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22968289

RESUMO

Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogs, Sch 52900 (2), verticillin A (3), gliocladicillin C (4), Sch 52901 (5), 11'-deoxyverticillin A (6) and gliocladicillin A (7). The structures of compounds 1-7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds (1-7) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC(50) values ranging from 1.2 µM to 10 nM. Compounds 1-5 were examined for activity in the NF-κB assay, where compounds 2 and 3 revealed activity in the sub-micromolar range. Additionally, compounds 1, 3 and 4 were tested for EGFR inhibition using an enzymatic assay, while compound 3 was examined against an overexpressing EGFR(+ve) cancer cell line.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Dissulfetos/isolamento & purificação , Dissulfetos/farmacologia , Hypocreales/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Piperazinas/isolamento & purificação , Piperazinas/farmacologia , Compostos de Terfenil/isolamento & purificação , Compostos de Terfenil/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Dissulfetos/química , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Humanos , Alcaloides Indólicos/química , Indóis/química , Indóis/isolamento & purificação , Indóis/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Piperazinas/química , Compostos de Terfenil/química
14.
Anticancer Res ; 32(7): 2415-21, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22753698

RESUMO

AIM: (5Z)-7-Oxozeaenol was studied to reveal the path through which it exerts its effects on triple-negative MDA-MB-231 breast cancer cells. MATERIALS AND METHODS: The apoptotic effect of (5Z)-7-oxozeaenol on MDA-MB-231 cancer cells was analyzed by cell flow cytometry. The effects of (5Z)-7-oxozeaenol on the expression of the nuclear factor kappa B (NF-κB) p65, p50, IκB kinase (IKKα), IKKß and caspase-7 were analyzed by western blot. The expression of intracellular reactive oxygen species (ROS) and effects on cell adhesion were also assessed. Cell viability was determined using the 3[4,5-dimethylthiazol-2-yl-]2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: (5Z)-7-Oxozeaenol down-regulated NF-κB in a dose-dependent manner. Intracellular levels of ROS increased in a dose-dependent manner when treated with (5Z)-7-oxozeaenol and potentiated in the presence of H(2)O(2), when compared to paclitaxel which was used as positive control. Treatment with (5Z)-7-oxozeaenol resulted in G1-phase arrest of treated cells and inhibition of cell proliferation. Cell adhesion was notably affected in treated cells. (5Z)-7-Oxozeaenol also significantly enhanced apoptosis of treated cells, through the activation of caspase-7. CONCLUSION: Our findings suggest that (5Z)-7-oxozeaenol is a potent up-stream inhibitor of the NF-κB pathway, enhances the sensitivity of treated cells to apoptosis induced by ROS, and affects cell adhesion of MDA-MB-231 breast cancer cells. Thus, (5Z)-7-oxozeaenol is a potential new lead for breast cancer drug development since it might, in combination therapy, enhance the efficacy of current treatments and reduce resistance to chemotherapy of triple negative breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Zearalenona/análogos & derivados , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estrogênios não Esteroides/farmacologia , Feminino , Citometria de Fluxo , Humanos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Zearalenona/farmacologia
15.
Anticancer Res ; 32(7): 2665-71, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22753724

RESUMO

AIM: As part of an on going investigation of novel anticancer agents from natural origin, the biological and cellular effects of (5Z)-7-oxozeaenol on cancer cells were investigated. MATERIALS AND METHODS: The expression of nuclear factor kappa B (NF-κB), IκB kinase (IKKα), IKKß and caspase-3 were analyzed by western blot. Reactive oxygen species (ROS) fluorescence and caspase luminescent assays were used to assess the intracellular effects in HeLa cervical and HT-29 colon cancer cell lines. The mitochondrial transmembrane potential (MTP) was analyzed by fluorescence-activated cell sorting (FACS). RESULTS: Cells treated with (5Z)-7-oxozeaenol exhibited down-regulation of NF-κB in a dose-dependent manner. Treatment with (5Z)-7-oxozeaenol significantly enhanced the levels of ROS in HeLa and HT-29 cells. MTP was reduced in HT-29 cells. The expression of caspase-3 and -7 was induced in (5Z)-7-oxozeaenol treated HeLa cells, in comparison with those treated with paclitaxel. CONCLUSION: Our findings suggest that (5Z)-7-oxozeaenol is a potent inhibitor of the NF-κB pathway and potentiates the production of ROS, as well as induces caspase-3 and -7 in HeLa and HT-29 cancer cells. Thus, (5Z)-7-oxozeaenol represents a new lead compound for drug development, particularly as a new cancer chemotherapeutic agent, since programmed cell death might be mediated through the activation of a caspase-arbitrated pathway.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Zearalenona/análogos & derivados , Caspase 3/metabolismo , Caspase 7/metabolismo , Neoplasias do Colo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo/métodos , Células HT29 , Células HeLa , Humanos , Immunoblotting , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Zearalenona/farmacologia
16.
J Pept Sci ; 18(8): 500-10, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22744757

RESUMO

As part of an ongoing investigation of filamentous fungi for anticancer leads, an active culture was identified from the Mycosynthetix library (MSX 70741, of the order Hypocreales, Ascomycota). The fungal extract exhibited cytotoxic activity against the H460 (human nonsmall cell lung carcinoma) cell line, and bioactivity-directed fractionation yielded peptaibols 1-12 and harzianums A (13) and B (14). Structure elucidation of 1-12 was facilitated by high-resolution MS/MS using higher-energy collisional dissociation and by high field NMR (950 MHz). The absolute configuration was determined by Marfey's analysis of the individual amino acids; the time required for such analysis was decreased via the development of a 10-min ultra performance liquid chromatography method. The isolated peptaibols (1-12), along with three other peptaibols isolated and elucidated from a different fungus (MSX 57715) of the same order (15-17), were examined for activity in a suite of biological assays, including those for cytotoxic, antibacterial, and anthelmintic activities.


Assuntos
Anti-Helmínticos/farmacologia , Antibacterianos/farmacologia , Hypocreales/química , Peptaibols/química , Peptaibols/farmacologia , Animais , Anti-Helmínticos/química , Antibacterianos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Haemonchus/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular
17.
J Antibiot (Tokyo) ; 65(1): 3-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22068158

RESUMO

Two new xanthone-anthraquinone heterodimers, acremoxanthone C (5) and acremoxanthone D (2), have been isolated from an extract of an unidentified fungus of the order Hypocreales (MSX 17022) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Two known related compounds, acremonidin A (4) and acremonidin C (3) were also isolated, as was a known benzophenone, moniliphenone (1). The structures of these isolates were determined via extensive use of spectroscopic and spectrometric tools in conjunction with comparisons to the literature. All compounds (1-5) were evaluated against a suite of biological assays, including those for cytotoxicity, inhibition of the 20S proteasome, mitochondrial transmembrane potential and nuclear factor-κB.


Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antineoplásicos/isolamento & purificação , Hypocreales/química , Xantonas/isolamento & purificação , Xantonas/farmacologia , Antraquinonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ressonância Magnética Nuclear Biomolecular , Rotação Ocular , Complexo de Endopeptidases do Proteassoma/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Xantonas/química
18.
Tetrahedron Lett ; 52(40): 5128-5230, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-22025810

RESUMO

A fungal extract (MSX 63619), from the Mycosynthetix library of over 50,000 fungi, displayed promising cytotoxicity against a human tumor cell panel. Bioactivity-directed fractionation led to the isolation of an o-pyranonaphthoquinone decaketide, which we termed obionin B (1). The structure of 1 was deduced via spectroscopic and spectrometric techniques. The IC(50) value of 1 was moderate, ranging from 3 to 13 µM, depending on the cell line tested.

19.
J Nat Prod ; 74(5): 1126-31, 2011 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-21513293

RESUMO

As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 63935; related to Phoma sp.). The initial extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) and SF268 (human astrocytoma) cell lines and was selected for further study. Bioactivity-directed fractionation yielded resorcylic acid lactones (RALs) 1 (a new natural product) and 3 (a new compound) and the known RALs zeaenol (2), (5E)-7-oxozeaenol (4), (5Z)-7-oxozeaenol (5), and LL-Z1640-1 (6). Reduction of (5E)-7-oxozeaenol (4) with sodium borohydride produced 3, which allowed assignment of the absolute configuration of 3. Other known resorcylic acid lactones (7-12) were purchased and assayed in parallel for cytotoxicity with isolated 1-6 to investigate structure-activity relationships in the series. Moreover, the isolated compounds (1-6) were examined for activity in a suite of biological assays, including antibacterial, mitochondria transmembrane potential, and NF-κB. In the latter assay, compounds 1 and 5 displayed sub-micromolar activities that were on par with the positive control, and as such, these compounds may serve as a lead scaffold for future medicinal chemistry studies.


Assuntos
Lactonas/isolamento & purificação , Lactonas/farmacologia , NF-kappa B/antagonistas & inibidores , Zearalenona/análogos & derivados , Antibacterianos/farmacologia , Fungos/química , Humanos , Hidroxibenzoatos/química , Lactonas/química , Estrutura Molecular , Resorcinóis , Relação Estrutura-Atividade , Zearalenona/química , Zearalenona/farmacologia
20.
Tetrahedron Lett ; 52(44): 5733-5735, 2011 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-22566715

RESUMO

As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 55526; from the Order Sordariales). Bioactivity-directed fractionation yielded the known ergosterol peroxide (2) and 5α,8α-epidioxyergosta-6,9(11),22-trien-3ß-ol(3), and a new benzoate trimer, termed thielavin B methyl ester (1). The structure elucidation of 1 was facilitated by the use of HRMS coupled to an APPI (atmospheric pressure photoionization) source. Compound 1 proved to be moderately active against a panel of three cancer cell lines.

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